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Journal of Medical Toxicology logoLink to Journal of Medical Toxicology
. 2017 Aug 1;13(3):203–226. doi: 10.1007/s13181-017-0627-3

The Toxicology Investigators Consortium Case Registry—the 2016 Experience

Lynn A Farrugia 1,, Sean H Rhyee 2, Diane P Calello 3, Sharan L Campleman 4, Anne M Riederer 4, Hannah R Malashock 5, Anthony Pizon 6, Timothy Wiegand 7, Paul M Wax 4,8, Jeffrey Brent 9; On behalf of the Toxicology Investigators Consortium Study Group
PMCID: PMC5570732  PMID: 28766237

Abstract

The Toxicology Investigators Consortium (ToxIC) Case Registry was established by the American College of Medical Toxicology in 2010. The Registry contains data from participating sites with the agreement that all bedside medical toxicology consultations will be entered. Currently, 83% of accredited medical toxicology fellowship programs in the USA participate. The Registry continues to grow each year, and as of 31 December 2016, a new milestone was reached, with more than 50,000 cases reported since its inception. The objective of this seventh annual report is to summarize the Registry’s 2016 data and activity with its additional 8529 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2016. Detailed data was collected from these cases and aggregated to provide information which includes the following: demographics (age, gender, race, ethnicity, HIV status), reason for medical toxicology evaluation (intentional pharmaceutical exposure, envenomation, withdrawal from a substance), agent and agent class, clinical signs and symptoms (vital sign abnormalities, organ system dysfunction), treatments and antidotes administered, fatality and life support withdrawal data. Fifty percent of cases involved females, and adults aged 19–65 were the most commonly reported. There were 86 patients (1.0%) with HIV-positive status known. Non-opioid analgesics were the most commonly reported agent class, with acetaminophen the most common agent reported. There were 126 fatalities reported in 2016 (1.5% of cases). Major trends in demographics and exposure characteristics remained similar overall with past years’ reports. While treatment interventions were commonly required, fatalities were rare.

Electronic supplementary material

The online version of this article (doi:10.1007/s13181-017-0627-3) contains supplementary material, which is available to authorized users.

Keywords: Poisonings, Overdose, Epidemiology, Medical toxicology

Introduction

The Toxicology Investigators Consortium (ToxIC) was created by the American College of Medical Toxicology (ACMT) in 2010 as a tool for clinical toxicology research and toxicosurveillance [1]. Unlike other poisoning databases, ToxIC is a prospective case registry based on medical toxicologists’ experience performing consultations in both inpatient and ambulatory settings. Cases where a formal consultation was not done, such as where advice was given over the telephone, are not included in the database.

The ToxIC Registry is unique in several important ways. Because all information was entered by treating medical toxicologists, the toxicological data reflects the best professional judgment of skilled clinicians. Much of the information on the database is not available from other sources and includes not only medical data but also demographics including race and ethnicity and HIV status.

In 2016, there was a 2.0% decrease in sites included in the ToxIC Registry, with four sites added and five withdrawn or dropped from participation because they withdrew or failed to meet quality standards set by the Registry. Two of the international sites were not included in 2016 due to withdrawal or lack of case entry. At the end of 2016, there were 46 sites, comprising 79 facilities with active case entry. Currently, 83% of active accredited medical toxicology fellowship programs in the USA participate in the ToxIC Registry. The objective of this report is to summarize the Registry’s 2016 data and activity. Cases entered in 2016 are described in this seventh annual report.

Since its inception, several supplemental or subregistries have been created within ToxIC. These are designed to collect more detailed information in specific areas. Our subregistries studying caustic ingestions and prescription opioid abuse were closed at the end of 2016; data from these subregistries are now being analyzed. Subregistries on lipid resuscitation therapy, North American snake bites, and extracorporeal substance removal continued to collect data in 2016 and are continuing into 2017. Three additional subregistries were approved and developed in 2016 and became live on January 1, 2017; these include subregistries on plant, mushroom and herbal toxicity; pediatric opioid exposures; and pediatric marijuana exposures.

In 2016, 14 abstracts and five manuscripts using ToxIC Registry data were published and are listed on http://www.ToxICRegistry.org (Farrugia et al. [2]; Beauchamp et al. [3]; Judge et al. [4]; Riederer et al. [5]; Wang et al. [6]).

In 2016, ToxIC was supported by a continuation of a grant from the US National Institutes of Health on cardiovascular drug toxicity, a new contract with the US Food and Drug Administration, and the continuation of unrestricted grant support from BTG International, which was used to support the North American Snakebite Registry.

Methods

A detailed description of the creation and design of the ToxIC Registry has been previously reported by Wax et al. [1]. To be part of the consortium, all medical toxicologists at participating institutions agree to enter data into the ToxIC Registry on all medical toxicology consultations performed. Cases are entered on a password-protected encrypted online data collection form. The site is maintained by ACMT with oversight by the ToxIC Leadership Group. The Registry is compliant with the Health Insurance Portability and Accountability Act (HIPAA) and does not collect any protected health information or otherwise identifying fields. Registry participation is pursuant to the participating institution’s Institutional Review Board (IRB) approval and compliant with their policies and procedures. The Registry has also been independently reviewed by the Western IRB and determined not to meet the threshold of human subject research under federal regulation 45 CFR 46 and associated guidance.

Data collected on each case include presenting signs and symptoms, clinical course, treatments, limited patient demographics, outcome, laboratory values, and circumstances of and reasons for toxicological exposure. The term “consultation” is used in this report to describe any in-person encounter with a medical toxicologist in which a formal evaluation was conducted and placed in the medical record. Such encounters may include admission to a medical toxicology in-patient service, or evaluation by a medical toxicologist as a consulting physician in an emergency department, inpatient unit, or outpatient clinic. The online data collection form is formatted to ensure data entry remains organized and searchable. Free text entry fields allow providers to provide further detail or supplementary information. As part of the Registry’s toxicosurveillance mission, one component of the standard data form is a sentinel detection field that signals novel or unusual cases. Analysis of novel exposure surveillance data in the Registry has begun, with results to be published in a separate report.

For this report, a search of the database was performed to identify cases recorded from January 1, 2016, through December 31, 2016. Additional data from the subregistries will be published separately. This descriptive report summarizes case demographics, source and location of consultation, and reasons for encounter, and provides case frequencies by individual agent class and treatment provided.

In the tables describing individual agents or agent classes, unless otherwise indicated, values with fewer than five occurrences were not listed as separate items but are further grouped as “miscellaneous.” Percentages noted in tables for individual agents represent their relative proportion within their respective agent class.

For clinical signs or symptoms, the tables provide the percentage of individual signs or symptoms relative to the total number of Registry cases in 2016. Signs and symptoms include the presence or absence of a toxidrome, vital sign abnormalities, and a variety of organ system-based derangements which may arise from a toxic exposure. For each subheading in the data collection instrument, investigators are required to either select an abnormality, or “None,” to improve the accuracy of data collection. In the detailed treatment tables, percentages for each treatment modality represent the relative frequency among all treatments rendered.

Results

A total of 8529 cases were entered in the ToxIC Registry in 2016, up slightly from 8115 in 2015 (Fig. 1) [2]. Table 1 lists the individual sites entering cases in 2016.

Fig. 1.

Fig. 1

Case numbers

Table 1.

Participating institutions providing cases to ToxIC in 2016

Arizona
 Phoenix
  Banner- University Medical Center Phoenix
  Phoenix Children’s Hospital
California
 Fresno
  UCSF Fresno Medical Center
 Loma Linda
  Loma Linda University Medical Center
 Los Angeles
  University of Southern California Verdugo Hills
 San Diego
  Rady Children’s Hospital
 San Francisco
  San Francisco General Hospital
Colorado
 Denver
  Children’s Hospital Colorado
  Denver Health Medical Center
  Porter and Littleton Adventist Hospital
  Swedish Medical Center
  University of Colorado Medical Center
Connecticut
 Hartford
  Hartford Hospital
Georgia
 Atlanta
  Children’s Healthcare of Atlanta Egelston
  Children’s Healthcare of Atlanta Hughes Spalding
  Emory University Hospital
  Emory University Hospital Midtown
  Grady Health System
  Grady Memorial Hospital
Illinois
 Chicago
  Cook County Hospital
 Evanston
  Evanston North Shore University Health System
Indiana
 Indianapolis
  IU-Eskenazi Hospital
  IU-Indiana University Hospital
  IU-Methodist Hospital-Indianapolis
  IU-Riley Hospital for Children
  IU Wishard Memorial Hospital
Massachusetts
 Boston
  Beth Israel Boston
  Children’s Hospital Boston
 Worcester
  University of Massachusetts Memorial Medical Center
Michigan
 Grand Rapids
  Spectrum Health Hospitals
Minnesota
 St. Paul
  Regions Hospital
Missouri
 Kansas City
  Children’s Mercy Hospitals & Clinics
 St. Louis
  Washington University School of Medicine
Nebraska
 Omaha
  University of Nebraska Medical Center
New Mexico
 Albuquerque
  University of New Mexico
New Jersey
 Morristown
  Morristown Medical Center
 New Brunswick
  Robert Wood Johnson University Hospital
 Newark
  NJMS/Rutgers
New York
 Albany
  Albany Medical Center
 Manhasset
  Long Island Jewish
  North Shore University Hospital
 New York
  Bellevue Medical Center
  Mount Sinai Hospital
  NYU Langone Medical Center
 Staten Island
  Staten Island University Hospital
 Rochester
  Highland Hospital
  Strong Memorial Hospital
 Syracuse
  Upstate Medical University-Downtown Campus
North Carolina
 Charlotte
  Carolinas Medical Center
 Greenville
  Vidant Medical Center
Oregon
 Portland
  Doernbecher Children’s Hospital
  Oregon Health & Science University Hospital
Pennsylvania
 Harrisburg
  PinnacleHealth-Community General Osteopathic
  PinnacleHealth-Harrisburg Hospital
  PinnacleHealth-West Shore
 Lehigh Valley
  Lehigh Valley Hospital Cedar Crest
  Lehigh Valley Hospital Muhlenberg
 Philadelphia
  Hahnemann University Hospital
  Mercy Fitzgerald Hospital
  Mercy Hospital of Philadelphia
  St. Christopher’s Hospital for Children
 Pittsburgh
  UPMC Children’s Hospital of Pittsburgh
  UPMC Magee Women’s Hospital
  UPMC Mercy Hospital
  UPMC Presbyterian/Shadyside
Texas
 Dallas
  Children’s Medical Center Dallas
  Parkland Memorial Hospital
  University of Texas Southwestern Clinic
  William P Clements University Hospital
 Houston
  Ben Taub General Hospital
  Texas Children’s Hospital
 San Antonio
  San Antonio Military Medical Center
Utah
 Salt Lake City
  Primary Children’s Hospital
  University of Utah Hospital
Virginia
 Charlottesville
  University of Virginia Health Systems
 Richmond
  Virginia Commonwealth University Medical Center
Wisconsin
 Milwaukee
  Froedtert Memorial Lutheran Hospital
Israel
 Haifa
  Rambam Health Care Campus

Demographics

Selected demographics are summarized in Tables 2, 3, 4, 5, 6, 7, and 8. In 2016, male (50.0%) and female (50.0%) cases were distributed evenly and 0.6% were pregnant. Adults age 19–65 years comprised the majority (67.0%) of cases, with children age 13–18 years the next most common (16.8%). There were a total of 2280 (26.7%) pediatric cases (0–18 years) overall. The most commonly reported race categories were Caucasian (58.1%) and black/African (14.1%), with 18.0% unknown/uncertain. Nine hundred fifty-one cases (11.2%) reported Hispanic ethnicity, while 19.1% reported ethnicity as unknown. Race and ethnicity are not self-reported in the Registry, and limitations in these data points continue to be addressed with ongoing quality improvement measures.

Table 2.

ToxIC 2016 case demographics—age and gender

N (%)
Gender
 Male 4267 (50.0)
 Female 4262 (50.0)
Pregnant 47 (0.6)
Age (years)
 <2 270 (3.2)
 2–6 358 (4.2)
 7–12 215 (2.5)
 13–18 1437 (16.8)
 19–65 5714 (67.0)
 66–89 477 (5.6)
 >89 21 (0.2)
 Unknown 29 (0.4)
Total 8529 (100)

Table 3.

