Failure of Crotalidae Immune F(ab')2 Equine Antivenom to Achieve Control in a Southern Pacific Rattlesnake Envenomation.

Rattlesnake envenomation can result in significant cutaneous and hematologic toxicity. While Cotalidae polyvalent immune Fab (ovine) antivenom (marketed as CroFab) was available for years, it is associated with increased late hematologic toxicity compared with its predecessor. Consequently, Crotalidae Immune F(ab')2 equine antivenom [marketed as Anavip; F(ab')2AV] has been recently become available. In this paper, we report a case of a 53 year-old man envenomated on his right hand by a Southern Pacific rattlesnake (Crotalus helleri). Edema was present, and his initial platelets were not able to be measured, prompting the administration of 10 vials of F(ab')2AV. Ultimately, he received a total of 52 vials of antivenom, before his platelets peaked at 102,000/µL, 56 hours post envenomation. Within hours, his platelets began to fall again. Ultimately, his platelets reached a post-antivenom nadir of 65,000/µL. He was observed closely as an outpatient without additional antivenom, and ultimately had normalization of his platelets (211,000/µL) 20 days post envenomation. This case is one of the first cases demonstrating an inability to achieve control of the hematologic toxicity following Southern Pacific rattlesnake envenomation after treatment with F(ab')2AV.

Outcomes following Naloxone Administration by Bystanders and First Responders.

Background: Naloxone is widely available to bystanders and first responders to treat patients with suspected opioid overdose. In these patients, the prognostic factors and potential benefits associated with additional naloxone administered by emergency medical services (EMS) are uncertain. Objectives: We sought to identify prognostic factors for admission to the hospital following prehospital administration of naloxone for suspected opioid overdose by bystanders and first responders. We secondarily examined whether administration of additional naloxone by paramedics after initial treatment by non-EMS personnel was associated with improvement in level of consciousness prior to hospital arrival. Methods: This is a retrospective cross-sectional study of patients treated within a single urban EMS system from 2013 to 2016. Inclusion criteria were administration of naloxone by bystanders or first responders and transport to one of three academic medical centers. For the secondary analysis, only patients with a Glasgow Coma Scale (GCS) score ≤12 on paramedic arrival were included. We performed univariate and multivariable analyses examining a primary outcome of hospital admission and secondary outcome of improvement in consciousness as defined by GCS >12 in patients with initial GCS ≤12. Results: Of 359 patients identified for the primary analysis, 60 were admitted to the hospital. Factors associated with increased rate of admission included higher total naloxone dosage (OR 1.36, 95% CI 1.09-1.70) and presence of alternate/additional non-opioid central nervous system (CNS) depressants (OR 2.51, 95% CI 1.13-5.56). Among 178 patients who had poor neurologic status (GCS ≤12) on paramedic arrival following naloxone administered by bystander or first responder, administration of additional naloxone was not associated with a better rate of neurologic improvement prior to hospital arrival (77% improved with additional naloxone, 81% improved without additional naloxone; OR 0.82, 95% CI 0.39-1.76). Conclusions: Among patients with suspected opioid overdose treated with naloxone by bystanders and first responders, a higher total dose of naloxone and polysubstance intoxication with additional CNS depressants were predictors of admission. Administration of additional naloxone by paramedics was not associated with a higher rate of neurologic improvement prior to hospital arrival, suggesting a ceiling effect on naloxone efficacy in opioid overdose.

Pulmonary Complications of Opioid Overdose Treated With Naloxone.

