A Decade in Review: Trends in Female Authorship in Peer-Reviewed Toxicology Journals.

BACKGROUND: Gender diversity in both emergency medicine and medical toxicology has grown over the last decade. However, disparities in promotion, awards, and speakership still exist. No studies have examined gender disparities in authorship in medical toxicology journals. RESEARCH QUESTIONS: Does the proportion of female first authors and female senior authors in medical toxicology publications increase over time? What factors predict female authorship in the first author or last author positions in two major medical toxicology journals? METHODS: We performed a retrospective review of all non-abstract publications in two medical toxicology journals, Clinical Toxicology and Journal of Medical Toxicology, between 2011 and 2020. We collected author names, number of authors, publication type, and publication year. Author names were used to identify author gender using Gender-API integrative tool. Data on the percentages of female medical toxicology fellows and medical toxicologists was provided by the American Board of Emergency Medicine (ABEM). RESULTS: A total of 2212 publications were reviewed and 2171 (97.9%) were included in the dataset. Overall, 31.7% of first authors were identified as female and 67.0% were identified as male by the Gender-API tool. There were 46.8% male-male author dyads, 24.2% female-male author dyads, 12.1% male-female author dyads, and 5.7% female-female author dyads. Predictors of female first authorship included research and case report articles, and percentage of ABEM female toxicologists. Predictors of female senior authorship included number of authors and percentage of ABEM female toxicologists. The proportion of female authorship in both categories increased over the study period. CONCLUSIONS: The frequency of female authorship in the first author position has grown over the last decade and is associated with increasing female representation in medical toxicology and specific manuscript subtypes, specifically research manuscripts.

Pediatric Methamphetamine Toxicity: Clinical Manifestations and Therapeutic Use of Antipsychotics-One Institution's Experience.

INTRODUCTION: Methamphetamine toxicity is common in the Southwest region of the United States and presents diagnostic and treatment challenges in the pediatric population. The aim of our study was to characterize signs and symptoms of methamphetamine toxicity in pediatric patients, highlighting manifestations unique to this population. Additionally, our study sought to evaluate treatment modalities, specifically antipsychotics, in this population with the intent to characterize their adverse effects. METHODS: This is a retrospective review of pediatric patients (age > 2 months ≤ 18 years) at a tertiary care pediatric hospital with ICD-9 or ICD-10 codes suggestive of stimulant exposure between September 1, 2010, and July 31, 2017. Patients with clinical manifestations of sympathomimetic toxicity and confirmation of methamphetamine on urine drug testing via GC/MS were included. Nature, source, and route of exposure along with clinical manifestations including signs, complications, treatments utilized, and adverse events related to treatment were recorded. Specifically, adverse effects following administration of antipsychotics were studied. RESULTS: Seventy-nine patients met inclusion criteria: median age 2.0 years. Typical manifestations of sympathomimetic toxicity were common, including tachycardia (93.4%), hypertension (85.7%), agitation (79.7%), and abnormal motor activity (55.8%). The prominence of gastrointestinal signs (26.3%) and unique abnormal motor activity were notable. The most common treatments were intravenous fluids (96.1%) and benzodiazepines (77.9%). Antipsychotics were administered in 40.5% of cases, with haloperidol used in the majority. No patients developed seizures, dystonia, torsades de pointes, or hyperthermia after antipsychotic administration. CONCLUSIONS: Pediatric patients with methamphetamine toxicity commonly manifest sympathomimetic signs. Antipsychotics were often used as an adjunct treatment in this cohort of patients, and no adverse events were reported. Clinicians should be aware of prominent gastrointestinal signs and abnormal motor activity and neurologic manifestations unique to pediatric patients that will assist in making the correct diagnosis in cases of suspected methamphetamine toxicity.

One Bite, Two Patients: Disparate Clinical Courses Following Simultaneous Crotalus oreganus abyssus Envenomation.

A number of crotaline species have been associated with neurotoxic envenomation in North America. One clinical sign that can occur is myokymia: fine, involuntary, wave-like muscle movements occurring at regular intervals. We report an unusual scenario in which a single snakebite resulted in simultaneous envenomation of 2 patients. Both developed myokymia, with 1 having respiratory compromise. One patient also developed a hypersensitivity reaction to antivenom. Envenomation by the Grand Canyon rattlesnake, Crotalus oreganus abyssus, can produce significant neurotoxicity and resultant respiratory compromise. Antivenom may be helpful but can produce hypersensitivity reactions.

The Relationship Between Circulating Acetaminophen-Protein Adduct Concentrations and Alanine Aminotransferase Activities in Patients With and Without Acetaminophen Overdose and Toxicity.