ToxIC 2016 case demographics—race and Hispanic ethnicity

N (%)
Race
 Caucasian 4953 (58.1)
 Unknown/uncertain 1537 (18.0)
 Black/African 1201 (14.1)
 Other 466 (5.5)
 Asian 169 (2.0)
 American Indian/Alaska Native 76 (0.9)
 Mixed 108 (1.3)
 Native Hawaiian or Pacific Islander 18 (0.2)
 Australian aboriginal 1 (0.0)
 Total 8529 (100)
Hispanic ethnicitya
 Hispanic 951 (11.2)
 Non-Hispanic 5949 (69.8)
 Unknown 1629 (19.1)
 Total 8529 (100)

aHispanic ethnicity as indicated exclusive of race

Table 4.

ToxIC 2016 case demographics—HIV-positive patients

N (%)
Reason for encounter
 Intentional pharmaceutical 42 (49.0)
  Attempt at self-harm 27 (31.4)
  Misuse/abuse 8 (9.3)
  Therapeutic use 3 (3.5)
  Unknown 4 (4.7)
 Intentional non-pharmaceutical 24 (28.0)
  Attempt at self-harm 1 (1.1)
  Misuse/abuse 19 (22.1)
  Unknown 3 (3.5)
  Use for therapeutic intent 1 (1.1)
 Unintentional pharmaceutical 1 (1.1)
 Unintentional non-pharmaceutical 4 (5.0)
Race
 American Indian/Alaskan Native 1 (1.1)
 Black/African 29 (33.7)
 Caucasian 36 (42.0)
 Other 9 (10.5)
 Unknown/uncertain 11 (12.8)
Ethnicity
 Hispanic 10 (11.6)
 Not Hispanic 62 (72.1)
 Unknown 14 (16.3)
Total HIV-positive patients 86 (100)

Table 5.

ToxIC 2016 case referral sources by inpatient/outpatient status

N (%)
Emergency department (ED) or inpatient (IP)a
 ED 4772 (59.8)
 Admitting service 2085 (26.1)
 Outside hospital transfer 729 (9.1)
 Request from another hospital service (not ED) 362 (4.5)
 Poison Center 27 (0.3)
 Primary care provider or other outpatient treating physician 5 (0.1)
 Self-referral 5 (0.1)
 ED/IP total 7985 (100)
Outpatient (OP)/clinic/office consultationb
 Primary care provider or other OP physician 231 (42.5)
 Self-referral 211 (38.8)
 Poison Center 42 (7.7)
 Employer/independent medical eval 39 (7.2)
 ED 15 (2.8)
 Admitting service 3 (0.6)
 Request from another hospital service (not ED) 3 (0.6)
 OP total 544 (100)

aPercentage based on the total number of cases (N = 7985) seen by a medical toxicologist as consultant (ED or IP) or as attending (IP)

bPercentage based on the total number of cases (N = 544) seen by a medical toxicologist as outpatient, clinic visit, or office consultation

Table 6.

ToxIC 2016 cases—primary reason for medical toxicology encounter

N (%)
Intentional exposure—pharmaceutical 4591 (53.8)
Intentional exposure—non-pharmaceutical 1038 (12.2)
Unintentional exposure—pharmaceutical 659 (7.7)
Organ system dysfunction 309 (3.6)
Unintentional exposure—non-pharmaceutical 296 (3.5)
Envenomation—snake 285 (3.3)
Unknown 275 (3.2)
Withdrawal—opioid 264 (3.1)
Interpretation of toxicology data 177 (2.1)
Environmental evaluation 149 (1.7)
Withdrawal—ethanol 140 (1.6)
Occupational evaluation 121 (1.4)
Ethanol abuse 90 (1.1)
Envenomation—spider 43 (0.5)
Withdrawal—sedative/hypnotic 27 (0.3)
Malicious/criminal 22 (0.3)
Withdrawal—other 13 (0.2)
Envenomation—other 10 (0.1)
Envenomation—scorpion 7 (0.1)
Marine/fish poisoning 7 (0.1)
Withdrawal—cocaine/amphetamine 6 (0.1)
Total 8529 (100)

Table 7.

ToxIC 2016 cases—detailed reason for encounter, intentional pharmaceutical exposures

N (%)
Reason for intentional pharmaceutical exposure subgroupa
 Attempt at self-harm 3099 (67.5)
 Misuse/abuse 915 (19.9)
 Therapeutic use 376 (8.2)
 Unknown 202 (4.4)
 Total 4592 (100)
Attempt at self-harm—suicidal intent subclassificationb
 Suicidal intent 2700 (87.1)
 No suicidal intent 115 (3.7)
 Suicidal intent unknown 284 (9.2)
 Total 3099 (100)

aPercentage of total number of cases (N = 4592) indicating primary reason for encounter due to intentional pharmaceutical exposure

bPercentage of number of cases (N = 3099) indicating attempt at self-harm

Table 8.

ToxIC 2016 case demographics—race/gender/ethnicity and exposure type

Intentional pharmaceutical, N (%) Intentional non-pharmaceutical, N (%) Unintentional pharmaceutical, N (%) Unintentional non-pharmaceutical, N (%)
Race
 American Indian/Alaskan Native 44 (57.9) 11 (14.5) 2 (2.6) 3 (4.0)
 Asian 82 (48.5) 24 (14.2) 13 (7.7) 6 (3.6)
 Black/African 598 (49.8) 186 (15.5) 112 (9.3) 67 (5.6)
 Caucasian 2765 (55.8) 576 (11.6) 358 (7.2) 130 (2.6)
 Mixed 53 (49.1) 14 (13.0) 9 (8.3) 7 (6.5)
 Native Hawaiian or Pacific Islander 13 (72.2) 1 (5.6) 1 (5.6) 1 (5.6)
 Other 224 (48.1) 65 (14.0) 39 (8.8) 29 (6.2)
 Unknown/uncertain 812 (52.8) 161 (10.5) 125 (8.1) 53 (3.5)
Ethnicity
 Hispanic 485 (51.0) 119 (12.5) 71 (7.5) 60 (6.3)
 Not Hispanic 3277 (55.1) 733 (12.3) 450 (7.6) 190 (3.2)
 Unknown 829 (50.9) 186 (11.4) 138 (8.5) 46 (2.8)
Gender
 Female 2714 (63.7) 289 (6.8) 323 (7.6) 117 (2.8)
 Male 1877 (44.0) 749 (17.6) 336 (7.9) 179 (4.2)

Table 4 presents demographic data on the 86 HIV-positive patients (1.0%) reported in the Registry. Table 5 details the referral source of medical toxicology evaluations. Table 6 provides information on the type of exposure which prompted a medical toxicology encounter. More detailed information on the intent surrounding the intentional pharmaceutical exposures is provided in Table 7. Table 8 depicts the frequency of common types of exposures as broken down by race, ethnicity, and gender. In all races, and for both Hispanics, non-Hispanics, and both genders, intentional pharmaceutical exposures were more common than intentional non-pharmaceutical exposures.

Agent Classes

There were 11,352 individual agent entries in 2016 for 8529 reported cases with 2519 (29.5%) cases involving multiple agents. The top agent classes were the same as 2015 [2], with non-opioid analgesics the most common (12.8%), followed by sedative-hypnotics/muscle relaxants (11.8%), antidepressants (11.1%), and opioids (9.8%) (Table 9).

Table 9.

ToxIC 2016—agent classes

N (%)a
Analgesic 1453 (12.8)
Sedative-hypnotic/muscle relaxant 1339 (11.8)
Antidepressant 1256 (11.1)
Opioid 1118 (9.8)
Sympathomimetic 728 (6.4)
Anticholinergic/antihistamine 704 (6.2)
Ethanol 694 (6.1)
Cardiovascular 654 (5.8)
Antipsychotic 642 (5.7)
Anticonvulsant 370 (3.3)
Envenomation and marine 317 (2.8)
Psychoactive 296 (2.6)
Lithium 176 (1.6)
Diabetic medication 161 (1.4)
Cough and cold products 145 (1.3)
Metals 145 (1.3)
Herbal products/dietary supplements 144 (1.3)
Gases/irritants/vapors/dusts 125 (1.1)
Toxic alcohol 123 (1.1)
Hydrocarbon 94 (0.8)
Caustic 85 (0.7)
Household products 83 (0.7)
Plants and fungi 80 (0.7)
Antimicrobial 73 (0.6)
Other pharmaceutical product 62 (0.5)
Other non-pharmaceutical product 50 (0.4)
Anticoagulant 42 (0.4)
Chemotherapeutic/immunological 42 (0.4)
Insecticide 38 (0.3)
Endocrine 29 (0.3)
Gastrointestinal agents 20 (0.2)
Rodenticide 17 (0.1)
Anesthetic 12 (0.1)
Anti-parkinsonism drugs 9 (0.1)
Amphetamine-like hallucinogen 6 (0.1)
Pulmonary 6 (0.1)
Herbicide 5 (0.0)
WMD/riot agent/radiological 4 (0.0)
Ingested foreign body 3 (0.0)
Fungicide 2 (0.0)
Total 11,352 (100)

aPercentages are out of total number of reported agent entries per year; 2519 cases (29.5%) reported multiple agents

Individual Agents by Class

Tables 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26 show frequencies of individual agent entries by class, presented in order of most to least common class. Three agents—ethanol, lithium, and amphetamine-like hallucinogens—are their own classes but are reported with other agent classes (toxic alcohols, anticonvulsants and mood stabilizers, and psychoactives, respectively) for brevity. Tables S1S18 in the Supplementary Material present frequencies for agent classes with little diversity, few overall cases, or when infrequently reported miscellaneous agents made up a significant portion of entries.

Table 10.

ToxIC 2016 agent entries—analgesics

N (%)
Acetaminophen 987 (67.9)
Aspirin 197 (13.6)
Ibuprofen 164 (11.3)
Naproxen 39 (2.7)
Salicylic acid 26 (1.8)
Acetylsalicylic acid 15 (1.0)
Diclofenac 4 (0.3)
Miscellaneousa 22 (1.5)
Class total 1453 (100)

aIncludes aminophenazone, unspecified analgesic, carprofen, indomethacin, ketorolac, meloxicam, metamizole (dipyrone), methylsalicylate, unspecified NSAID, phenazopyridine, salicylamide, and salsalate

Table 11.

ToxIC 2016 agent entries—sedative-hypnotics/muscle relaxants

N (%)
Benzodiazepines 704 (52.6)
 Alprazolam  276 (20.6)
 Clonazepam  207 (15.5)
 Lorazepam  99 (7.4)
 Diazepam  55 (4.1)
 Benzodiazepine unspecified  36 (2.7)
 Temazepam  18 (1.3)
 Miscellaneousa  13 (1.0)
Muscle relaxants 260 (19.4)
 Cyclobenzaprine  92 (6.9)
 Baclofen  89 (6.6)
 Carisoprodol  37 (2.8)
 Tizanidine  20 (1.5)
 Methocarbamol  12 (0.9)
 Metaxalone  7 (0.5)
 Miscellaneousb  3 (0.2)
Other sedatives 230 (17.2)
 Gabapentin  157 (11.7)
 Buspirone  29 (2.2)
 Pregabalin  18 (1.3)
 Phenibut  8 (0.6)
 Etizolam  7 (0.5)
 Sedative-hypnotic/muscle relaxant unspecified  7 (0.5)
 Miscellaneousc  4 (0.3)
Non-benzodiazepine agonists (“Z” drugs) 93 (6.9)
 Zolpidem  83 (6.2)
 Eszopiclone  8 (0.6)
 Miscellaneousd  2 (0.1)
Barbiturates 52 (3.9)
 Butalbital  24 (1.8)
 Phenobarbital  20 (1.5)
 Miscellaneouse  8 (0.6)
Class total 1339 (100)

aIncludes chlordiazepoxide, clorazepate, midazolam, triazolam, flubromazepam, and oxazepam

bIncludes orphenadrine and atracurium

cIncludes propofol and chlomethiazole

dIncludes eszopiclone and zaleplon

eIncludes butabarbital, barbiturate unspecified, and pentobarbital

Table 12.