STUDY OBJECTIVE: We aim to determine whether administration of higher doses of naloxone for the treatment of opioid overdose is associated with increased pulmonary complications. METHODS: This was a retrospective, observational, cross-sectional study of 1,831 patients treated with naloxone by the City of Pittsburgh Bureau of Emergency Medical Services. Emergency medical services and hospital records were abstracted for data in regard to naloxone dosing, route of administration, and clinical outcomes, including the development of complications such as pulmonary edema, aspiration pneumonia, and aspiration pneumonitis. For the purposes of this investigation, we defined high-dose naloxone as total administration exceeding 4.4 mg. Multivariable analysis was used to attempt to account for confounders such as route of administration and pretreatment morbidity. RESULTS: Patients receiving out-of-hospital naloxone in doses exceeding 4.4 mg were 62% more likely to have a pulmonary complication after opioid overdose (42% versus 26% absolute risk; odds ratio 2.14; 95% confidence interval 1.44 to 3.18). This association remained statistically significant after multivariable analysis with logistic regression (odds ratio 1.85; 95% confidence interval 1.12 to 3.04). A secondary analysis showed an increased risk of 27% versus 13% (odds ratio 2.57; 95% confidence interval 1.45 to 4.54) when initial naloxone dosing exceeded 0.4 mg. Pulmonary edema occurred in 1.1% of patients. CONCLUSION: Higher doses of naloxone in the out-of-hospital treatment of opioid overdose are associated with a higher rate of pulmonary complications. Furthermore, prospective study is needed to determine the causality of this relationship.

Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning.

OBJECTIVES: Carbon monoxide poisoning affects 50,000 per year in the United States alone. Mortality is approximately 3%, and up to 40% of survivors suffer from permanent neurocognitive and affective deficits. Hyperbaric oxygen therapy has shown benefit on reducing the long-term neurologic sequelae of carbon monoxide poisoning but has not demonstrated improved survival. The objective of this study is to assess the efficacy of hyperbaric oxygen for acute and long-term mortality in carbon monoxide poisoning using a large clinical databank. DESIGN: Retrospective analysis. SETTING: University of Pittsburgh Medical Center healthcare system (Pittsburgh, PA). PATIENTS: One-thousand ninety-nine unique encounters of adult patients with carbon monoxide poisoning. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical information from charting were obtained from the electronic medical record. In propensity-adjusted analysis, hyperbaric oxygen therapy was associated with a reduction in inpatient mortality (absolute risk reduction, 2.1% [3.7-0.9%]; p = 0.001) and a reduction in 1-year mortality (absolute risk reduction, 2.1% [3.8-0.4%]; p = 0.013). CONCLUSIONS: These data demonstrate that hyperbaric oxygen is associated with reduced acute and reduced 1-year mortality. Further studies are needed on the mortality effects of hyperbaric oxygen therapy in carbon monoxide poisoning.

Adjunct Ketamine Use in the Management of Severe Ethanol Withdrawal.

OBJECTIVES: Ketamine offers a plausible mechanism with favorable kinetics in treatment of severe ethanol withdrawal. The purpose of this study is to determine if a treatment guideline using an adjunctive ketamine infusion improves outcomes in patients suffering from severe ethanol withdrawal. DESIGN: Retrospective observational cohort study. SETTING: Academic tertiary care hospital. PATIENTS: Patients admitted to the ICU and diagnosed with delirium tremens by Diagnostic and Statistical Manual of Mental Disorders V criteria. INTERVENTIONS: Pre and post guideline, all patients were treated in a symptom-triggered fashion with benzodiazepines and/or phenobarbital. Postguideline, standard symptom-triggered dosing continued as preguideline, plus, the patient was initiated on an IV ketamine infusion at 0.15-0.3 mg/kg/hr continuously until delirium resolved. Based upon withdrawal severity and degree of agitation, a ketamine bolus (0.3 mg/kg) was provided prior to continuous infusion in some patients. MEASUREMENTS AND MAIN RESULTS: A total of 63 patients were included (29 preguideline; 34 postguideline). Patients treated with ketamine were less likely to be intubated (odds ratio, 0.14; p < 0.01; 95% CI, 0.04-0.49) and had a decreased ICU stay by 2.83 days (95% CI, -5.58 to -0.089; p = 0.043). For ICU days outcome, correlation coefficients were significant for alcohol level and total benzodiazepine dosing. For hospital days outcome, correlation coefficients were significant for patient age, aspartate aminotransferase, and alanine aminotransferase level. Regression revealed the use of ketamine was associated with a nonsignificant decrease in hospital stay by 3.66 days (95% CI, -8.40 to 1.08; p = 0.13). CONCLUSIONS: Mechanistically, adjunctive therapy with ketamine may attenuate the demonstrated neuroexcitatory contribution of N-methyl-D-aspartate receptor stimulation in severe ethanol withdrawal, reduce the need for excessive gamma-aminobutyric acid agonist mediated-sedation, and limit associated morbidity. A ketamine infusion in patients with delirium tremens was associated with reduced gamma-aminobutyric acid agonist requirements, shorter ICU length of stay, lower likelihood of intubation, and a trend toward a shorter hospitalization.

