Introduction:Lead is an environmental toxin that may cause severe damage to vital organs including the brain, kidneys, liver, and bones. Children are particularly susceptible due to higher rates of gastrointestinal absorption and detrimental effects of lead on their developing nervous systems. Methods:This report highlights the case of a 4-year-old boy with severe lead poisoning resulting from prolonged exposure to ayurvedic herbal supplements. Results:The child was initially admitted with anemia, arterial hypertension, abdominal pain, and mild neurological impairment. His blood smear revealed pronounced basophilic stippling of erythrocytes. His venous blood lead level (BLL) was markedly elevated at 123 μg/dl. Detailed review of his history uncovered that he had been ingesting an ayurvedic herbal medicine for asthma. He received chelation therapy with 2,3-dimercapto-1-propanesulfonic acid and calcium disodium EDTA, resulting in rapid resolution of symptoms and gradually decreasing BLLs. Conclusions:The case is a striking example of the significant health risks due to heavy metal contamination in ayurveda products. Better strategies to control the composition of ayurvedic products and educate families about their possible heavy metal contamination are essential to reduce the risk of lead poisoning.

INTRODUCTION:Chlorfenapyr, a N-substituted halogenated pyrrole, is a broad-spectrum insecticide. The insecticidal activity of chlorfenapyr depends on its biotransformation by hepatic cytochrome P450 monooxygenases to tralopyril, which uncouples mitochondrial oxidative phosphorylation and disrupts adenosine triphosphate production. Neither the metabolism of chlorfenapyr nor the mechanism of tralopyril is completely elucidated. Acute human chlorfenapyr poisoning is not well characterized, and best practice in management following acute exposure is unclear. The purpose of this review is to characterize acute human chlorfenapyr poisoning by its clinical course, laboratory investigations, and imaging findings and propose a management plan for acute human chlorfenapyr exposure. METHODS:We systematically searched PubMed, Web of Science, Google Scholar, and EMBASE from inception to April 2024 across all languages for human chlorfenapyr and tralopyril cases, with descriptions of exposure, clinical manifestations, and clinical course included. Only manuscripts and abstracts from scientific conferences with sufficient clinical data following acute human exposures were included. In vitro studies, animal studies, agricultural studies, environmental impact studies, and non-clinical human studies were excluded. We then reviewed citations of included studies for additional eligible publications. Non-English publications were translated using Google Translate or primarily translated by our authors. The study adhered to Preferred Reporting for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews. RESULTS:We identified 3,376 publications of which 48 met study inclusion criteria, describing 75 unique cases of human poisoning from ingestion, inhalation, dermal exposure, and intra-abdominal injection of chlorfenapyr. No cases of tralopyril exposure were identified. The median time from exposure to symptom onset was six hours (interquartile range 1-48 hours). The most frequent initial or presenting signs/symptoms included diaphoresis, nausea and/or vomiting, and altered mental status. While hyperthermia (≥38 degrees centigrade) was less common at presentation, hyperthermia developed in 61 percent of all patients and was temporally associated with clinical deterioration and death. Most common laboratory abnormalities included elevated blood creatine kinase activity, hepatic aminotransferase activities, and lactate concentration. Imaging studies of the central nervous system often showed extensive symmetrical white matter abnormalities with swelling. Case fatality was 76 percent, and survivors commonly experienced sustained neurological sequelae. Management strategies were highly varied, and the effectiveness of specific medical interventions was unclear. DISCUSSION:Acute human chlorfenapyr poisoning is characterized by a latent period as long as 14 days, deterioration over hours to days, and can result in serious morbidity and mortality. Development of hyperthermia, likely driven by oxidative phosphorylation uncoupling by tralopyril, is an ominous clinical sign and is temporally associated with clinical decompensation and death. Laboratory abnormalities, particularly elevated creatine kinase activity, hepatic aminotransferase activities, and lactate concentration, were common, but only creatine kinase activity differed amongst survivors and fatalities. Best clinical practice in the management of patients exposed to chlorfenapyr is unclear, and we opine that a conservative approach with close clinical monitoring and supportive care is prudent. LIMITATIONS:The limitations of all reviews include their inherent retrospective and observational nature as well as publication bias that emphasizes severe outcomes, thus impacting the spectrum of illness and skewing mortality percentage. In addition, we interrogated a finite number of databases for publications on human chlorfenapyr exposure and there were limited cases with laboratory testing to confirm chlorfenapyr poisoning. Analysis of our systematic review was not powered to detect differences between groups, comparative statistics were not performed, and significance is not reported. CONCLUSIONS:Acute human chlorfenapyr toxicity is characterized by a latent period following exposure, development of new or progression of established signs/symptoms, potential for critical illness, rapid deterioration, serious morbidity, and mortality. A conservative approach to patient management is prudent.

