Meghan B. Spyres

A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

Background SCN5A encodes the α-subunit (Nav1.5) of the principle Na+ channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Nav1.5 channel. Pharmacological targeting of mutation-altered Na+ channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults. Methods and Results Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na+ channel blockers flecainide and mexiletine. Our goal was to determine the Na+ channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na+ channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na+ channels revealed significant changes in channel biophysics, all contributing to the probands phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically. Significance The results of our study provide further evidence of the grave vulnerability of newborns to Na+ channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young.

Toxin-Induced Cardiovascular Failure

Adverse cardiovascular events comprise a large portion of the morbidity and mortality in drug overdose emergencies. Adverse cardiovascular events encountered by emergency physicians treating poisoned patients include myocardial injury, hemodynamic compromise with shock, tachydysrhythmias, and cardiac arrest. Early signs of toxin-induced cardiovascular failure include bradycardia, tachycardia, and specific ECG findings. Treatment of toxicologic tachycardia relies on rapid supportive care along with proper use of benzodiazepines for sedation. Treatment of toxicologic bradycardia consists of the use of isotonic fluids, atropine, calcium salts, and glucagon. High-dose insulin euglycemia should be used early in the course of suspected severe poisoning and intravenous lipid emulsion given to patients who suffer cardiac arrest.

The Epidemiology, Clinical Course, and Management of Snakebites in the North American Snakebite Registry

The American College of Medical Toxicology established the North American Snakebite Registry (NASBR), a national database of detailed, prospectively collected information regarding snake envenomation in the United States, in 2013. This report describes the epidemiology, clinical course, and management of snakebites in the NASBR. All cases entered into the NASBR between January 1, 2013 and December 31, 2015 were identified. Descriptive statistics are used to report results. Fourteen sites in 10 states entered 450 snakebites. Native species comprised 99% of cases, almost all of which were pit viper bites. 56.3% were identified as rattlesnakes and 29.4% as copperheads. 69.3% were male and 28.2% were children age 12 and under. Fifty-four percent of bites were on the lower extremity. Twenty-seven percent of patients with lower extremity bites were not wearing shoes. Common tissue findings associated with envenomation were swelling, ecchymosis, and erythema. Systemic effects and hematologic toxicity were more common in rattlesnake than copperhead or cottonmouth envenomations. Crotalidae Polyvalent Immune Fab antivenom was given to 84% of patients. Twelve patients (4.3%) were re-admitted to the hospital after completion of treatment. Eight were re-treated with antivenom. The NASBR gathers detailed data on venomous snakebites across the US. In its initial years, useful information has already been gained. Data regarding footwear will inform public health interventions and education, and information regarding the clinical presentation may help physicians better anticipate effects and manage snakebite. As the number of cases in the NASBR grows, associations between patient-related factors and outcomes may be studied.

Measurement of Mitochondrial Respiration and Motility in Acute Care Sepsis, Trauma, and Poisoning

Metabolic biomarkers have potentially wider use in disease diagnosis and prognosis as well as in monitoring disease response to treatment. While biomarkers such as interleukins, microRNA, and lactate have been proposed for disease surveillance, there are still conflicting results regarding their clinical utility. Treatment of commonly encountered disease of acute care such as sepsis, trauma, and poisoning often relies on clinical diagnosis and therapy guided by use of surrogate markers of illness severity. The measurement of mitochondrial function, including respiration and motility, may offer superior alternatives to such markers. Assessing mitochondrial function in a clinical context has the potential to impact the area of acute care in terms of diagnosis, prognosis, and treatment. The study of mitochondrial bioenergetics has become critical in understanding the pathophysiology and treatment of complex diseases such as diabetes and cardiovascular disorders.

Epidemiology and clinical outcomes of snakebite in the elderly: a ToxIC database study*

Abstract Introduction: Epidemiologic studies of snakebites in the United States report typical victims to be young men. Little is known regarding other demographics including children and the elderly. The objective of this study was to describe the epidemiology and clinical manifestations of snake bite in elderly patients reported to the ToxIC (Toxicology Investigators Consortium) North American Snakebite Registry (NASBR) Methods: This was a multicenter analysis of a prospectively collected cohort of patients with snakebite reported to the ToxIC NASBR between 1 January 2013 and 31 December 2015. Inclusion criterion was age >65. Variables collected included patient demographics, medical comorbidities, medications, date the case was reported to the registry, location of exposure, bite location, snake species, clinical manifestations, outcomes, and management. Results: Of the 450 cases reported, 30 (6.7%) occurred in elderly patients, with an average age of 74 years. Rattlesnake envenomations were common (93.3%). The majority of patients were men (66.7%) and reported at least one medical comorbidity (83.3%). Most patients were on cardiac medications (60%) and use of antiplatelet or anticoagulant medications was common (33%). Hemotoxicity occurred in 30% of patients on initial presentation and 11.5% of patients on initial follow-up. No clinically significant early or late bleeding was observed. Conclusions: Elderly patients with North American snake envenomation are likely to have co-morbidities and to take medications that may increase their risk for hemotoxicity, however risk of bleeding or other complications was not increased in this group.