ToxIC 2016 agent entries—antidepressants

N (%)
Other antidepressants 487 (38.8)
 Bupropion  260 (20.7)
 Trazodone  153 (12.2)
 Mirtazapine  57 (4.5)
 Vilazodone  5 (0.4)
 Miscellaneousa  12 (1.0)
Selective serotonin reuptake inhibitors (SSRIs) 431 (34.3)
 Sertraline  144 (11.5)
 Fluoxetine  100 (8.0)
 Citalopram  96 (7.6)
 Escitalopram  73 (5.8)
 Paroxetine  18 (1.4)
Tricyclic antidepressants (TCAs) 190 (15.1)
 Amitriptyline  125 (10.0)
 Doxepin  42 (3.3)
 Nortriptyline  18 (1.4)
 Miscellaneousb  5 (0.4)
Serotonin-norepinephrine reuptake inhibitors (SNRIs) 148 (11.8)
 Venlafaxine  90 (7.2)
 Duloxetine  49 (3.9)
 Desvenlafaxine  5 (0.4)
 Miscellaneousc  4 (0.3)
Class total 1256 (100)

aIncludes antidepressant unspecified, phenelzine, vortioxetine, levomilnacipran, tranylcypromine, and nefazodone

bIncludes clomipramine, imipramine, and desipramine

cIncludes fluvoxamine

Table 13.

ToxIC 2016 agent entries—opioids

N (%)
Heroin 316 (28.3)
Oxycodone 199 (17.8)
Methadone 99 (8.9)
Opioid unspecified 90 (8.1)
Tramadol 87 (7.8)
Hydrocodone 86 (7.7)
Morphine 57 (5.1)
Buprenorphine 47 (4.2)
Fentanyl 46 (4.1)
Codeine 36 (3.2)
Hydromorphone 19 (1.7)
Loperamide 9 (0.8)
Oxymorphone 7 (0.6)
Naltrexone 5 (0.4)
Miscellaneousa 15 (1.3)
Class total 1118 (100)

aIncludes 3-methylfentanyl, desomorphine, naloxone, pentazocine, propoxyphene, remifentanil, tapentadol, and U47700 (designer opioid)

Table 14.

ToxIC 2016 agent entries—sympathomimetics

N (%)
Cocaine 250 (34.3)
Methamphetamine 187 (25.7)
Amphetamine 90 (12.4)
Methylphenidate 48 (6.6)
Dextroamphetamine 32 (4.4)
Methylenedioxy-N-methamphetamine 31 (4.3)
Lisdexamfetamine 24 (3.3)
Phenylephrine 10 (1.4)
Pseudoephedrine 9 (1.2)
Phentermine 8 (1.1)
Cathinone 6 (0.8)
Phentermine 7 (1.2)
Sympathomimetic unspecified 5 (0.7)
Miscellaneousa 28 (3.8)
Class total 728 (100)

aIncludes 25I-NBOMe, atomoxetine, clenbuterol, dexmethylphenidate, ephedrine, 2C series drugs, epinephrine, 2,5-dimethoxy-4-bromophenethylamine, 4-fluoroamphetamine, 6-(2-Aminopropyl)benzofuran, butylone, N-ethylhexedrone, norepinephrine, phenylethylamine designer drug unspecified, prolintane, and tetrahydrozoline

Table 15.

ToxIC 2016 agent entries—anticholinergics and antihistamines

N (%)
Diphenhydramine 416 (59.1)
Hydroxyzine 105 (14.9)
Chlorpheniramine 34 (4.8)
Doxylamine 32 (4.5)
Benztropine 29 (4.1)
Promethazine 16 (2.3)
Loratadine 15 (2.1)
Cetirizine 9 (1.3)
Dicyclomine 6 (0.9)
Antihistamine unspecified 5 (0.7)
Cyproheptadine 5 (0.7)
Miscellaneousa 32 (4.5)
Class total 704 (100)

aIncludes anticholinergic unspecified, atropine, belladonna, brompheniramine, cyclopentolate, dimenhydrinate, fexofenadine, glycopyrrolate, hyoscyamine, meclizine, oxybutynin, pyrilamine, scopolamine, trihexyphenidyl, and triprolidine

Table 16.

ToxIC 2016 agent entries— ethanol and toxic alcohols

N (%)
Ethanola 694 (100)
Non-ethanol alcohols and glycols
 Ethylene glycol 56 (45.5)
 Isopropanol 40 (32.5)
 Methanol 17 (13.8)
 Propylene glycol 4 (3.3)
 Miscellaneousb 6 (4.9)
Class total 123 (100)

aEthanol is considered a separate agent class

bIncludes acetone, denatured alcohol non-ethanol, diethylene glycol, glycol ethers, and toxic alcohol unspecified

Table 17.

ToxIC 2016 agent entries—cardiovascular

N (%)
Beta blockers 181 (27.7)
 Metoprolol  70 (10.7)
 Propranolol  56 (8.6)
 Atenolol  24 (3.7)
 Carvedilol  16 (2.4)
 Labetalol  7 (1.1)
 Miscellaneousa  8 (1.2)
Sympatholytics 169 (25.8)
 Clonidine  141 (21.6)
 Guanfacine  28 (4.3)
Calcium channel antagonists 113 (17.3)
 Amlodipine  63 (9.6)
 Diltiazem  23 (3.5)
 Verapamil  18 (2.8)
 Nifedipine  8 (1.2)
 Miscellaneousb  <5 (<0.8)
Angiotensin-converting enzyme (ACE) inhibitors 52 (8.0)
 Lisinopril  47 (7.2)
 Miscellaneousc  5 (0.8)
Cardiac glycosides 46 (7.0)
 Digoxin  44 (6.7)
 Digitoxin  2 (0.3)
Other antihypertensives and vasodilators 32 (4.9)
 Prazosin  16 (2.4)
 Miscellaneousd  16 (2.4)
Antidysrhythmics and other cardiovascular agents 27 (4.1)
 Atorvastatin  8 (1.2)
 Simvastatin  6 (1.0)
 Miscellaneouse  13 (2.0)
Diuretics 25 (3.8)
 Hydrochlorothiazide  16 2.4)
 Furosemide  5 (0.8)
 Miscellaneousf  4 (0.6)
Angiotensin receptor blockers 9 (1.4)
 Losartan  5 (0.8)
 Miscellaneousg  4 (0.6)
Class total 654 (100)

aIncludes nebivolol, bisoprolol, nadolol, and timolol

bIncludes nicardipine

cIncludes benazepril, enalapril, and quinapril

dIncludes hydralazine, nitroprusside, isosorbide, nitroglycerin, terazosin, alkyl nitrite, doxazosin, and minoxidil

eIncludes flecainide, sotalol, amiodarone, midodrine, cardiovascular agent unspecified, quinidine, pravastatin

fIncludes chlorthalidone, acetazolamide, spironolactone

gIncludes valsartan, irbesartan, olmesartan

Table 18.

ToxIC 2016 agent entries—antipsychotics

N (%)
Quetiapine 307 (47.8)
Olanzapine 87 (13.6)
Aripiprazole 52 (8.1)
Risperidone 41 (6.4)
Haloperidol 39 (6.1)
Clozapine 26 (4.0)
Lurasidone 20 (3.1)
Ziprasidone 17 (2.6)
Chlorpromazine 15 (2.3)
Paliperidone 9 (1.4)
Perphenazine 7 (1.1)
Fluphenazine 6 (0.9)
Miscellaneousa 16 (2.5)
Class total 642 (100)

aIncludes antipsychotic unspecified, asenapine, brexpiprazole, loxapine, penfluridol, prochlorperazine, thiothixene, and trifluoperazine

Table 19.

ToxIC 2016 agent entries—anticonvulsants and mood stabilizers, and lithium

N (%)
Lithiuma 176 (100)
Lamotrigine 100 (27.0)
Valproic acid 98 (26.5)
Phenytoin 56 (15.1)
Carbamazepine 42 (11.4)
Topiramate 29 (7.8)
Oxcarbazepine 20 (5.4)
Levetiracetam 9 (2.4)
Miscellaneousb 16 (4.3)
Class total 370 (100)

aLithium is considered a separate agent class

bIncludes anticonvulsant unspecified, divalproex, fosphenytoin, lacosamide, and zonisamide

Table 20.

ToxIC 2016 agent entries—envenomations and marine poisonings

N (%)
Crotalus spp. 106 (34.1)
Agkistrodon spp. 96 (30.9)
Snake unspecified 64 (20.6)
Loxosceles spp. 13 (4.2)
Latrodectus spp. 10 (3.2)
Centuroides spp. 5 (1.6)
Hymenoptera 5 (1.6)
Spider unspecified 5 (1.6)
Miscellaneousa 7 (2.3)
Class total 311 (100)

aIncludes Naja nigricinta, Vipera palaestinae, Micrurus spp., scorpion unspecified, and stingray

Table 21.

ToxIC 2016 agent entries—psychoactives

N (%)
Cannabinoid synthetic 95 (31.5)
Marijuana 88 (29.1)
LSD 22 (7.3)
Phencyclidine 20 (6.6)
Gamma hydroxybutyrate 16 (5.3)
Cannabinoid non-synthetica 12 (4.0)
Ketamine 11 (3.6)
Nicotine 9 (3.0)
Molly-amphetamine-like hallucinogenb 6 (2.0)
Miscellaneousc 23 (7.6)
Class total 302 (100)

aThe cannabinoid nonsynthetic group refers to exposures to unspecified naturally occurring cannabinoids, such as cannabis extracts or cannabidiol

bAmphetamine-like hallucinogens are presented with psychoactives for brevity, though listed as an individual Registry class

cIncludes 1-propionyl-lysergic acid diethylamide (1P-LSD), 3-methoxyphencyclidine, dimethyltryptamine (DMT), donepezil, gamma butyrolactone, hallucinogen unspecified, hallucinogenic amphetamines, methylenedioxymethamphetamine, methylone, pharmaceutical tetrahydrocannabinol (THC), psychoactive unspecified, and varencicline

Table 22.

ToxIC 2016 agent entries—diabetic medications

N (%)
Metformin 66 (41.0)
Insulin 40 (24.8)
Glipizide 26 (16.1)
Glyburide 14 (8.7)
Glimepiride 8 (5.0)
Miscellaneousa 7 (4.3)
Class total 161 (100)

aIncludes empagliflozin, exenatide, gliclazide, and saxagliptin

Table 23.

ToxIC 2016 agent entries—metals

N (%)
Lead 44 (30.3)
Iron 30 (20.7)
Mercury 20 (13.8)
Chromium 11 (7.6)
Cobalt 7 (4.8)
Arsenic 5 (3.4)
Copper 5 (3.4)
Miscellaneousa 23 (15.9)
Class total 145 (100)

aIncludes manganese, metal unspecified, cadmium, silver, titanium, antimony, barium, magnesium, nickel, selenium, thorium, uranium, and zinc sulfate

Table 24.

ToxIC 2016 agent entries—gases, irritants, vapors, and dusts

N (%)
Carbon monoxide 54 (43.2)
Hydrogen sulfide 14 (11.2)
Cyanide 11 (8.8)
Smoke 10 (8.0)
Chlorine 5 (4.0)
Gas/irritant/vapor/dust unspecified 5 (4.0)
Miscellaneousa 26 (20.8)
Class total 125 (100)

aIncludes petroleum vapors, silica, chloramine, diesel exhaust, dust, ethylene oxide, sewer gas, acetonitrile, duster (canned air), ethylene, natural gas, nitric oxide, ozone, plastic fumes, polyurethane vapors, welding fumes, and vaping NOS

Table 25.

ToxIC 2016 agent entries—household products

N (%)
Sodium hypochlorite ≤6% 26 (31.3)
Cleaning solutions and disinfectants 17 (20.5)
Laundry detergent pod 11 (13.3)
Ammonia ≤10% 6 (7.2)
Paint 5 (6.0)
Miscellaneousa 18 (21.7)
Class total 83 (100)

aIncludes deodorants and antiperspirants, dishwasher detergent, dishwasher detergent pod, flower food, hair product, hand sanitizer unspecified, household product unspecified, mouthwash unspecified, perfume, phenylenediamine (hair dye), soaps and detergents, sunscreens, and windshield washer fluid

Table 26.

ToxIC 2016 agent entries—plants and fungi

N (%)
Mold unspecified 33 (41.3)
Mushroom, other/unknown 9 (11.3)
Mitragyna speciosa (kratom) 6 (7.5)
Mushroom, psilocibin 4 (5.0)
Valerian root 4 (5.0)
Miscellaneousa 24 (30.0)
Class total 80 (100)

aIncludes aconitum, Agastache scrophulariifolia (purple giant hyssop), Amanita muscaria, Brugmansia (angels trumpet), Convallaria majalis (lily of the valley), Crataegus (hawthorn), Datura inoxia (moonflower, thornapple), Dieffenbachia, Ganoderma mushroom, kola nut, kombucha tea, Nerium oleander, petasites (butterbur), Phytolacca americana (pokeweed), Piper methysticum (kava), plants and fungi unspecified, poppy seeds (Papaver), Ricinus communis (castor beans), and Sanseviera (Snake plant, Mother in Laws tongue)

Table 10 presents the non-opioid analgesics class. This has been the most frequently reported agent class since 2013 [2, 7, 8]. The most common agent was acetaminophen (67.9%), which was also the most common agent in the Registry overall, involved in 11.6% cases, consistent with previous years.