Two siblings aged 5 and 15 years from Connecticut were hospitalized with petechial rash, oral mucositis, and severe thrombocytopenia approximately 10 days after they played with a jar of elemental mercury they found in their home. Before the mercury exposure was disclosed, the siblings were treated with platelet transfusions, intravenous immune globulin (IVIG) for possible immune thrombocytopenic purpura, and antibiotics for possible infectious causes. When their conditions did not improve after 6 days, poison control facilitated further questioning about toxic exposures including mercury, testing for mercury, and chelation with dimercaptosuccinic acid. The older sibling soon recovered, but the younger child required a prolonged hospitalization for severe thrombocytopenia, ultimately receiving repeated doses of IVIG, steroids, and romiplostim, a thrombopoietin receptor agonist. Close collaboration among multiple agencies was required to identify the extent of mercury contamination, evaluate and treat the other family members, and decontaminate the home. These cases demonstrate the importance of ongoing public health outreach to promote early detection of elemental mercury toxicity, and the need to evaluate for environmental exposures when multiple close contacts experience similar signs and symptoms.

Objectives The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. Methods We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. Results The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower C-max, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. Conclusions Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower C-max and later T-max than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Alcohol-based hand sanitizer is a liquid, gel, or foam that contains ethanol or isopropanol used to disinfect hands. Hand hygiene is an important component of the U.S. response to the emergence of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). If soap and water are not readily available, CDC recommends the use of alcohol-based hand sanitizer products that contain at least 60% ethyl alcohol (ethanol) or 70% isopropyl alcohol (isopropanol) in community settings (1); in health care settings, CDC recommendations specify that alcohol-based hand sanitizer products should contain 60%-95% alcohol (≥60% ethanol or ≥70% isopropanol) (2). According to the Food and Drug Administration (FDA), which regulates alcohol-based hand sanitizers as an over-the-counter drug, methanol (methyl alcohol) is not an acceptable ingredient. Cases of ethanol toxicity following ingestion of alcohol-based hand sanitizer products have been reported in persons with alcohol use disorder (3,4). On June 30, 2020, CDC received notification from public health partners in Arizona and New Mexico of cases of methanol poisoning associated with ingestion of alcohol-based hand sanitizers. The case reports followed an FDA consumer alert issued on June 19, 2020, warning about specific hand sanitizers that contain methanol. Whereas early clinical effects of methanol and ethanol poisoning are similar (e.g., headache, blurred vision, nausea, vomiting, abdominal pain, loss of coordination, and decreased level of consciousness), persons with methanol poisoning might develop severe anion-gap metabolic acidosis, seizures, and blindness. If left untreated methanol poisoning can be fatal (5). Survivors of methanol poisoning might have permanent visual impairment, including complete vision loss; data suggest that vision loss results from the direct toxic effect of formate, a toxic anion metabolite of methanol, on the optic nerve (6). CDC and state partners established a case definition of alcohol-based hand sanitizer-associated methanol poisoning and reviewed 62 poison center call records from May 1 through June 30, 2020, to characterize reported cases. Medical records were reviewed to abstract details missing from poison center call records. During this period, 15 adult patients met the case definition, including persons who were American Indian/Alaska Native (AI/AN). All had ingested an alcohol-based hand sanitizer and were subsequently admitted to a hospital. Four patients died and three were discharged with vision impairment. Persons should never ingest alcohol-based hand sanitizer, avoid use of specific imported products found to contain methanol, and continue to monitor FDA guidance (7). Clinicians should maintain a high index of suspicion for methanol poisoning when evaluating adult or pediatric patients with reported swallowing of an alcohol-based hand sanitizer product or with symptoms, signs, and laboratory findings (e.g., elevated anion-gap metabolic acidosis) compatible with methanol poisoning. Treatment of methanol poisoning includes supportive care, correction of acidosis, administration of an alcohol dehydrogenase inhibitor (e.g., fomepizole), and frequently, hemodialysis.

Vitamin K1 Treatment Duration in Brodifacoum Poisoning The rodenticide brodifacoum, a long-acting vitamin K epoxide cycle antagonist, can produce life-threatening hemorrhage in exposed humans. Its ...