INTRODUCTION: Measurement of serum acetaminophen-protein adducts (APAP-CYS) has been suggested to support or refute a diagnosis of acetaminophen (APAP)-induced hepatotoxicity when ingestion histories are unreliable or unavailable and when circulating APAP concentrations are low or undetectable. Non-APAP overdose patients commonly have used APAP products in non-toxic quantities and, thus, will have measurable APAP-CYS concentrations, even when hepatic injury results from other causes, such as ischemic hepatitis. The relationship between alanine aminotransferase (ALT) activity and APAP-CYS concentration might assist in distinguishing between toxic and non-toxic APAP doses in patients suspected of drug overdose. METHODS: We measured serial levels of serum APAP-CYS and ALT activities in 500 overdose patients in whom APAP toxicity was suspected on inpatient admission, but who were then classified at time of discharge and before results of APAP-CYS concentrations were available into three groups: 1) definite APAP group; 2) definitely not APAP group; and 3) indeterminate group. Subjects in the definite and definitely not APAP groups were selected in whom a plasma ALT activity was measured within ± 4 h of a serum APAP-CYS concentration. Regressions with correlation coefficients between APAP-CYS and ALT were calculated for repeat measures in the 335 subjects (908 blood samples) in the definite APAP group and 79 subjects (231 samples) in the definitely not APAP group, with an emphasis on APAP-CYS concentrations and calculation of 95% prediction intervals when ALT was ≥ 1000 IU/L. RESULTS: A strong correlation was found between APAP-CYS and ALT in the definite APAP group over all ALT activities (r = 0.93, p < 0.001; N = 335), and when ALT was > 1000 IU/L (r = 0.82, p < 0.001, N = 144). In the 79 definitely not APAP subjects, no significant correlation was found when ALT exceeded 1000 IU/L (r = 0.04; p = 0.84, N = 32). All subjects in the definitely not APAP group displayed APAP-CYS concentrations < 3 µM. In definitely not APAP subjects, the great majority of APAP-CYS levels were below the 95% prediction interval for APAP-CYS concentrations in definite APAP group subjects when ALT was ≥ 1000 IU/L. However, some definitely not APAP group subjects who had ingested non-toxic doses of APAP displayed APAP-CYS concentrations as high as 2.8 µM in the face of ALT elevation from ischemic hepatitis. CONCLUSION: The interpretation of serum APAP-CYS concentrations must always be made in light of detailed clinical information and the population being tested, especially because of some overlap in APAP-CYS levels in subjects with and without APAP toxicity.

Severe bark scorpion envenomation in adults.

INTRODUCTION: The preponderance of medical literature regarding severe bark scorpion envenomation describes pediatric patients; however, the majority (>66%) of annual poison center calls pertain to adults. This retrospective review sought to evaluate the clinical manifestations of adults with severe Centruroides sculpturatus envenomation and determine if significant morbidity occurred. METHODS: This is a retrospective review of adults presenting to a single tertiary referral center with Grade-III or Grade-IV scorpion envenomation from 1 January 2007 to 3 March 2013. The primary objective is to describe clinical findings, treatment strategies, complications and short-term outcomes. RESULTS: Thirty-three patients were included; 61% were female (20/33), average age was 40.7 (19-81) years. The average time to healthcare facility was 142 (14-720) minutes. The most common signs and symptoms of envenomation were: pain/paresthesias 94%, opsoclonus 82%, excessive motor activity 76%, visual disturbance 76%. Benzodiazepines 85% (29/33) and opioids 83% (28/33) were the most frequently used agents to control envenomation. Cardiac evaluation was performed in 24% of patients, 6% were pregnant and underwent fetal monitoring, 6% were intubated and 3% developed rhabdomyolysis. Average length of stay (LOS) was 28.3 (1.5-307) hours; 58% (19/33) required hospital admission. Four patients had LOS >48 h, with pre-existing cardiac disease, substance misuse disorder, acute ethanol withdrawal and medical errors identified as factors contributing to prolonged LOS. CONCLUSIONS: Bark scorpion envenomation in adults may be severe, necessitating medical intervention and hospital admission. Comorbid conditions and complications arising from treatment may contribute to prolonged LOS.

Comparison of Prothrombin Time and Aspartate Aminotransferase in Predicting Hepatotoxicity After Acetaminophen Overdose.