Table 11 reports the sedative-hypnotics/muscle relaxants class. Benzodiazepines were the most frequently reported (52.6%) with alprazolam (20.6%), clonazepam (15.5%), and lorazepam (7.4%) the top three reported. In 2016, alprazolam eclipsed clonazepam as the most commonly reported benzodiazepine for the first time since the ToxIC Registry began [2, 711]. Other commonly reported agents in this class included the muscle relaxants cyclobenzaprine and baclofen, gabapentin (in the “Other sedatives” subclass), and zolpidem (in the “Non-benzodiazepine agonists” subclass). Barbiturates were infrequently mentioned, consistent with prior years.

Table 12 presents the antidepressant class. Bupropion (in the “Other antidepressants” subclass) was the most frequently reported, comprising 20.7% of antidepressant cases and 3.0% of 2016 Registry cases overall, consistent with prior years. The selective serotonin reuptake inhibitors (SSRIs), particularly sertraline and fluoxetine, were the second most common subclass (34.3%), followed by the tricyclic antidepressants (TCAs) (15.1%) (e.g., amitriptyline), and the serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine).

Table 13 summarizes opioid frequencies, including naturally derived, synthetic, and semisynthetic agents. As in previous years, heroin was the most commonly reported (28.3%), followed by oxycodone (17.8%) and methadone (8.9%).

Table 14 reports the sympathomimetic class. Cocaine was the most commonly reported (34.3%), followed by methamphetamine (25.7%) and amphetamine (12.4%), consistent with previous years. The pharmaceutical stimulants methylphenidate and lisdexamfetamine together accounted for 9.9% of the class. A number of designer stimulant drugs were reported, with methylenedioxy-N-methamphetamine the most common (4.3%). Less common designer agents, combined in the miscellaneous category, included the 2C series drugs, 25I-NBOMe, and other unspecified phenethylamines.

Table 15 describes the anticholinergic and antihistamine class (Table 15), and the most commonly reported agent was diphenhydramine (59.1%), which was also one of the most commonly reported agents in the Registry overall, involved in 4.9% of cases. Hydroxyzine was the next most common (14.9%), followed by other first-generation antihistamines chlorpheniramine and doxylamine. Second-generation antihistamines were reported less frequently.

Table 16 presents frequencies for ethanol and the toxic alcohols. Ethanol was again the second most commonly reported agent overall in the Registry (N = 694), involved in 8.1% of cases. Among the toxic alcohols, ethylene glycol was the most common (45.5%), followed by isopropanol (32.5%), while methanol was less commonly reported (13.8%).

Table 17 presents the cardiovascular agent class. The 654 cardiovascular agent entries comprised 5.8% of all Registry entries in 2016. In this class, beta adrenergic receptor antagonists (beta-blockers) were the most commonly reported (27.7%), followed by sympatholytics (25.8%), similar to prior years. Metoprolol was the most common beta-blocker. Clonidine (21.6%) was the most common sympatholytic reported with guanfacine also reported but to a much lower extent (4.3%). Together, the calcium channel antagonists comprised 17.3% of the agent class, with amlodipine the most common, followed by diltiazem and verapamil. Angiotensin-converting enzyme (ACE) inhibitors comprised only 8.0% of the cardiovascular agent mentions, with lisinopril accounting for >90% of these. Forty-six cardiac glycoside cases were reported, with all involving digoxin except for two digitoxin cases. Other subgroups of cardiovascular agents were less commonly reported.

Table 18 summarizes the 642 antipsychotic agents reported, which accounted for 5.7% of all Registry entries in 2016. Consistent with prior years, quetiapine was by far the most commonly encountered antipsychotic agent. There were more than three times as many quetiapine cases reported (47.8%) as olanzapine (13.6%), the next most common agent. On its own, quetiapine was listed in 3.6% of all Registry cases in 2016. Aripiprazole was also frequently reported (8.1%), similar to past years. Risperidone, haloperidol, and clozapine together accounted for an additional 16.5% of the antipsychotic agent class.

Table 19 shows anticonvulsants and mood stabilizers. Lithium is considered a unique agent class and reported separately in Table 19. Lithium was reported in 176 cases, representing 2.1% of total Registry cases in 2016. Lamotrigine and valproic acid were the two most commonly reported agents in the anticonvulsants and mood stabilizers class. These were followed by phenytoin, carbamazepine, oxcarbazepine, and topiramate.

Table 20 presents information on envenomations and marine poisonings. This class was dominated by snake envenomations in 2016, consistent with prior years. Crotalus spp. were the most commonly reported (34.1%), followed by Agkistrodon spp. (30.9%), and unspecified snakes (20.6%). Spider envenomations (e.g., Loxosceles spp., Latrodectus spp., and unspecified spider) were less common, together making up 9.0% of the class.

Table 21 summarizes the psychoactive agent class, which includes marijuana and other cannabinoid receptor agonists, hallucinogens, and dissociatives. Synthetic cannabinoids were the most frequently entered (32.1%), followed by marijuana, lysergic acid diethylamide (LSD), phencyclidine, and gamma hydroxybutyrate. Amphetamine-like hallucinogens are reported with the psychoactives in Table 21.

Table 22 reports data on diabetic medications. Agent frequencies were similar to previous years, with metformin (41.0%) and insulin (24.8%) the most common. These were followed by the sulfonylurea agents: glipizide, glyburide, and glimepiride.

Table 23 presents the metals agent class which was dominated by lead (30.3%), iron (20.7%), and mercury (13.8%), followed by chromium (7.6%) and cobalt (4.8%). The miscellaneous subclass, comprised of 13 different agents, accounted for 15.9% of entries.

Table 24 presents the gases, irritants, vapors, and dusts class. Carbon monoxide was the predominant agent (43.2%), followed hydrogen sulfide (11.2%), and cyanide and smoke (16.8% combined).

Table 25 reports household product exposures. Sodium hypochlorite ≤6% (household bleach) was the most common (31.3%), followed by other cleaning solutions and disinfectants (20.5%) and laundry detergent pods (13.3%). Caustic agents are described separately in Table S4 in the Supplemental Material.

Table 26 presents the diverse species of the plants and fungi agent class. Consistent with prior years, unspecified mold and unknown mushrooms were the predominant agents, followed by Mitragyna speciosa (kratom), and a miscellaneous category containing 19 different plant and fungi agents.

Additional agent classes presented in the Supplementary Material include cough and cold products (Table S1), herbal products and dietary supplements (Table S2), hydrocarbons (Table S3), caustics (Table S4); antimicrobials (Table S5), other pharmaceutical products (Table S6), other non-pharmaceutical products (Table S7), anticoagulants (Table S8), chemotherapeutic/immunological agents (Table S9), pesticides, including herbicides, insecticides, rodenticides, and fungicides (Table S10), endocrine agents (Table S11), gastrointestinal agents (Table S12), anesthetics (Table S13), anti-parkinsonism drugs (Table S14), pulmonary agents (Table S15), weapons of mass destruction/riot/radiological agents (Table S16), and ingested foreign bodies (Table S17).

Clinical Signs and Symptoms

Table 27 summarizes the 3134 clinical toxidromes reported in 2016. The frequencies of reported toxidromes were similar to past years with sedative-hypnotic the most common (14.9%), followed by anticholinergic (7.4%), sympathomimetic (4.5%), and opioid (4.4%).

Table 27.

ToxIC 2016 cases—toxidromes

N (%)a
Sedative-hypnotic 1261 (14.9)
Anticholinergic 629 (7.4)
Sympathomimetic 386 (4.5)
Opioid 378 (4.4)
Serotonin syndrome 259 (3.0)
Alcoholic ketoacidosis 87 (1.0)
Sympatholytic 50 (0.6)
Washout syndrome 36 (0.4)
NMS 19 (0.2)
Cholinergic 16 (0.2)
Overlap syndromes (MCS, chronic fatigue, etc.) 10 (0.1)
Miscellaneousb 8 (0.1)
Total 3134 (36.7)

NMS neuroleptic malignant syndrome

aPercentage equals number cases reporting specific toxidrome relative to total number of Registry cases in 2016 (N = 8529)

bIncludes anticonvulsant hypersensitivity and fume fever

Table 28 summarizes the 2627 major vital sign abnormalities recorded in 2016. Tachycardia was the most common (12.1%), followed by hypotension (8.0%), bradycardia (4.6%), and several others affecting <4% of total cases. Note that some cases reported more than one major vital sign abnormality. Additionally, cases may include more than one of the other signs/symptom categories described below.

Table 28.

ToxIC 2016 cases—major vital sign abnormalities

N (%)a
Tachycardia (HR >140) 1031 (12.1)
Hypotension (systolic BP < 80 mmHg) 684 (8.0)
Bradycardia (HR < 50) 393 (4.6)
Bradypnea (RR < 10) 249 (2.9)
Hypertension (systolic BP > 200 mmHg and/or diastolic BP > 120 mmHg) 224 (2.6)
Hyperthermia (temperature > 105 °F) 46 (0.5)
Total 2627 (30.8)b

HR heart rate, BP blood pressure, RR respiratory rate

aPercentage equals the number of cases relative to the total number of Registry cases in 2016 (N = 8259)

bTotal reflects cases reporting at least one major vital sign abnormality; cases may be associated with more than one major vital sign abnormality

Table 29 summarizes the neurological signs and symptoms reported in 2016. While the overall numbers of cases with neurological signs and symptoms increased from previous years, the order remained similar, with coma/central nervous system depression the most common (34.7%), followed by agitation (16.7%) and delirium (11.8%).

Table 29.

ToxIC 2016 cases—neurological signs and symptoms

N (%)a
Coma/CNS depression 2959 (34.7)
Agitation 1421 (16.7)
Delirium 1005 (11.8)
Hyperreflexia/myoclonus/tremor 635 (7.4)
Seizures 459 (5.4)
Hallucinations 366 (4.3)
Weakness/paralysis 142 (1.7)
Dystonia/rigidity/extrapyramidal symptoms 112 (1.3)
Numbness/Paresthesia 79 (0.9)
Peripheral neuropathy 25 (0.3)
Total 4970 (58.3)a,b

CNS central nervous system

aPercentage equals number of cases relative to total number of Registry cases in 2016 (N = 8529)

bTotal reflects cases reporting at least one neurological symptom; cases may be associated with more than one neurological symptom

Table 30 summarizes the cardiovascular and pulmonary signs and symptoms reported in 2016. Although the total number of cardiovascular and pulmonary signs reported was higher this year than in previous years, the order remained similar, with prolonged QTc (≥500ms) the most common cardiovascular sign (5.6%), followed by prolonged QRS (≥120 ms) (1.8%). The most common pulmonary sign was respiratory depression (11.1%).

Table 30.

ToxIC 2016 cases—cardiovascular and pulmonary signs

N (%)a
Cardiovascular
 Prolonged QTc (≥500 ms) 480 (5.6)
 Prolonged QRS (≥120 ms) 150 (1.8)
 Ventricular dysrhythmia 102 (1.2)
 Myocardial injury or infarction 61 (0.7)
 AV block (>1st degree) 41 (0.5)
 Total 834 (9.8)b
Pulmonary
 Respiratory depression 946 (11.1)
 Aspiration pneumonitis 182 (2.1)
 Acute lung injury/ARDS 117 (1.4)
 Asthma/reactive airway disease 60 (0.7)
 Total 1305 (15.3)b

ARDS acute respiratory distress syndrome

aPercentage equals number cases reporting signs of symptoms relative to total number of Registry cases in 2016 (N = 8529)

bTotal reflects cases reporting at least one cardiovascular or pulmonary symptom; cases may be associated with more than one symptom

Table 31 summarizes signs and symptoms involving other organ systems. As in the past years, metabolic signs (e.g., elevated anion gap, metabolic acidosis) were common, reported in 12.2% of cases. Renal and musculoskeletal signs (e.g., rhabdomyolysis, acute kidney injury) were also common (10.3%), followed by hematological (6.2%), gastrointestinal/hepatic (5.3%), and dermal (3.4%) signs and symptoms.