Multimodal analgesia in crotalid snakebite envenomation: A novel use of femoral nerve block.

Snakebite envenomations occur throughout the United States, with most envenomations resulting from Crotalid bites. These envenomations can result in severe pain despite aggressive analgesia due to effects of venom toxins. We report a case in which we treated a 44- year-old man who sustained a Copperhead (Agkistrodon contortrix) bite to his left hallux with progressive local toxicity, including severe pain radiating into his upper leg, without evidence of compartment syndrome or coagulopathy. His pain was unresponsive to multiple doses of opioids. We performed a fascia iliaca compartment femoral nerve block under dynamic ultrasound guidance with 20 mL of 0.25% bupivacaine, which provided substantial pain relief in his upper leg. To our knowledge, this is a novel application of regional anesthesia with peripheral nerve block. We demonstrate fascia iliaca compartment femoral nerve block may be a safe, beneficial technique for emergency physicians to utilize in providing multimodal analgesia in Crotalid envenomation.

Ricin Poisoning after Oral Ingestion of Castor Beans: A Case Report and Review of the Literature and Laboratory Testing.

BACKGROUND: Ricin is a protein toxin derived from the castor bean plant Ricinus communis. Several cases secondary to its consumption have been published and, more recently, its use as a potential bioterrorism agent has also been reported. Oral absorption of ricin is highly erratic, leading to a wide spectrum of symptoms. In addition, conventional urine drug screening tests will not be able to detect this compound, posing a diagnostic challenge. CASE REPORT: A male teenager intended to die by ingesting 200 castor beans after mixing and blending them with juice. Eight hours later, he presented with weakness, light-headedness, nausea, and vomiting and sought medical treatment. The patient was admitted and treated conservatively. An immune-based standard urine toxicology drug screen panel was reported as negative. A comprehensive untargeted urine drug screen test showed the presence of ricinine, a surrogate marker of ricin intoxication. He was transferred to the psychiatric service 3 days after admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the importance of knowing the peculiar pharmacokinetic properties of ricin after oral ingestion of castor beans and toxin release through mastication. Emergency physicians should be aware that oral absorption of ricin is dependent on several factors, such type and size of seeds and the geographic harvesting region, making it extremely difficult to estimate its lethality based solely on the number of ingested beans. Finally, comprehensive untargeted urine drug screening testing is highly valuable as a diagnostic tool in this context.

A Patient With Alcoholic Ketoacidosis and Profound Lactemia.

BACKGROUND: Alcoholic ketoacidosis (AKA) is a complex syndrome that results from disrupted metabolism in the setting of excessive alcohol use and poor oral intake. Dehydration, glycogen depletion, high redox state, and release of stress hormones are the primary factors producing the characteristic anion gap metabolic acidosis with an elevated ß-hydroxybutyrate (ß-OH) and lactate. CASE REPORT: We present the case of a 47-year-old man who presented to the emergency department with metabolic acidosis and profoundly elevated lactate levels who had AKA. He recovered completely with intravenous fluids and parenteral glucose administration. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should always consider the immediately life-threatening causes of a severe anion gap metabolic acidosis and treat aggressively based on the situation. This case highlights the fact that AKA can present with an impressively elevated lactate levels. Emergency physicians should keep AKA in the differential diagnosis of patients who present with a similar clinical picture.

Heart-Brain 346-7 Score: the development and validation of a simple mortality prediction score for carbon monoxide poisoning utilizing deep learning.