Despite decades of experience with acetaminophen (APAP) overdoses, it remains unclear whether elevated hepatic transaminases or coagulopathy develop first. Furthermore, comparison of the predictive value of these two variables in determining hepatic toxicity following APAP overdoses has been poorly elucidated. The primary objective of this study is to determine the test characteristics of the aspartate aminotransferase (AST) and the prothrombin time (PT) in patients with APAP toxicity. A retrospective chart review of APAP overdoses treated with IV N-acetylcysteine at a tertiary care referral center was performed. Of the 304 subjects included in the study, 246 with an initial AST less than 1000 were analyzed to determine predictors of hepatic injury, defined as an AST exceeding 1000 IU/L. The initial AST >50 was 79.5 % sensitive and 82.6 % specific for predicting hepatic injury. The corresponding negative and positive predictive values were 95.5 and 46.3 %, respectively. In contrast, an initial abnormal PT had a sensitivity of 82.1 % and a specificity of 63.6 %. The negative and positive predictive values for initial PT were 94.9 and 30.2 %, respectively. Although the two tests performed similarly for predicting a composite endpoint of death or liver transplant, neither was a useful predictor. Initial AST performed better than the initial PT for predicting hepatic injury in this series of patients with APAP overdose.

Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose.

Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 µM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back-extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP-CYS, suggesting approximate APAP-protein adduct molecular weights ≥ 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts.

Prevalence of Rhabdomyolysis in Sympathomimetic Toxicity: a Comparison of Stimulants.

Synthetic cathinones have emerged as popular drugs of abuse and produce sympathomimetic toxicity. It is unknown if rhabdomyolysis occurs more frequently following the use of synthetic cathinones compared to other stimulants. This retrospective study sought to determine the prevalence of rhabdomyolysis in patients with sympathomimetic toxicity and compare rates among patients using specific agents. Patients greater than 14 years of age with sympathomimetic toxicity and detection of a stimulant agent in urine via gas chromatography-mass spectroscopy (GC-MS) were included. Patients were excluded if clinical sympathomimetic toxicity was not present, a serum creatine kinase (CK) was not measured, or urine GC-MS was not performed. Rhabdomyolysis and severe rhabdomyolysis were defined as CK > 1000 and 10,000 IU/L, respectively. Prevalence of rhabdomyolysis and severe rhabdomyolysis were reported. Logistic regression was performed to determine the relative effect in single-agent exposures of a synthetic cathinone compared to other sympathomimetics on rhabdomyolysis. A secondary outcome, a composite endpoint defined as need for mechanical ventilation, renal replacement therapy, development of compartment syndrome, or death, was also analyzed. One hundred two subjects met inclusion criteria; median age (IQR) was 32 (25-42) years with a range of 14-65 years; 74 % were male. Rhabdomyolysis occurred in 42 % (43/102) of subjects. Patients whose sympathomimetic toxicity could be ascribed to a single agent were considered for further statistical analysis and placed into four groups: methamphetamine (n = 55), synthetic cathinone (n = 19), cocaine (n = 9), and other sympathomimetic (n = 6). In 89 subjects with single stimulant exposure, the prevalence of rhabdomyolysis was as follows: synthetic cathinone, 12/19 (63 %); methamphetamine, 22/55 (40 %); cocaine, 3/9 (33 %); and other single agent, 0/6 (0 %). The occurrence of severe rhabdomyolysis (CK > 10,000 IU/L) for each of the four groups was synthetic cathinone with 5/19 (26 %), methamphetamine with 2/55 (3.6 %), cocaine with 1/9 (11 %), and other with 0/6 (0 %). Median maximal CK (range) by groups was as follows: synthetic cathinone, 2638 (62-350,000+) IU/L; methamphetamine, 665 (61-50,233) IU/L; cocaine, 276 (87-25,614) IU/L; and other, 142 (51-816) IU/L. A statistically significant difference (p = 0.004) was found when comparing maximal CK among the four groups. Exposure to a synthetic cathinone compared with other sympathomimetics was associated with increased risk of developing rhabdomyolysis and severe rhabdomyolysis with odds ratios of 3.09 and 7.98, respectively. In this cohort of patients with sympathomimetic toxicity, 42 % developed rhabdomyolysis. Synthetic cathinones were associated with an increased risk of rhabdomyolysis and severe rhabdomyolysis compared with other stimulants.

Methemoglobinemia after a mediastinal stab wound.

BACKGROUND: Methemoglobinemia is a relatively common, potentially fatal syndrome resulting from oxidative stress. Of the numerous causes identified, toxins are the most common precipitating event. OBJECTIVES: Describe methemoglobinemia after a stab wound in a man with previously undiagnosed cytochrome b5 reductase deficiency. CASE REPORT: In this case report, we describe a 27-year-old man with no past medical history who developed clinically significant methemoglobinemia after a mediastinal stab wound. After an extensive toxicologic work-up failed to reveal the etiology of the symptoms, genetic testing was performed, which revealed the individual to have a previously undiagnosed cytochrome b5 reductase deficiency. It is hypothesized that the physiologic stress from the expanding mediastinal stab wound resulted in enough oxidative stress to cause methemoglobinemia in this predisposed individual. A discussion of methemoglobinemia ensues. CONCLUSION: This case describes an uncommon presentation of a common toxicologic condition and presents a discussion regarding the evaluation, management, and pathophysiology of methemoglobinemia.