Table 31.

ToxIC 2016 cases—clinical signs—other organ systems

N (%)a
Metabolic
 Elevated anion gap (>20) 459 (5.4)
 Metabolic acidosis (pH <7.2) 387 (4.5)
 Hypoglycemia (glucose <50 mg/dL) 126 (1.5)
 Elevated osmole gap (>20) 61 (0.7)
 Total 1033 (12.1)b
Gastrointestinal/hepatic
 Hepatotoxicity (AST ≥1000 IU/L) 296 (3.5)
 Pancreatitis 64 (0.8)
 Gastrointestinal bleeding 49 (0.6)
 Corrosive injury 42 (0.5)
 Intestinal ischemia 5 (0.1)
 Total 456 (5.3)b
Hematological
 Coagulopathy (PT >15 s) 199 (2.3)
 Leukocytosis (WBC >20 K/μL) 131 (1.5)
 Thrombocytopenia (platelets <100 K/μL) 102 (1.2)
 Hemolysis (Hgb <10 g/dL) 56 (0.7)
 Pancytopenia 21 (0.2)
 Methemoglobinemia (MetHgb ≥2%) 18 (0.2)
 Total 527 (6.2)b
Renal/musculoskeletal
 Rhabdomyolysis (CPK >1000 IU/L) 489 (5.7)
 Acute kidney injury (creatinine >2.0 mg/dL) 386 (4.5)
 Total 875 (10.3)b
Dermatological
 Rash 165 (1.9)
 Blister/bullae 71 (0.8)
 Necrosis 31 (0.4)
 Angioedema 25 (0.3)
 Total 292 (3.4)b

AST aspartate aminotransferase, PT prothrombin time, WBC white blood cells, Hgb hemoglobin, CPK creatine phosphokinase

aPercentage equals the number of cases reporting specific clinical signs compared to the total number of Registry cases in 2016 (N = 8529)

bTotal reflects cases reporting at least one sign in the category; cases may be associated with more than one symptom

Fatalities

Tables 32 and 33 present data on ToxIC 2016 cases involving exposures which resulted in fatalities, with Table 32 including cases involving single agent exposures and Table 33 including cases involving multiple agents. Table S18 in the Supplementary Information summarizes information on fatality cases with no suspected toxicologic exposure, or an unknown exposure(s).

Table 32.

ToxIC 2016 fatality cases with known toxicological exposure, single agent

Age/sexa Agents involved Clinical findings Life support withdrawn Brain death confirmed Treatmentb
40M Acetaminophen HT, CNS, MA, AG, HPT, PNC, CPT, PLT, AKI, RBM No Unknown NAC, vitamin K, vasopressors, anticonvulsants, neuromuscular blockers, opioids, continuous renal replacement, intubation, IV fluids
41F Acetaminophen TC, RD, AGT, CNS, AG, HPT, PNC, HYS, AKI, RBM Yes Unknown NAC, vitamin K, benzodiazepines, intubation, IV fluids
21F Heroin HT, BC, BP, VD, RD, CNS, MA Yes Yes Physostigmine, vasopressors, antiarrhythmics, CPR, intubation, IV fluids, therapeutic hypothermia
41F Acetaminophen HT, RD, CNS, MA, AG, HPT, CPT, WBC, RBM Yes No NAC, NaHCO3, vitamin K, vasopressors, anticonvulsants, benzodiazepines, opioids, continuous renal replacement, intubation, IV fluids
43M Methanol HT, QRS, RD, CNS, MA, AG, OG, CPT, AKI, RBM Yes Yes Folate, fomepizole, hemodialysis, intubation, IV fluids
29F Acetaminophen HT, TC, CNS, HGY, HPT, CPT, AKI Yes No NAC, NaHCO3, vitamin K, benzodiazepines, glucose, neuromuscular blockers, opioids, vasodilators, hemodialysis, continuous renal replacement, intubation, IV fluids, transfusion
52M Ethanol HT, TC, MA, AG, HPT, PNC, PLT, AKI Unknown Unknown NAC, vasopressors, continuous renal replacement, cardioversion, intubation, IV fluids
35F Amitriptyline HT, TC, BP, VD, QRS, RD, CNS, MA, AG, HPT, AKI Yes Yes Naloxone, NaHCO3, vasopressors, CPR, intubation, IV fluids
54M Ethanol CNS Yes Yes Fomepizole, NAC, hemodialysis, intubation, transfusion
80M Carbon monoxide HT, AVB, RD, CNS, WKN, MA, OTH1 Yes No Hydroxocobalamin, vasopressors, intubation, IV fluids
77M Metoprolol HT, BC, AVB, RD, CNS Yes No Insulin-euglycemic therapy, vasopressors, glucose, intubation, IV fluids
51F Acetaminophen HT, TC, BC, BP, VD, ALI, RD, CNS, MA, AG, HPT, HYS, CPT, PLT, WBC, AKI Yes No Lipid resuscitation, methylene blue, NAC, NaHCO3, vasopressors, intubation, transfusion
51F Heroin HT, BP, RD, CNS, HPT, WBC, RBM Yes Yes NaHCO3, vasopressors, benzodiazepines, intubation, IV fluids
24F Acetaminophen HT, VD, CNS, HGY, MA, AG, HPT, PNC, PLT Yes No NAC, vasopressors, benzodiazepines, glucose, continuous renal replacement, intubation, IV fluids, therapeutic hypothermia
63F Acetaminophen HT, BC, BP, VD, ALI, RD, CNS, MA, AG, HPT, PNC, INT, CPT, PLT, WBC No No NAC, vasopressors, CPR, intubation, IV fluids
60M Colchicine HT, VD, MA, AG, CPT, PLT, PCT, WBC No No Vasopressors, antiarrhythmics, continuous renal replacement, intubation, IV fluids
51M Metformin HT, TC, ALI, MA, AG, RBM Unknown Unknown Hemodialysis, intubation
83F Diltiazem HT, BC, CNS, MA, AG, Unknown Unknown Glucagon, insulin-euglycemic therapy, lipid resuscitation, vasopressors, intubation, IV fluids
40F Heroin BP, CNS, MA Yes Yes NAC, naloxone,
57M Bupropion VD, AP, ALI, CNS, SZ, AKI No No Lipid resuscitation, NaHCO3, vasopressors, benzodiazepines, CPR, intubation, IV fluids
19M Fentanyl RD, CNS Yes Yes Naloxone, CPR, intubation
14F Diphenhydramine HT, VD, QTc, QRS, CNS, SZ, MA, AG Yes No Vasopressors, antiarrhythmics, anticonvulsants, benzodiazepines, intubation, IV fluids
63F Doxepin RD, CNS, AKI Yes No Glucagon, NaHCO3, intubation, IV fluids
22F Acetaminophen HT, TC, RD, CNS, SZ, MA, AG, HPT, CPT Yes Yes NAC, vasopressors, anticonvulsants, benzodiazepines, intubation, IV fluids,
14F Bupropion HT, QRS, ALI, RD, CNS, SZ, MA, AKI, RBM Yes Unknown Insulin-euglycemic therapy, lipid resuscitation, NaHCO3, vasopressors, urinary alkalinization, CPR, intubation, IV fluids, therapeutic hypothermia
60F Quinidine MET No No Calcium, methylene blue, NaHCO3, vitamin K, vasopressors, hypoglycemia, exchange transfusion, IV fluids, transfusion
52M Sevoflurane HTN, TC, HYT, VD, QTc, QRS, EPS Yes No Dantrolene, NaHCO3, intubation, IV fluids
32M Cyanide HT, TC, CNS, MA No No Hydroxocobalamin, intubation, IV fluids
19F Acetaminophen None listed No No NAC, IV fluids
47M Hydromorphone AP No No NAC, IV fluids
65F Digoxin HT, BC, WKN Yes No Digoxin Fab, vasopressors, IV fluids
60F Amitriptyline HT, TC, VD, QRS, RAD, ALI, RD, Yes No NaHCO3, vasopressors, intubation, intubation, IV fluids
17F Cocaine TC, RD, AGT, CNS, DLM, SZ, MA, AG, HPT, HYS, CPT, PLT, WBC, AKI Yes No Vasopressors, anticonvulsants, benzodiazepines, glucose, opioids, hemodialysis, CPR, intubation, IV fluids, transfusion
32M Cyanide HT, VD, RAD, AGT, CNS, MA No No Hydroxocobalamin, thiosulfate, vasopressors, CPR, intubation, IV fluids
51M Warfarin CNS, CPT, WBC Yes Yes Anticoagulant reversal, anticonvulsants, neuromuscular blockers, intubation
33M Hydrogen sulfide HT, TC, VD, ALI, RD, CNS, MA Yes Unknown Vasopressors, antiarrhythmics, benzodiazepines, CPR, cardioversion, intubation, IV fluids
61M Ethanol HT, DLM, HCN, HPT, PNC, HYS, PLT Yes Unknown Calcium, folate, octreotide, thiamine, benzodiazepines, IV fluids, transfusion
21F Acetaminophen HT, BC, VD, ALI, RD, CNS, MA, AG, HPT, CPT, AKI No No NAC, NaHCO3, vasopressors, antiarrhythmics, benzodiazepines, CPR, cardioversion, intubation, IV fluids
45M Codeine HT, BC, VD, RD, CNS, MA, AG, Yes Yes NAC, NaHCO3, vasopressors, antiarrhythmics, anticonvulsants, beta blockers, opioids, CPR, cardioversion, intubation, IV fluids, therapeutic hypothermia
>89M Carbon monoxide HT, VD, RD, CNS, AG No No Thiosulfate, vasopressors, intubation, IV fluids
68M Digoxin HT, QRS, RD, AGT, CNS Yes Unknown Digoxin Fab, pacemaker
39F Gabapentin HT, VD, QTc, MI, RD, CNS, MA, AG, HPT, MI, WBC, AKI, RBM Yes No Vasopressors, antiarrhythmics, CPR, intubation, therapeutic hypothermia
38F Acetaminophen HT, TC, MI, ALI, CNS, MA, AG, HPT, GIB, HYS, CPT, PLT, PCT, AKI, RBM Yes Unknown NAC, NaHCO3, vitamin K, vasopressors, glucose, continuous renal replacement, intubation, IV fluids
68M Chlorine HT, QTc, MI, ALI, RD, CNS No No Vasopressors, neuromuscular blockers, intubation, IV fluids
68M Copper HT, CRV, GIB, MET, WBC, AKI No No BAL, penicillamine, vasopressors, hemodialysis, continuous renal replacement, CPR, intubation, IV fluids, transfusion
46M Amlodipine HT, RAD, CNS, MA, AKI Yes No Lipid resuscitation, methylene blue, NaHCO3, thiamine, vitamin K, vasopressors, bronchodilators, antiarrhythmics, benzodiazepines, neuromuscular blockers, opioids, steroids, intubation, IV fluids
24M Opioid unspecified VD, QTc, QRS, MI, AP, RD, CNS, MA, Yes Yes None listed
74M Ciguatera PST, WKN Yes No None listed
27M Morphine HT, BP, MI, RAD, ALI, RD, CNS, MA, AG. CPT, AKI, RBM Yes Yes Naloxone, vasopressors, CPR, intubation, IV fluids, therapeutic hypothermia
38M Heroin HT, TC, MI, ALI, CNS, NP, MA, WBC Unknown Unknown Folate, naloxone, vasopressors, intubation, IV fluids
31M Heroin HT, VD, QRS, MI, RAD, RD, CNS, MA, AG, AKI Yes Yes None listed
58M Amphetamine QRS, QTc, AGT, MA, AG, OG, INT, PLT, AKI Yes Unknown Fomepizole, vasopressors, hemodialysis, continuous renal replacement, intubation
44F Heroin HT, BP, VD, RD, CNS, MA, AG, No No Naloxone, vasopressors, CPR, intubation, IV fluids
34M Heroin RD, CNS Unknown Unknown Naloxone, CPR
26M Heroin CNS Yes Yes Naloxone, intubation
70M Diltiazem HT, CNS Yes Yes Calcium, insulin-euglycemic therapy, vasopressors, IVF
65M Opioid unspecified None listed No No Antihypertensives, opioids,
62F Ethanol HT, BC, MI, RD, CNS, MA,AG, OG, GIB, WBC, RBM No No Fomepizole, vasopressors, continuous renal replacement, CPR, intubation, IV fluids
60M Acetaminophen None listed No No NAC
32F Aspirin HT, BC, VD, RD, CNS, No No NaHCO3, vasopressors, CPR, intubation, IV fluids
32M Cyanide RD, CNS, AG, MET Yes Yes Hydroxocobalamin, methylene blue, NaHCO3, vasopressors, intubation, IV fluids
44M Acetaminophen AP, HPT, MET, MYS, CPT, AKI, RBM Yes No NAC, hemodialysis, continuous renal replacement, intubation, IV fluids, transfusion
43M Methanol TC, RD, CNS, SZ, MA, AG, OG Yes Yes Folate, fomepizole, thiamine, vasopressors, anticonvulsants, benzodiazepines, hemodialysis, intubation, IV fluids