Assessing the Effect of a Medical Toxicologist in the Care of Rattlesnake‐envenomated Patients

BACKGROUND Rattlesnake envenomation is an important problem in the United States, and the management of these envenomations can be complex. Despite these complexities, however, the majority of such cases are managed without the involvement of a medical toxicologist. The primary objective of this study was to evaluate the impact of a medical toxicology service (MTS) on the length of stay (LOS) of such patients. METHODS The authors conducted a retrospective study at six centers in California. Patients were included if they were admitted in the 2 years before the establishment of a MTS (pre-MTS) or in the 2 years after the creation of a MTS (post-MTS). RESULTS A total of 300 subjects were included (169 pre-MTS, 131 post MTS). Baseline characteristics between the pre-MTS and post-MTS groups were very similar. The creation of a MTS was associated with a significant reduction in the mean (95% confidence interval) LOS (69.5 [59.1-79.9] hours vs. 48.1 [41.4-54.8] hours). This reduced LOS was not associated with any statistically significant change in readmission rates. CONCLUSION Rattlesnake bite patients treated by a medical toxicologist have a significantly reduced LOS compared to those without direct involvement of a medical toxicologist.

Case 16 Snake Bite to the Hand

Bites from pit vipers (subfamily Crotalinae, including rattlesnakes, copperheads, and cottonmouths) comprise the overwhelming majority of venomous snakebites in the United States. Envenomation by these species causes tissue necrosis, edema, and coagulopathy. Rarely, systemic effects including anaphylaxis may also occur. We report a case of a 52-year-old man who sustained a rattlesnake bite to the hand. This case emphasizes the spectrum of clinical effects seen in rattlesnake bites. We describe appropriate treatment including prehospital care, laboratory testing, indications for antivenom administration, criteria for safe discharge, and necessary follow-up.

Ultrasound to evaluate effectiveness of hyperbaric oxygen therapy

A 45-year-old man developed chest and abdominal pain, vomiting, and right-sided weakness after an accidental ingestion. Upon arrival in the emergency department (ED), the chest pain and weakness had resolved, and vital signs were unremarkable. The patient had persistent abdominal pain and vomiting refractory to antiemetics. An abdominal CT scan was remarkable for severe esophagitis and gastritis, portal venous air, and pneumatosis of the stomach wall with concern for impending gastric rupture. Bedside ultrasound (US) was performed (Fig. 1a). A treatment was administered, and a repeat US was obtained (Fig. 1b). The patient reported drinking approximately 100 mL of 35 % H2O2 that was in an unlabeled water bottle in his refrigerator. H2O2 is available in both dilute (3–9 %) and concentrated (27.5–70 %) forms. Higher concentration H2O2 is typically used in the commercial setting, but is now available in health food stores as ‘‘hyperoxygenation therapy.’’ Although small ingestions of dilute H2O2 typically cause only mild irritation, ingestions of higher concentrations H2O2 can result in significant caustic injury. In addition, each 1 mL 35 % H2O2 liberates approximately 100 mL oxygen upon interaction with tissue catalase, leading to a potential for air embolism and end organ ischemia even in accidental ingestions [1–3]. The use of H2O2 in closed spaces or under high pressure also transmits risk of embolization, and such complications have been reported after irrigation of surgical wounds with lower concentration (3 %) H2O2 [4, 5]. Hyperbaric oxygen therapy (HBOT) at 3 atmospheres was pursued. Thirty minutes prior to HBOT, bedside US demonstrated portal venous air (Fig. 1a). The pain resolved during HBOT, and repeat US 30 min after treatment showed resolution of portal venous air (Fig. 1b). Indications for HBOT after H2O2 ingestion are not standardized. Though controversial, some recommend prophylactic HBOT for the presence of portal venous air [3]. In these cases, repeat CT imaging is often obtained to document resolution of air after HBOT, exposing patients to additional radiation. US may be an easy, radiation-free alternative to detect and show resolution of air in the cases of H2O2 ingestion. & Meghan B. Spyres mspyres@gmail.com

Limitations of the evidence supporting use of undetectable acetaminophen levels obtained <4 hours post-ingestion to rule out toxicity

Sir,We thank our esteemed colleagues for this important and thoughtful paper addressing the utilization of early acetaminophen concentrations [1]. For those of us frequently asked to interpret an e...

Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications

Study objective: In recent years, the use of novel anticoagulants and antiplatelet agents has become widespread. Little is known about the toxicity and bleeding risk of these agents after acute overdose. The primary objective of this study is to evaluate the relative risk of all bleeding and major bleeding in patients with acute overdose of novel antiplatelet and anticoagulant medications. Methods: This study is a retrospective study of acute ingestion of apixaban, clopidogrel, ticlopidine, dabigatran, edoxaban, prasugrel, rivaroxaban, and ticagrelor reported to 7 poison control centers in 4 states during a 10‐year span. The prevalence of bleeding for each agent was calculated, and hemorrhage was classified as trivial, minor, or major. Results: A total of 322 acute overdoses were identified, with the majority of cases involving clopidogrel (260; 80.7%). Hemorrhage occurred in 16 cases (4.9%), including 7 cases of clopidogrel, 6 cases of rivaroxaban, 2 cases of dabigatran, and 1 case of apixaban. Most cases of hemorrhage were classified as major (n=9). Comparing the novel anticoagulants with the P2Y12 receptor inhibitors, the relative risk for any bleeding with novel anticoagulant was 6.68 (95% confidence interval 2.63 to 17.1); the relative risk of major bleeding was 18.1 (95% confidence interval 3.85 to 85.0). Conclusion: Acute overdose of novel anticoagulants or antiplatelet agents is associated with a small risk of significant hemorrhage. The risk is greater with the factor Xa inhibitors and direct thrombin inhibitors than with the P2Y12 receptor antagonists.