INTRODUCTION: Acute mortality from carbon monoxide poisoning is 1-3%. The long-term mortality risk of survivors of carbon monoxide poisoning is doubled compared to age-matched controls. Cardiac involvement also increases mortality risk. We built a clinical risk score to identify carbon monoxide-poisoned patients at risk for acute and long-term mortality. METHODS: We performed a retrospective analysis. We identified 811 adult carbon monoxide-poisoned patients in the derivation cohort, and 462 adult patients in the validation cohort. We utilized baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical charting information in the electronic medical record in Stepwise Akaike's Information Criteria with Firth logistic regression to determine optimal parameters to create a prediction model. RESULTS: In the derivation cohort, 5% had inpatient or 1-year mortality. Three variables following the final Firth logistic regression minimized Stepwise Akaike's Information Criteria: altered mental status, age, and cardiac complications. The following predict inpatient or 1-year mortality: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. The sensitivity of the score was 82% (95% confidence interval: 65-92%), the specificity was 80% (95% confidence interval: 77-83%), negative predictive value was 99% (95% confidence interval: 98-100%), positive predictive value 17% (95% confidence interval: 12-23%), and the area under the receiver operating characteristic curve was 0.81 (95% confidence interval: 0.74-0.87). A score above the cut-off point of -2.9 was associated with an odds ratio of 18 (95% confidence interval: 8-40). In the validation cohort (462 patients), 4% had inpatient death or 1-year mortality. The score performed similarly in the validation cohort: sensitivity was 72% (95% confidence interval: 47-90%), specificity was 69% (95% confidence interval: 63-73%), negative predictive value was 98% (95% confidence interval: 96-99%), positive predictive value was 9% (95% confidence interval: 5-15%) and the area under the receiver operating characteristic curve was 0.70 (95% confidence interval: 60%-81%). CONCLUSIONS: We developed and validated a simple, clinical-based scoring system, the Heart-Brain 346-7 Score to predict inpatient and long-term mortality based on the following: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. With further validation, this score will hopefully aid decision-making to identify carbon monoxide-poisoned patients with higher mortality risk.

Ethylene glycol elimination kinetics and outcomes in patients managed without hemodialysis.

STUDY OBJECTIVE: Ethylene glycol remains an important toxic cause of metabolic acidosis and acute renal failure. Traditionally, inhibition of alcohol dehydrogenase along with hemodialysis has been used for treatment. Because of reported long elimination half-life of ethylene glycol during alcohol dehydrogenase inhibition, hemodialysis has been used in patients who are otherwise doing well to clear ethylene glycol. We study ethylene glycol elimination kinetics in patients treated with fomepizole, but without hemodialysis. METHODS: This was a retrospective, multicenter cohort study of patients older than 15 years who were treated at one of 3 medical centers during an 8-year period. Inclusion criteria were peak serum ethylene glycol concentration greater than 20 mg/dL, lack of renal failure on admission, treatment with fomepizole but without hemodialysis, and availability of serial serum ethylene glycol concentrations, allowing calculation of elimination half-life. The primary outcome variable was ethylene glycol elimination half-life; mortality and onset of renal failure were secondary outcome variables. RESULTS: During the study period, 85 patients were treated for ethylene glycol toxicity, of whom 40 met inclusion criteria. The mean serum ethylene glycol elimination half-life was 14.2 hours (SD=3.7 hours; 95% confidence interval 13.1 to 15.3 hours). One patient presented with metabolic acidosis on admission and developed mild transient renal insufficiency but did not require hemodialysis. No patient died. CONCLUSION: The mean elimination half-life of ethylene glycol in this population was shorter than previously reported without hemodialysis, and this select group of patients did well without enhanced elimination by hemodialysis.

Predictors of severe outcome following opioid intoxication in children.

INTRODUCTION: While the opioid crisis has claimed the lives of nearly 500,000 in the U.S. over the past two decades, and pediatric cases of opioid intoxications are increasing, only sparse data exist regarding risk factors for severe outcome in children following an opioid intoxication. We explore predictors of severe outcome (i.e., intensive care unit [ICU] admission or in-hospital death) in children who presented to the Emergency Department with an opioid intoxication. METHODS: In this prospective cohort study we collected data on all children (0-18 years) who presented with an opioid intoxication to the 50 medical centers in the US and two international centers affiliated with the Toxicology Investigators Consortium (ToxIC) of the American College of Medical Toxicology, from August 2017 through June 2020, and who received a bedside consultation by a medical toxicologist. We collected relevant demographic, clinical, management, disposition, and outcome data, and we conducted a multivariable logistic regression analysis to explore predictors of severe outcome. The primary outcome was a composite severe outcome endpoint, defined as ICU admission or in-hospital death. Covariates included sociodemographic, exposure and clinical characteristics. RESULTS: Of the 165 (87 females, 52.7%) children with an opioid intoxication, 89 (53.9%) were admitted to ICU or died during hospitalization, and 76 did not meet these criteria. Seventy-four (44.8%) children were exposed to opioids prescribed to family members. Fentanyl exposure (adjusted OR [aOR] = 3.6, 95% CI: 1.0-11.6; p = 0.03) and age ≥10 years (aOR = 2.5, 95% CI: 1.2-4.8; p = 0.01) were independent predictors of severe outcome. CONCLUSIONS: Children with an opioid toxicity that have been exposed to fentanyl and those aged ≥10 years had 3.6 and 2.5 higher odds of ICU admission or death, respectively, than those without these characteristics. Prevention efforts should target these risk factors to mitigate poor outcomes in children with an opioid intoxication.