Based on response from medical toxicologist “Did the patient have a toxicological exposure?” equals yes, with known agent(s)

AG anion gap, AGT agitation, AKI acute kidney injury, ALI acute lung injury/ARDS, AP aspiration pneumonia, AVB AV block, BC bradycardia, BP bradypnea, CNS coma/CNS depression, CPT coagulopathy, CRV corrosive injury, DLM delirium, EPS dystonia/rigidity, GIB GI bleeding, HCN hallucinations, HGY hypoglycemia, HPT hepatoxicity, HT hypotension, HTN hypertension, HYS hemolysis, HYT hyperthermia, INT intestinal ischemia, MA metabolic acidosis, MET methemoglobinemia, MI myocardial injury/ischemia, NP neuropathy, OG osmole gap, OTH1 rash, OTH2 skin blisters, necrosis, PCT pancytopenia, PLT thrombocytopenia, PNC pancreatitis, PST paresthesia, QRS QRS prolongation, QTc QTc prolongation, RAD asthma/reactive airway disease, RBM rhabdomyolysis, RD respiratory depression, RFX hyperreflexia/tremor, SZ seizures, TC tachycardia, VD ventricular dysrhythmia, WBC leukocytosis, WKN weakness/paralysis, BAL dimercaprol, CPR cardiopulmonary resuscitation, ECMO extra-corporeal membrane oxygenation, NAC n-acetyl cysteine, NaHCO 3 sodium bicarbonate

aAge in years unless otherwise stated

bPharmcological and non-pharmacological support as reported by medical toxicologist

Table 33.

ToxIC 2016 fatality cases with known toxicological exposure, multiple agents

Age/sexa Agents involved Clinical findings Life support withdrawn Brain death confirmed Treatmentb
45F Carbon monoxide, cyanide HT, TC, ALI, RD, CNS, MA, AG, Yes Yes Hydroxocobalamin, intubation
30M Heroin, cocaine, diphenhydramine, dextromethorphan, citalopram TC, AP, CNS, RFX, MA, HPT, CPT, WBC, AKI, RBM, OTH2 Yes No NaHCO3, antihypertensives, benzodiazepines, neuromuscular blockers, opioids, hemodialysis, intubation, IV fluids
59M Acetaminophen, ethanol HT, RD, CNS, HGY, GIB, CPT Unknown Unknown NAC, intubation, IV fluids
16M Acetaminophen, ethanol DLM Unknown Unknown None listed
52F Nicotine, caffeine, dextromethorphan, venlafaxine VD, QRS, AP, CNS, GIB Yes Yes NAC, NaHCO3, vasopressors
62M Heroin, cocaine HT, BC, QTc, ALI, CNS, MA, AG, HPT, AKI, RBM Yes Yes NAC, naloxone, vasopressors, continuous renal replacement, intubation, IV fluids
68F Nortriptyline, duloxetine, zolpidem, oxycodone HTN, HT, TC, AP, ALI, RD, AGT, DLM, RFX, MA, PNC, PLT, AKI, RBM Yes No Naloxone, vasopressors, benzodiazepines, neuromuscular blockers, continuous renal replacement, intubation, IV fluids
Unknown F Fentanyl, diazepam HT, RD, CNS, MA Yes Yes Vasopressors, intubation, IV fluids
15F Ibuprofen, quetiapine HT, TC, VD, QRS, RAD, CNS, MA, AG, Yes Unknown Insulin-euglycemic therapy, lipid resuscitation, NaHCO3, vasopressors, antiarrhythmics, activated charcoal, hemodialysis, ECMO
32F Fentanyl, heroin BC, BP, RD, CNS, SZ, AKI Yes No Naloxone, intubation, IV fluids, therapeutic hypothermia
28M Methadone, marijuana CNS, SZ, MA Unknown Unknown Benzodiazepines, neuromuscular blockers, intubation, IV fluids
65F Hydrocodone, alprazolam, diazepam HT, RD, CNS Yes No Calcium, glucagon, insulin-euglycemic therapy, NAC, naloxone, vasopressors, intubation, IV fluids
35M Olanzapine, valproic acid HT, TC, AGT, DLM No No NAC, NaHCO3, vasopressors, glucose, hemodialysis, intubation, IV fluids
21F Dextroamphetamine, lithium AGT, RBM Unknown Unknown IV fluids
33M Heroin, valproic acid HT, BC, VD, AP, AP, ALI, RD, CNS Yes No Carnitine, NaHCO3, intubation, IV fluids
50M Norepinephrine, argatroban CPT, PLT, WBC, RBM, OTH2 Yes Unknown Vasopressors, continuous renal replacement, intubation, IV fluids, transfusion
70M Warfarin, methadone, oxycodone, cocaine, heroin HT, RD, CNS, CPT, AKI Yes Yes Vitamin K, vasopressors, IV fluids
57M Acetaminophen, metformin HT, BC, RD, CNS, SZ, MA, AG, HPT, PNC, PLT, AKI No No NAC, vasopressors, anticonvulsants, steroids, continuous renal replacement, CPR, intubation
38M Methamphetamine, amphetamine, marijuana, benzodiazepine HTN, TC No No Antihypertensives, benzodiazepines, CPR, intubation
54M Ethanol, ibuprofen, acetaminophen HT, CNS, MA, AG, HPT, PLT, AKI No No Fomepizole, NAC, vitamin K, vasopressors, hemodialysis, continuous renal replacement, IV fluids
47M Oxycodone, alprazolam, diazepam HT, TC, BC, BP, VD, MI, RD, CNS, MA, AKI Unknown Unknown None listed
Unknown M Cyanide, carbon monoxide HT, VD, ALI, RD, CNS, AG Yes Yes Hydroxocobalamin, vasopressors, hyperbaric oxygen, intubation, IV fluids
66F Fentanyl, hydromorphone BP, RD, CNS, HGY, MA No No Naloxone, glucose, opioids, intubation, IV fluids
77M Metoprolol, amlodipine HT, BC, AVB, QRS, ALI, CNS, MA, HPT Yes No Atropine, calcium, glucagon, insulin-euglycemic therapy, vasopressors, glucose, neuromuscular blockers, intubation, IV fluids
53F Insulin, zolpidem, venlafaxine AP, CNS Yes Yes Glucagon, naloxone, glucose, intubation, IV fluids
56M Cocaine, opioid unspecified MI, AP, RD, CNS, AKI, RBM Yes No Antihypertensives, benzodiazepines, glucose, opioids, intubation, IV fluids
53F Amlodipine, toluene, doxepin, carisoprodol, clonazepam HT, BC, VD, QTc, QRS, RD, CNS, RFX, HGY No No Calcium, methylene blue, naloxone, NaHCO3, methylene blue, naloxone, NaHCO3, thiamine, vasopressors, antiarrhythmics, benzodiazepines, glucose, steroids, intubation, IV fluids
41F Iron, diphenhydramine HT, TC, BP, VD, ALI, CNS, MA, AG, HPT No No NaHCO3, deferoxamine, vasopressors, hemodialysis, intubation, IV fluids
21F Hydroxyzine, fluoxetine, melatonin HT, BP, QTc, RD, CNS, MA, AG, HPT, CPT, AKI, RBM No No NAC, naloxone, vasopressors, CPR, cardioversion, intubation, IV fluids, therapeutic hypothermia
43F Heroin, cocaine VD, RD, CNS Yes Yes NaHCO3, vasopressors, intubation, IV fluids
14M Bupropion, fluoxetine, meclizine HT, TC, BC, BP, VD, QTc, AP, AGT, CNS, SZ, RFX, MA, RBM Yes No Lipid resuscitation, vasopressors, antiarrhythmics, anticonvulsants, benzodiazepines, neuromuscular blockers, opioids, CPR, ECMO, intubation
57M Acetaminophen, metformin HT, CNS, SZ, HGY, MA, AG, HPT, CPT, WBC, AKI, RBM No No NAC, vitamin K, vasopressors, benzodiazepines, steroids, continuous renal replacement, intubation, transfusion
64M Cyclobenzaprine, gabapentin, acetaminophen, codeine CNS, AG Yes Yes Naloxone, physostigmine
53M Metformin, atenolol HTN, HT, QTc, QRS, MI, MA, AG, HPT, AKI, RBM No No Calcium, lipid resuscitation, NaHCO3, vasopressors, activated charcoal, hemodialysis, intubation, IV fluids

Based on response from medical toxicologist “Did the patient have a toxicological exposure?” equals yes, with known agent(s)

AG anion gap, AGT agitation, AKI acute kidney injury, ALI acute lung injury/ARDS, AP aspiration pneumonia, AVB AV block, BC bradycardia, BP bradypnea, CNS coma/CNS depression, CPT coagulopathy, CRV corrosive injury, DLM delirium, EPS dystonia/rigidity, GIB GI bleeding, HCN hallucinations, HGY hypoglycemia, HPT hepatoxicity, HT hypotension, HTN hypertension, HYS hemolysis, HYT hyperthermia, INT intestinal ischemia, MA metabolic acidosis, MET methemoglobinemia, MI myocardial injury/ischemia, NP neuropathy, OG osmole gap, OTH1 rash, OTH2 skin blisters, necrosis, PCT pancytopenia, PLT thrombocytopenia, PNC pancreatitis, PST paresthesia, QRS QRS prolongation, QTc QTc prolongation, RAD asthma/reactive airway disease, RBM rhabdomyolysis, RD respiratory depression, RFX hyperreflexia/tremor, SZ seizures, TC tachycardia, VD ventricular dysrhythmia, WBC leukocytosis, WKN weakness/paralysis, BAL dimercaprol, CPR cardiopulmonary resuscitation, ECMO extra-corporeal membrane oxygenation, NAC n-acetyl cysteine, NaHCO 3 sodium bicarbonate

aAge in years unless otherwise stated

bPharmcological and non-pharmacological support as reported by medical toxicologist

The number of fatalities increased again in 2016 to 126, along with an increased percentage of cases reporting a fatality (1.5%), up from 98 fatalities (1.2%) in 2015, and 89 fatalities (1.0%) in 2014 [2, 7]. Of these 126 fatalities, 63 (0.7%) involved single agent exposures and 35 (0.4%) cases involved multiple agent exposures. The remaining 28 (0.3%) fatalities were categorized as not a toxicological exposure, or unknown with respect to toxicity and presentation and are presented in Table S18.

Six fatalities (four females, two males) involved pediatric (age 0–18 year) patients. All six were adolescents, with ages ranging from 14 to 17 years, constituting 4.8% of fatalities. Five of these were intentional pharmaceutical exposures, with some intent to self-harm, and four were reported as definitive suicide attempts. An additional case reported toxicology involvement to assist with interpretation of lab data and evaluation of malicious or criminal intent. Three pediatric fatalities involved single agents (bupropion, cocaine, and diphenhydramine) and three involved multiple agents (acetaminophen, bupropion, ethanol, fluoxetine, ibuprofen, meclizine, and quetiapine). Life support measures were withdrawn in five of the six pediatric fatality cases. The sixth case is reported as unknown whether life support was withdrawn in a 16-year-old male with an exposure to acetaminophen and ethanol, and no treatment interventions are listed. This entry was categorized as misuse or abuse of a substance by taking higher doses than recommended of an over the counter product without an attempt at self-harm. No further details were provided to describe the lack of interventions or treatments recorded such as pronounced on arrival, or family or religious preference.

Among the single agent fatalities (all ages), there were four deaths attributed to ethanol; of these, three were intubated and mechanically ventilated and received either continuous renal replacement or hemodialysis. Eight single agent fatalities (age range 21–51 years) were attributed to heroin and one to fentanyl (a 19-year-old). Of the multiple agent fatalities, six involved heroin and three involved fentanyl. Fourteen fatalities overall were single agent exposures to opioids, while 15 multiple agent fatalities involved one or more opioids including 4 cases involving a combination of cocaine with heroin or other opioid.