Obstetric toxicology: teratogens.

The emergency physician frequently encounters women who seek care because of pregnancy- and nonpregnancy-related complaints. Many medications are safe for use during pregnancy, including several that are listed as potential teratogens based on the Food and Drug Administration's (FDA) pregnancy classification; but it is important that the emergency physician know and recognize which drugs can be given in pregnancy and which drugs are absolutely contraindicated. Expert resources should be identified and used because the FDA's classification of drugs based on pregnancy risk does not represent the most up-to-date or accurate assessment of a drug's safety.

Toxicology in the ICU: Part 2: specific toxins.

This is the second of a three-part series that reviews the generalized care of poisoned patients in the ICU. This article focuses on specific agents grouped into categories, including analgesics, anticoagulants, cardiovascular drugs, dissociative agents, carbon monoxide, cyanide, methemoglobinemia, cholinergic agents, psychoactive medications, sedative-hypnotics, amphetamine-like drugs, toxic alcohols, and withdrawal states. The first article discussed the general approach to the toxicology patient, including laboratory testing; the third article will cover natural toxins.

Cardiotoxicity and serotonin syndrome complicating a milnacipran overdose.

Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor, recently approved for use in the USA for treatment of fibromyalgia. This case report describes a 59-year-old woman who ingested 3,000 mg of milnacipran in a suicide attempt. Following the ingestion, she became obtunded and developed autonomic instability. She required mechanical ventilation, treatment for hypertension, and then ultimately vasopressor support for refractory hypotension. In addition, she developed a transient, acute cardiac dysfunction with global hypokinesis and an ejection fraction of 30%. Resolution of the cardiac dysfunction was documented on repeat echocardiogram 2 days after the initial study. This was confirmed by cardiac catheterization performed 4 days after the acute ingestion in which coronary arteriogram was normal and left ventricular ejection fraction was 70%. Acute overdose was confirmed by quantification of plasma milnacipran concentration of 8,400 ng/mL obtained 5 h post-ingestion. To our knowledge, this represents the first case of cardiac toxicity complicating a milnacipran overdose in the medical literature.

Acute tacrolimus toxicity in a non-transplant patient.

INTRODUCTION: Tacrolimus is an immunosuppressant widely used in recipients of solid organ transplants to prevent rejection. Toxicity is usually reported in transplant patients. We report the first case of tacrolimus toxicity in a non-transplant patient. CASE REPORT: A 42 year-old, 48 kg woman complained of neck pain following a motor vehicle collision and was admitted for observation. On examination, her pulse was 112 beats/minute and her blood pressure 188/134 mmHg. Because the hypertension and tachycardia might be ethanol withdrawal, she was admitted and treated with multivitamins, folate, and thiamine in her maintenance fluids. She was discharged after 4 days in hospital. The day after her discharge, she was asked to return after it was discovered that she had inadvertently received tacrolimus (total of 400 mg) instead of thiamine. She was admitted with non-oliguric renal failure and metabolic acidosis. A tacrolimus concentration 27 hours after her last exposure was 96.8 ng/mL (therapeutic 5 to 20 ng/mL). Treatment was supportive and she was discharged after 4 days without sequellae. DISCUSSION: Our patient's tacrolimus dose was 2.1 mg/kg/day for 4 days (therapeutic 0.03 to 0.05 mg/kg/day). Her tacrolimus elimination half-life was 16.5 hours, compared to a mean half-life in healthy volunteers of 34.2 +/- 7.7 hours. CONCLUSION: Clinical toxicity, similar to that seen in transplant patients, can develop in non-transplant patients following intravenous administration of supra-therapeutic doses of tacrolimus.

Cerebrovascular and cardiovascular complications of alcohol and sympathomimetic drug abuse.

Alcohol and stimulant abuse represents a major cause of cerebrovascular and cardiovascular disease in young adults. Although mild-to-moderate alcohol consumption has been linked to a decreased risk for stroke and CVD, excessive use is associated with an increased risk for intracranial hemorrhage and cardiomyopathy. Cocaine represents the single largest,cause of medical complications related to illegal drug use. Cocaine has been associated with cerebral infarction, intracranial hemorrhage, myocardial infarction, cardiomyopathy, and cardiac arrhythmias. Abuse of amphetamines is associated with complications similar to those of cocaine. The complications associated with stimulant abuse are thought to be primarily mediated through excess catecholamines, resulting in acute arterial hypertension, vasospasm, thrombosis, and accelerated atherosclerosis. Because many complications of alcohol and stimulant abuse are preventable and reversible, it is important to screen for these in patients with cerebrovascular and cardiovascular disease.