Hypoglycemia after accidental pediatric sulfonylurea ingestions.

BACKGROUND: Because the prevalence of type 2 diabetes increases annually, there has been an increase in pediatric exposures to sulfonylureas. These medications are associated with delayed and often prolonged hypoglycemia. As such, most authorities but not all recommend admission for all pediatric patients with an accidental sulfonylurea ingestion. METHODS: This study is a retrospective chart review of all pediatric patients with sulfonylurea exposures admitted for 9 years at an urban, pediatric teaching hospital. The incidence and characteristics of the hypoglycemia were recorded and analyzed. RESULTS: During this time span, 93 patients with accidental sulfonylurea exposures were admitted, with a median age of 1.83 years. Glyburide and glipizide accounted for most sulfonylureas. Hypoglycemia (blood glucose level <50 mg/dL) developed in 25 (58.1%) of 43 patients who ingested glipizide, compared with 10 (25.6%) of 39 patients who ingested glyburide. The overall incidence of hypoglycemia was 44%. Hypoglycemia was more likely to occur with glipizide ingestion than glyburide (odds ratio, 3.89 [95% confidence interval, 1.51-9.98]). No patient with a known time of ingestion developed hypoglycemia after 13 hours. CONCLUSIONS: Hypoglycemia is common after accidental sulfonylurea exposures. The results of this study support mandatory admission to a monitored setting for at least 16 hours, with frequent glucose determinations.

Single versus continued dosing of fomepizole during hemodialysis in ethylene glycol toxicity.

BACKGROUND: In cases of ethylene glycol (EG) toxicity requiring hemodialysis (HD), fomepizole is dosed every four hours. HD efficiently clears EG and its toxic metabolites, and it's unclear if multiple doses (MD) of fomepizole improve patient outcomes or whether a single dose (SD) prior to initiation of HD is sufficient. METHODS: We reviewed cases of EG toxicity at a toxicology referral center from 2008 to 2018. Patients treated with HD with EG levels greater than 20 mg/dL were included. Duration of dialysis, creatinine at discharge, hospital length of stay (LOS), and complications were analyzed. We compared patients who received a single dose of fomepizole prior to HD to those who received continued dosing during and after HD. RESULTS: Twenty-five patient encounters were identified (MD: 20; SD: 5). Initial bicarbonate (11 [SD] vs. 9 mg/dL [MD]) and pH (7.1 vs. 7.1) were similar between the groups; however, there was a trend toward a greater proportion of patients with renal dysfunction in the MD group: 11 (55%) vs. 1 (20%). HD was initiated a median interval of 5.2 h [SD] vs. 5.7 h [MD] after a dose of fomepizole. There was one death in the MD group and none in the SD group. Median creatinine on the day of discharge was 0.7 mg/dL (IQR: 0.57-3.8) in the SD group and 2.0 mg/dL (0.90-7.0) in the MD group. LOS was similar (5.8 days [95% CI 3.6-8.0] vs. 7.6 days [5.3-9.9]) (p = .61). CONCLUSION: Patients with moderately severe EG toxicity (acidosis and no initial renal dysfunction) treated with a single dose of fomepizole prior to HD had similar outcomes to those receiving continued dosing of fomepizole during or after HD. This raises the possibility that a single dose of fomepizole may be sufficient if HD is initiated quickly.

Drug-specific risk of severe QT prolongation following acute drug overdose.