Abrin is a toxin of public health concern due to its lethality, lack of antidote, and potential for use as a bioterrorism agent. Possible routes of exposure include ingestion, inhalation, and injection. Onset of symptoms is often delayed, even in severe cases. In fatal cases, death occurs from multi-organ failure. We describe the clinical course, laboratory, and pathologic findings in a case of fatal human poisoning associated with abrin injection. The Abrus precatorius seeds in this case were obtained via the internet. The Centers for Disease Control and Prevention's Laboratory Response Network detected abrine in the urine confirming abrin exposure in this fatal poisoning.

We read with interest the letter by Hegemann and colleagues1Hegemann I. Ganter C. Widmer C.C. Becker M. Muller D. Spahn D.R. Ongoing redistribution of dabigatran necessitates repetitive application of idarucizumab.Br J Anaesth. 2018; 121: 505-508Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar describing an elderly woman with renal dysfunction on dabigatran (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA) therapy presenting with severe prolonged lower gastrointestinal bleeding. Their reference to idarucizumab (Boehringer Ingelheim Pharmaceuticals, Inc.) dosing, in the setting of excessive dabigatran body burden and high dabigatran doses impacting clotting time without affecting maximal clot firmness, merits further discussion. Hegemann and colleagues1Hegemann I. Ganter C. Widmer C.C. Becker M. Muller D. Spahn D.R. Ongoing redistribution of dabigatran necessitates repetitive application of idarucizumab.Br J Anaesth. 2018; 121: 505-508Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar reported that 'dabigatran activity was above 2000 ng ml−1 and global haemostasis tests were out of range' at presentation. It was also reported that 'after a first dose of idarucizumab, dabigatran activity was antagonised immediately, but bleeding continued… idarucizumab was given at accumulative dose of 15 g within 84 h because dabigatran continually redistributed from the extravascular space after each application of idarucizumab.' We believe the following are important considerations in formulating a treatment strategy for this patient. The recommended idarucizumab dose is 5 g based on calculations that it would neutralise the 99th percentile of plasma dabigatran concentrations during therapeutic dabigatran dosing (i.e. 150 mg twice daily) at steady-state in patients with mild to moderate renal dysfunction.2Reilly P.A. van Ryn J. Grottke O. Glund S. Stangier J. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects.Am J Med. 2016; 129: S64-S72Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In this patient population, the 90th percentile of plasma dabigatran concentrations is 383 ng ml−13Reilly P.A. Lehr T. Haertter S. et al.The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).J Am Coll Cardiol. 2014; 63: 321-328Crossref PubMed Scopus (655) Google Scholar and in patients with severe renal impairment the 95th percentile plasma dabigatran concentrations is 428 ng ml−1.4Sahre M.D. Rekic D. Florian J. Madabushi R. Mehta M.U. United States Food and Drug Administration, Center for Drug Evaluation and Research, application number: 761025Orig1s000 clinical pharmacology and biopharmaceutics review(s).https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/761025Orig1s000ClinPharmR.pdfDate accessed: November 7, 2018Google Scholar So, the 99th percentile of plasma dabigatran concentration in patients with normal or severe renal impairment is expected to be <500 ng ml−1, and 5 g of idarucizumab would be expected to neutralise no more than 500 ng ml−1 of dabigatran activity. The effectiveness of idarucizumab (5 g) to immediately reduce circulating plasma dabigatran concentrations to the lower limit of quantification and normalise coagulation assays (i.e. dilute thrombin time and ecarin clotting time) within minutes of idarucizumab administration in patients with plasma dabigatran concentrations similar to the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was demonstrated in patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study.5Pollack Jr., C.V. Reilly P.A. Eikelboom J. et al.Idarucizumab for dabigatran reversal.N Engl J Med. 2015; 373: 511-520Crossref PubMed Scopus (1287) Google Scholar, 6Pollack Jr., C.V. Reilly P.A. van Ryn J. et al.Idarucizumab for dabigatran reversal – full cohort analysis.N Engl J Med. 2017; 377: 431-441Crossref PubMed Scopus (661) Google Scholar While these data inform on the effectiveness of idarucizumab in correcting coagulation parameters to laboratory reference ranges in patients on therapeutic dabigatran dosing, they cannot inform on the effectiveness of idarucizumab in the treatment of patients with excessive dabigatran body burden as a result