Life support measures were withdrawn in 60 (61.2%) of the fatalities related to a toxicologic exposure (single or multi-agent), with brain death confirmed in 26 (43.3%). The 60 patients ranged in age from 14 to 80 years (including 5 pediatric patients), with two patients of unknown age. The mean and median ages for those with life support withdrawn were 44.6 and 43.5 years, respectively, with a sex distribution of 55.0% male and 45.0% female.

Adverse Drug Reactions

Table 34 presents information on adverse drug reactions (ADRs). In 2016, there were 320 cases (3.8% of Registry cases) that were categorized as ADRs, defined as any unintended response to a medication as used in standard therapeutic dosing. There were 455 total agent entries with 164 unique agents. Some cases reported multiple agents, possibly reflecting drug-drug interactions. The strength of association between the reported agent and the clinical presentation was recorded as definitive by rechallenge in 4.7% of cases, probable in 72.8%, and possible in 22.5%. The most frequently recorded drugs in ADR cases in 2016 were lithium (11.9%) and digoxin (5.9%).

Table 34.

ToxIC 2016—most common drugs associated with ADRs

N (%)a
Lithium 38 (11.9)
Digoxin 19 (5.9)
Haloperidol 14 (4.4)
Metformin 13 (4.1)
Metoprolol 12 (3.8)
Phenytoin 12 (3.8)
Valproic acid 12 (3.8)
Acetaminophen 9 (2.8)
Olanzapine 9 (2.8)
Sertraline 8 (2.5)

ADRs adverse drug reactions

aPercentages are calculated out of the total number of cases reporting an ADR (N = 320)

Treatment

In 2016, there were 3047 cases (35.7% of total Registry cases) with at least one antidote administered, and 3540 antidotes given overall (Table 35). Similar to prior years, N-acetylcysteine was the most common, accounting for more than one quarter of antidotes given in 2016 (27.5%), followed by naloxone/nalmefene (19.9%), and sodium bicarbonate (11.9%). In 2016, 2.7% of Registry cases reported antivenom therapy, with the vast majority of these (96.1%) receiving Crotalidae polyvalent immune fab (ovine), again reflecting the presence of the North American Snake Bite Registry within the overall Registry (Table 36).

Table 35.

Antidotal therapy administered in ToxIC in 2016

N (%)a
N-Acetylcysteine 974 (27.5)
Naloxone/nalmefene 705 (19.9)
Sodium bicarbonate 421 (11.9)
Thiamine 250 (7.1)
Folate 201 (5.7)
Physostigmine 147 (4.2)
Fomepizole 119 (3.4)
Calcium 110 (3.1)
Glucagon 98 (2.8)
Flumazenil 63 (1.8)
Cyproheptadine 58 (1.6)
Vitamin K 51 (1.4)
Atropine 47 (1.3)
L-Carnitine 44 (1.3)
Insulin-euglycemic therapy 44 (1.3)
Octreotide 44 (1.3)
Fab for digoxin 34 (1.0)
Lipid resuscitation 25 (0.8)
Pyridoxine 26 (0.7)
Hydroxocobalamin 17 (0.5)
Methylene blue 14 (0.4)
Dantrolene 9 (0.3)
2-PAM 7 (0.2)
Bromocriptine 6 (0.2)
Thiosulfate 6 (0.2)
Anticoagulation reversal 5 (0.1)
Botulinum antitoxin 3 (0.1)
Ethanol 2 (0.1)
Nitrites 2 (0.1)
Coagulation factor replacement 1 (<0.1)
Protamine 1 (<0.1)
Total 3540 (100)

aPercentages are out of the total number of antidotes administered (N = 3540); 3047 cases (35.7% of total Registry cases) received at least one antidote; some cases involve multiple antidotes

Table 36.

Antivenom therapy administered in ToxIC in 2016

N (%)a
Crotalidae polyvalent immune fab (ovine) 222 (96.1)
Other snake antivenom 5 (2.2)
Scorpion antivenom 3 (1.3)
Spider antivenom 1 (0.4)
Total 231 (100)

aPercentages are out of the total number of antivenom treatments administered (N = 231)

Tables 37 and 38, respectively, summarize the pharmacological and non-pharmacological supportive care intervention frequencies in 2016. A total of 3830 pharmacological and 4522 non-pharmacological supportive care interventions were reported. There were 2741 cases (32.1% of total Registry cases) reporting at least one form of pharmacologic treatment and 3508 cases (41.1% of total Registry cases) reporting at least one non-pharmacological intervention. Some cases involved more than one form of treatment. Similar to past years, benzodiazepines were used in half of the pharmacological interventions, followed by opioids (10.8%), vasopressors (10.3%), and antipsychotics (7.2%). Of the non-pharmacological interventions, intravenous fluid resuscitation was the most common (70.3%), followed by intubation and ventilatory management (25.1%).

Table 37.

Supportive care interventions administered in ToxIC in 2016—pharmacological

N (%)a
Benzodiazepines 1917 (50.1)
Opioids 415 (10.8)
Vasopressors 393 (10.3)
Antipsychotics 277 (7.2)
Neuromuscular blockers 172 (4.5)
Antihypertensives 160 (4.2)
Anticonvulsants 140 (3.7)
Glucose (concentration > 5%) 134 (3.5)
Corticosteroids 70 (1.8)
Albuterol (or other bronchodilator) 66 (1.7)
Antiarrhythmics 49 (1.3)
Beta blockers 27 (0.7)
Vasodilators 10 (0.3)
Total 3830 (100)

aPercentages are out of the total number of treatments administered (3830); 2741 Registry cases (31.8%) received at least one form of pharmacological treatment; cases may have involved multiple forms of treatment

Table 38.

Supportive care interventions administered in ToxIC in 2016—non-pharmacological

N (%)a
IV fluid resuscitation 3179 (70.3)
Intubation/ventilatory management 1133 (25.1)
CPR 81 (1.8)
Transfusion 41 (1.0)
Hyperbaric oxygen 19 (0.4)
Cardioversion 18 (0.4)
Therapeutic hypothermia 18 (0.4)
Pacemaker 16 (0.4)
ECMO 11 (0.2)
Aortic balloon pump 1 (0.02)
Organ transplantation 1 (0.02)
Total 4522 (100)

CPR cardiopulmonary resuscitation, ECMO extracorporeal membrane oxygenation

aPercentages are out of the total number of treatments administered (N = 4522); 3508 cases (41.1% of total Registry cases) received at least one form of non-pharmacological treatment; cases may have involved multiple forms of treatment

Table 39 summarizes the 31 chelation therapy interventions, which accounted for 0.4% of total Registry cases in 2016. Deferoxamine and dimercaptosuccinic acid (DMSA) were reported in equal numbers.

Table 39.

Chelation therapy administered in ToxIC in 2016

N (%)a
Deferoxamine 11 (35.5)
DMSA 11 (35.5)
Dimercaprol 4 (12.9)
EDTA 4 (12.9)
Pencillamine 1 (3.2)
Total 31 (100)

DMSA dimercaptosuccinic acid, EDTA ethylenediamine-tetraacetic acid

aPercentages are out of the total number of chelation treatments administered (N = 31); 28 cases (0.3% of total Registry cases) received at least one form of chelation treatment

Table 40 summarizes the 334 decontamination procedures reported in the Registry in 2016. There were 318 cases (3.7% of total Registry cases) in which at least one decontamination procedure was performed. Activated charcoal was most common (79.3%), followed by whole bowel irrigation (9.9%), and external irrigation (8.7%). Gastric lavage was uncommon with only seven cases (2.1%) reported.

Table 40.

Decontamination interventions administered in ToxIC in 2016

N (%)a
Activated charcoal 265 (79.3)
Whole bowel irrigation 33 (9.9)
External irrigation 29 (8.7)
Gastric lavage 7 (2.1)
Total 334 (100)

aPercentages are out of the total number of treatments administered (N = 334); 318 cases (3.7% of Registry total) received at least one form of decontamination

Table 41 reports enhanced elimination procedures. Enhanced elimination was performed in 280 cases (3.3% of total cases), with some cases reporting more than one, for a total of 321 reported treatments. Hemodialysis for toxin removal (32.1%) and urinary alkalinization (29.3%) were the most common. Hemodialysis for other indications comprised an additional 19.0% of enhanced elimination procedures.

Table 41.

Enhanced elimination interventions administered in ToxIC in 2016

N (%)a
Hemodialysis (toxin removal) 103 (32.1)
Urinary alkalinization 94 (29.3)
Hemodialysis (other indication) 61 (19.0)
Continuous renal replacement therapy 55 (17.1)
Multiple-dose activated charcoal 6 (1.9)
Exchange Transfusion 2 (0.6)
Total 321 (100)

aPercentages are out of the total number of treatments administered (N = 321); 280 cases (3.3% of total Registry cases) received at least one form of enhanced elimination

Discussion

This report summarizes the seventh year of data collected in ACMT’s ToxIC Case Registry. Although the Registry is not population based, it is a large source of information that can be used in conjunction with data from health agencies, poison centers, and other sources to produce a more detailed picture of poisoning trends and their public health implications. Novel exposure surveillance data from the Registry is not reported in this Annual Report, but is being analyzed, with results to be published separately. The most common agent classes, types of encounters, toxidromes, and treatments were similar to prior years. Some broad trends, both within the Registry itself and within the larger national context, are discussed.

Opioids

Opioid fatalities reported in the ToxIC Registry over the past few years mirror the national trends of steadily increasing age-adjusted death rates (per 100,000 population) from heroin and synthetic opioids other than methadone (e.g., fentanyl, tramadol) according to National Vital Statistics System data [12, 13]. In 2016, heroin-related deaths in ToxIC were the highest reported since the Registry’s inception, increasing both in absolute number and in percentage of all fatalities cases—11.1% of fatalities in 2016 versus 4.1% in 2015 and 6.7% in 2014 [2, 7]. Fentanyl-related deaths also increased in 2016 with four reported cases (3.2%), up from 0.0% in 2015 and 1.1% in 2014 [2, 7]. The total number of opioid-related fatalities (all agents) in ToxIC increased to 29 cases (23.0% of total fatalities) in 2016, compared to 14.2% in 2015 and 18.0% in 2014 [2, 7].

Deaths related to illicit street opioid use may be more complicated to ascribe definitively to heroin or to fentanyl and newer fentanyl derivatives since testing for these agents is not routinely conducted. Thus, it is possible that some of the deaths attributed to heroin in the ToxIC Registry may be related to newer synthetic opioids. Of note, the number of ToxIC cases (fatality and non-fatality) involving an “unspecified opioid” increased to 8.1% of total opioid cases in 2016, compared to 6.5, 4.1, and 0.6% in 2015, 2014, and 2013, respectively [2, 7, 8]. In addition, two fatalities were attributed to unspecified opioids as single agents and one to unspecified opioids with cocaine in 2016, in contrast to zero deaths from unspecified opioids in 2014 and 2015 [2, 7]. One possible explanation for the rise in unspecified opioid case reporting may be the difficulty in clinically identifying the specific illicit opioid responsible.

The increase in ToxIC opioid cases (both fatal and non-fatal) in 2016 likewise reflects the national opioid crisis. The percentage of opioid cases vs. total Registry cases increased from 8.8% in 2015 to 9.8% in 2016 [2]. As in 2015, heroin, oxycodone, and methadone were the most commonly reported opioids in 2016, each up slightly from 2015 in terms of absolute numbers and percent of total opioid cases [2]. In addition, several designer opioids—3-methylfentanyl, remifentanil, and U-47700—were reported for the first time in ToxIC in 2016. Of all the opioids reported, two decreased notably from 2015 to 2016: buprenorphine, down to 4.2% from 7.5% of opioid cases in 2015, and tramadol, down to 7.8% from 10.5% of opioid cases in 2015 [2].