Background: Severe QT prolongation (SQTP) has been identified as a strong predictor of adverse cardiovascular events in acute drug overdose, but drug-specific causes of SQTP in the setting of acute drug overdose remain unclear. We aimed to perform the most definitive study to date describing drug-specific risk of SQTP following acute drug overdose.Methods: This was a prospective multicenter cohort study at >50 hospital sites across the US using the ToxIC Registry between 2015 and 2018. Inclusion criteria were adults (≥18 years) receiving medical toxicology consultation for acute drug overdose. The primary outcome was SQTP, which was defined using the computer automated Bazett QT correction (QTc) on the ECG with the previously validated cut point of 500 milliseconds. Mean difference in QTc was also calculated for specific drugs. Drugs associated with SQTP were analyzed using multivariable logistic regression to control for known confounders of QT risk (age, sex, race, cardiac disease).Results: From 25,303 patients screened, 6473 met inclusion criteria with SQTP occurring in 825 (13%). Drugs associated with increased adjusted odds of SQTP included Class III antidysrhythmics (sotalol), sodium channel blockers (amitriptyline, diphenhydramine, doxepin, imipramine, nortriptyline), antidepressants (bupropion, citalopram, escitalopram, trazodone), antipsychotics (haloperidol, quetiapine), and the antiemetic serotonin antagonist ondansetron.Conclusions: This large US cohort describes drug-specific risk of SQTP following acute drug overdose. Healthcare providers caring for acute drug overdoses from any of these implicated drugs should pay close attention to cardiac monitoring for occurrence of SQTP.

Chemoinformatic methods for predicting interference in drug of abuse/toxicology immunoassays.

BACKGROUND: Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limited by cross-reacting compounds able to bind to the antibodies in a manner similar to the target molecule(s). To date, there has been little systematic investigation using computational tools to predict cross-reactive compounds. METHODS: Commonly used molecular similarity methods enabled calculation of structural similarity for a wide range of compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target molecules of DOA/toxicology screening assays. We used various molecular descriptors (MDL public keys, functional class fingerprints, and pharmacophore fingerprints) and the Tanimoto similarity coefficient. These data were then compared with cross-reactivity data in the package inserts of immunoassays marketed for in vitro diagnostic use. Previously untested compounds that were predicted to have a high probability of cross-reactivity were tested. RESULTS: Molecular similarity calculated using MDL public keys and the Tanimoto similarity coefficient showed a strong and statistically significant separation between cross-reactive and non-cross-reactive compounds. This result was validated experimentally by discovery of additional cross-reactive compounds based on computational predictions. CONCLUSIONS: The computational methods employed are amenable toward rapid screening of databases of drugs, metabolites, and endogenous molecules and may be useful for identifying cross-reactive molecules that would be otherwise unsuspected. These methods may also have value in focusing cross-reactivity testing on compounds with high similarity to the target molecule(s) and limiting testing of compounds with low similarity and very low probability of cross-reacting with the assay.

Using molecular similarity to highlight the challenges of routine immunoassay-based drug of abuse/toxicology screening in emergency medicine.

BACKGROUND: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class. METHODS: Molecular similarity analysis, a computational method commonly used in drug discovery, was used to calculate structural similarity of a wide range of clinically relevant compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target ('antigenic') molecules of DOA/Tox screening tests. These results were compared with cross-reactivity data in the package inserts of immunoassays marketed for clinical testing. The causes for false positives for phencyclidine and tricyclic antidepressant screening immunoassays were investigated at the authors' medical center using gas chromatography/mass spectrometry as a confirmatory method. RESULTS: The results illustrate three major challenges for routine DOA/Tox screening immunoassays used in emergency medicine. First, for some classes of drugs, the structural diversity of common drugs within each class has been increasing, thereby making it difficult for a single assay to detect all compounds without compromising specificity. Second, for some screening assays, common 'out-of-class' drugs may be structurally similar to the target compound so that they account for a high frequency of false positives. Illustrating this point, at the authors' medical center, the majority of positive screening results for phencyclidine and tricyclic antidepressants assays were explained by out-of-class drugs. Third, different manufacturers have adopted varying approaches to marketed immunoassays, leading to substantial inter-assay variability. CONCLUSION: The expanding structural diversity of drugs presents a difficult challenge for routine DOA/Tox screening that limit the clinical utility of these tests in the emergency medicine setting.