Benzodiazepines

Benzodiazepines were again the most commonly reported type of agent in the sedative-hypnotics/muscle relaxants class in 2016. For the first time since the start of the Registry, alprazolam was the most commonly reported benzodiazepine with 276 cases (20.6% of the sedative-hypnotics/muscle relaxants agent class). Clonazepam had previously been the most commonly reported, but was second this year with 207 cases (15.5% of the class). In 2016, the mean age reported for alprazolam ingestions was 33.4 years with 50.7% male. For clonazepam, the mean age reported was 34.5 years with 38.2% males. Lorazepam, the third most common benzodiazepine, had a mean age of 35.3 years in reported cases with 31.3% males. Coingestants were common in benzodiazepine exposures, being reported in 191 (69.2%) alprazolam cases, 165 (79.7%) clonazepam cases, and 76 (76.8%) lorazepam cases. Opioids were commonly reported coingestants for all three benzodiazepines. Eighty-five (30.8%) of alprazolam exposures involved at least one opioid. Cases could involve multiple opioid coingestants. Heroin was the most common opioid reported in alprazolam exposures with 25 cases (9.1%), followed by oxycodone 20 cases (7.2%) and methadone 11 cases (4.0%). Forty-three (20.8%) of the clonazepam exposures involved at least one opioid. As with alprazolam, cases could involve multiple opioid coingestants. Among clonazepam exposures, oxycodone was most commonly reported with 16 cases (7.7%), followed by heroin with 8 cases (3.9%) and hydrocodone with 6 cases (2.9%). Lorazepam exposures involved an opioid in only seven cases (7.1%).

Laundry Detergent Pods

Liquid laundry detergent pods have been responsible for a number of pediatric poisonings, both mild and severe, in the USA and several European countries, with young children (i.e., age 0–6 years) disproportionately affected [1424]. In response to public concern and warnings from the US Consumer Product Safety Commission (CPSC), the American Association of Poison Control Centers (AAPCC), and others, several manufacturers (including P&G, responsible for 80% of the share of the US market) recently agreed to adopt a new safety standard for detergent pod packaging released in 2015 by the American Society of Testing and Materials [2528]. Among other things, the standard mandates using opaque instead of clear packaging, adding a bittering agent to the outer membrane, and other features designed to make the pods less attractive to young children [27, 28].

Although it is unclear whether or not these changes have succeeded in reducing accidental pediatric ingestions, the early numbers are promising. Detergent pod cases reported annually to AAPCC/US poison control centers declined in absolute number from 2015 to 2016 (12,616 vs. 11,545 cases, respectively), and monthly case numbers reported in the first half of 2017 were consistently lower than the corresponding months of 2015 and 2016 [26]. Similarly, since the first detergent pod cases were recorded in the ToxIC Registry in 2012, cases involving young children (i.e., age 0–6 years) have declined both in absolute and relative terms, from a peak in 2013 of 32 cases (4.2% of total cases age 0–6 years) to 9 cases (1.4% of total cases age 0–6 years) in 2016 [8, 9]. In 2016, one ToxIC pediatric case involved a 9-year-old female, and all others were age ≤3 years. Among the pediatric cases, central nervous system depression was reported in four, bradypnea with respiratory depression in one, corrosive injury in two, and reactive airway disease and aspiration pneumonitis requiring intubation in one, with no fatalities reported. It is unclear what effect the new safety standards have had on cases of laundry pod exposures as reported to the Registry, though the continued decline is reassuring.

Adverse Drug Reactions

Lithium has been the most commonly reported ADR agent in ToxIC each year since the field was added in 2014 and was responsible for 11.9% of ADRs in 2016 [2, 7]. This is out of proportion to its overall Registry representation, with only 176 total cases involving lithium reported in 2016. Quetiapine was one of the most common medications involved in ADRs in 2014 and 2015 but did not top the list in 2016, despite being the most commonly reported antipsychotic drug in the Registry [2, 7]. Instead, haloperidol and olanzapine were both among the top 10 ADR-related drugs in 2016, together comprising 7.2% of reported ADRs. Digoxin was the second most commonly reported ADR-related drug this year, despite being infrequently reported in the Registry overall; 43.2% of digoxin cases in 2016 were categorized as ADRs. In 2016 acetaminophen was also one of the most common agents associated with an ADR, although ADRs were only implicated in 0.9% of all acetaminophen cases in the Registry. In five ADR cases the outcomes were fatal, with the strength of the association between the exposure and clinical presentation reported as probable in all five. Among those five ADRs which had a fatal outcome, the ages ranged from 41 to 76. Two of the cases were also recorded as medication errors.

Limitations

ToxIC contains data as reported by medical toxicologists treating patients at the bedside, with reliable associations between clinical signs and symptoms and the toxic agents responsible. Nonetheless, there are some inherent limitations of the Registry from a descriptive epidemiological perspective, as well as structural and data quality limitations that continue to be addressed through an ongoing quality improvement process. One inherent limitation is that the central case inclusion criterion—consultation by a medical toxicologist—likely creates a reporting bias toward more severe or unusual cases. At the site level, bias may be introduced through either the decision to consult and/or by the reporting medical toxicologist her/himself. We attempt to control this bias through written agreements with the participating sites that every case seen by the medical toxicologist will be logged in the Registry. In addition, ToxIC cases represent those presenting for clinical care, thus are likely biased toward severe/unusual exposures compared to sources such as Poison Control Centers.

Another inherent bias is the limited number of medical toxicologists in practice, currently estimated to be only a few hundred nationwide. This restricts the Registry cases to those geographic areas with actively practicing medical toxicologists, who have also agreed to ToxIC’s participation rules and guidelines. Indeed, the Registry has grown to include sites from 22 states across the country and thus includes a large, diverse collection of cases and practice patterns, which for some agents/exposures may reasonably be considered representative of national trends. But some areas, such as the southeastern and western USA, are underrepresented in ToxIC compared to others, so trends unique to those areas may not be fully reflected in the database. Limited case entries required that two of the international sites not be included in the Registry in 2016, thus limiting the scope of data collected largely to the USA.

In 2014, centralized, ongoing quality assurance procedures were initiated, designed to improve the accuracy of data entry and coding, and to minimize the number of missing entries. Year 2016 is also the second complete year of data collection since several data fields were made mandatory including include race, ethnicity, reason for encounter, presence of suicidal intent, signs and symptoms, treatments, other interventions, and fatalities. Prior to this, it was unknown if items left blank were not applicable or simply not recorded. This improvement has nearly eliminated missing responses in these fields, and future research will benefit from the improved clarity of responses.

Despite the fact that the race and ethnicity questions were made mandatory in 2014, approximately one quarter of cases were reported as unknown/uncertain race and/or ethnicity in both 2015 and 2016. These data are not self-reported and may not routinely be reflected in patient charts, requiring the examiner to specifically recall this information. For some participating clinicians, race and ethnicity may not be a routine part of their information gathering. Additionally, with the Registry’s potential bias toward more complicated and critically ill exposures, there may be a larger than expected number of patients unable to report this information to the examiner. Quality improvement efforts continue, with a goal of minimizing the number of cases reported as unknown or uncertain race and ethnicity.

Significant physical examination findings, vital sign abnormalities, supportive interventions, and some clinical laboratory data are collected; however, the severity of illness is not directly recorded. Although the completeness of the clinical data has improved since creating the mandatory fields, there remain some cases, such as fatalities, where multiple interventions might be expected but are not recorded. In addition, the timeline of events and cause of death are not described. Multiple agents may be reported, but unless free text fields are used, it may be unclear to what degree each agent contributed.

Additional limitations include those inherent in any database. Each case is unique, and some details may be too complicated to be adequately described in a series of programmed data fields. Free text fields are available to enter additional information at the medical toxicologist’s discretion, but the free text fields are not easily searchable and must be reviewed manually.

Conclusions

Since its inception in 2010, the ToxIC Registry has continued to grow and is the only database of its kind logging all cases encountered by participating medical toxicologists. While agent frequencies may vary from year to year, and new trends may emerge, overall the most common exposures, toxidromes, clinical abnormalities, and antidotes recorded in ToxIC represent the routine practice of the subspecialty of medical toxicology. It is thus potentially useful as an instructional tool for trainees in toxicology, valuable for toxicosurveillance and research, and as a resource for the practice of medical toxicologists.

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Acknowledgments

Toxicology Investigators Consortium (ToxIC) Study Group Collaborators:

Aks SE, Algren DA, Alwasiyah D, Beauchamp G, Bentur Y, Beuhler MC, Boyle KL, Bruccoleri RE, Burns, MM, Cahana A, Cannon RD, Caravati EM, Carey JL, Chhabra N, Chomin J, Christian MR, Conner K, Cook MD, Cumpston KL, Dissanayake V, Dribben WH, Eisenga BH, Engebretsen KM, Falkowitz D, Farkas A, Fenton A, Froberg BA, Furmaga JF, Ganetsky M, Garlich F, Geib AJ, Gorodetsky R, Greene S, Greller HA, Gummin DD, Hart K, Hendrickson RG, Hernandez S, Hoyte CO, Judge BS, Kazzi Z, Kerns W, Kessler BD, King J, Kirschner R, Kleinschmidt KC, Kostic MA, Kusin S, Leikin, JB,LeRoy JM, Levine M, Lo CY, Lowry JA, Lung D, Lurie Y, Maddry J, Majlesi N, Manini AF, Marlin MB, McKay C, McKeever RG, McKeown NJ, Meggs WJ, Miller SN, Minns A, Moore E, Morgan BW, Mullins ME, Nappe TM, Nogar JN, Oakley E, Olmedo R, Othong R, Parker-Cote J,Regina A, Riley BD, Rowden A, Ruha AM, Rusyniak DE, Schult, R, Schwarz ES, Seifert SA, Sessions D, Shulman J, Smolinske SC, Smollin C, Spyres MB, Steck A, Stellpflug SJ, Sullivan R, Toce MS, Troendle MM, Vearrier D, Warrick BJ, Watts DC, Wills BK, Wolk BJ, Zosel AE.

We also wish to thank study coordinators AB Adefeso, Mary Connie Aubin, Anita Kurt, Julie Licata, Misti Marshall, Maureen Morgan, Tammy Phan, Andrea Ramirez, and Melissa VandenBerg.

Compliance with Ethical Standards

Funding

ToxIC was supported by a continuation of a grant from the US National Institutes of Health on cardiovascular drug toxicity, a new contract with the US Food and Drug Administration, and the continuation of unrestricted grant support from BTG International, which was used to support the North American Snakebite Registry.

Conflicts of Interest

None

Previous Presentation of Data

None

Funding Sources

This study received funding from the NIH National Institute on Drug Abuse 1R56DA38366, and 1R01DA037317-01, a data sharing contract with the U.S. Food and Drug Administration, and BTG International Inc.

Footnotes

Electronic supplementary material

The online version of this article (doi:10.1007/s13181-017-0627-3) contains supplementary material, which is available to authorized users.

Contributor Information

Lynn A. Farrugia, Phone: 860-972-0001, Email: Lynn.Farrugia@hhchealth.org

On behalf of the Toxicology Investigators Consortium Study Group:

S. E. Aks, D. A. Algren, D. Alwasiyah, G. Beauchamp, Y. Bentur, M. C. Beuhler, K. L. Boyle, R. E. Bruccoleri, M. M. Burns, A. Cahana, R. D. Cannon, E. M. Caravati, J. L. Carey, N. Chhabra, J. Chomin, M. R. Christian, K. Conner, M. D. Cook, K. L. Cumpston, V. Dissanayake, W. H. Dribben, B. H. Eisenga, K. M. Engebretsen, D. Falkowitz, A. Farkas, A. Fenton, B. A. Froberg, J. F. Furmaga, M. Ganetsky, F. Garlich, A. J. Geib, R. Gorodetsky, S. Greene, H. A. Greller, D. D. Gummin, K. Hart, R. G. Hendrickson, S. Hernandez, C. O. Hoyte, B. S. Judge, Z. Kazzi, W. Kerns, B. D. Kessler, J. King, R. Kirschner, K. C. Kleinschmidt, M. A. Kostic, S. Kusin, J. B. Leikin, J. M. LeRoy, M. Levine, C. Y. Lo, J. A. Lowry, D. Lung, Y. Lurie, J. Maddry, N. Majlesi, A. F. Manini, M. B. Marlin, C. McKay, R. G. McKeever, N. J. McKeown, W. J. Meggs, S. N. Miller, A. Minns, E. Moore, B. W. Morgan, M. E. Mullins, T. M. Nappe, J. N. Nogar, E. Oakley, R. Olmedo, R. Othong, J. Parker-Cote, A. Regina, B. D. Riley, A. Rowden, A. M. Ruha, D. E. Rusyniak, R. Schult, E. S. Schwarz, S. A. Seifert, D. Sessions, J. Shulman, S. C. Smolinske, C. Smollin, M. B. Spyres, A. Steck, S. J. Stellpflug, R. Sullivan, M. S. Toce, M. M. Troendle, D. Vearrier, B. J. Warrick, D. C. Watts, B. K. Wills, B. J. Wolk, and A. E. Zosel

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1 (28.5KB, docx)

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