of renal dysfunction, or in patients with acute dabigatran overdose. It is expected that the recommended idarucizumab dose would be grossly inadequate to neutralise the dabigatran body burden in patients with renal dysfunction or after an acute dabigatran overdose.7Mumoli N. Cei M. Fiorini M. Pennati P. Testa S. Dentali F. Conservative management of intentional massive dabigatran overdose.J Am Geriatr Soc. 2015; 63: 2205-2207Google Scholar, 8Rottenstreich A. Jahshan N. Avraham L. Kalish Y. Idarucizumab for dabigatran reversal – does one dose fit all?.Thromb Res. 2016; 146: 103-104Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The next important consideration is the difference between laboratory and clinical haemostasis tests that range between 2.5 and 11.4 h.9Yip L. Deng J.F. Dabigatran reversal with idarucizumab.N Engl J Med. 2017; 377: 1690Crossref PubMed Scopus (6) Google Scholar, 10Yip L. Deng J.F. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: Comment.J Thromb Haemost. 2017; 15: 2466-2467Crossref PubMed Scopus (5) Google Scholar, 11Yip L. Deng J.F. Idarucizumab – Antidote for hemorrhage following therapeutic dabigatran dosing?.23 June 2017https://www.bmj.com/content/357/bmj.j2216/rrGoogle Scholar One reason for this difference is that the common laboratory bioassays (i.e. prothrombin time, international normalised ratio, activated partial thromboplastin time, and thrombin time) used to evaluate haemostasis are in vitro endpoints of the fibrin-clotting reaction (i.e. fibrin clot formation). However, fibrin clot formation in a closed system is not synonymous with haemostasis; a simple clotting endpoint cannot adequately evaluate haemostasis.12Mann K.G. Thrombin generation in hemorrhage control and vascular occlusion.Circulation. 2011; 124: 225-235Crossref PubMed Scopus (57) Google Scholar In haemorrhagic syndromes, in vitro formation of a visible fibrin clot occurs during the initiation phase of thrombin formation with <30 nmol L−1 of thrombin, which is <5% of the total thrombin produced.13Brummel K.E. Paradis S.G. Butenas S. Mann K.G. Thrombin functions during tissue factor-induced blood coagulation.Blood. 2002; 100: 148-152Crossref PubMed Scopus (315) Google Scholar The major surge in thrombin production occurs during the propagation phase when >96% of thrombin is produced. Depression of thrombin production during the propagation phase is the hallmark of uncontrolled haemorrhage. Both phases of thrombin formation are essential to haemostasis.14Mann K.G. Brummel K. Butenas S. What is all that thrombin for?.J Thromb Haemost. 2003; 1: 1504-1514Crossref PubMed Scopus (450) Google Scholar Another important consideration is that dabigatran is redistributed from peripheral tissues into the intravascular compartment after idarucizumab therapy.10Yip L. Deng J.F. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: Comment.J Thromb Haemost. 2017; 15: 2466-2467Crossref PubMed Scopus (5) Google Scholar, 15Yip L. Deng J.F. Idarucizumab dosing in kidney failure.Am J Kidney Dis. 2018; 71: 146Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Resurgence of dabigatran activity appears to occur after 6–8 h in patients with acute kidney injury or kidney failure, whereas resurgence of dabigatran activity occurs after about 12 h in patients with mild to moderate renal dysfunction.10Yip L. Deng J.F. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: Comment.J Thromb Haemost. 2017; 15: 2466-2467Crossref PubMed Scopus (5) Google Scholar, 15Yip L. Deng J.F. Idarucizumab dosing in kidney failure.Am J Kidney Dis. 2018; 71: 146Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar We propose the following strategy in managing patients with uncontrolled haemorrhage or high risk for serious bleeding while on dabigatran therapy complicated by excessive body dabigatran burden as a result of acute kidney injury or failure (Fig. 1). Our approach is to administer blood component therapy (e.g. prothrombin complex concentrate and activated prothrombin complex concentrate) as a bridge between the normalisation of the coagulation profile and the establishment of haemostasis,9Yip L. Deng J.F. Dabigatran reversal with idarucizumab.N Engl J Med. 2017; 377: 1690Crossref PubMed Scopus (6) Google Scholar, 10Yip L. Deng J.F. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: Comment.J Thromb Haemost. 2017; 15: 2466-2467Crossref PubMed Scopus (5) Google Scholar, 11Yip L. Deng J.F. Idarucizumab – Antidote for hemorrhage following therapeutic dabigatran dosing?.23 June 2017https://www.bmj.com/content/357/bmj.j2216/rrGoogle Scholar in addition to administering an adequate idarucizumab dose to rapidly neutralise intravascular dabigatran activity. The urgency to neutralise dabigatran activity is because dabigatran does not discriminate between endogenous and exogenous sources of thrombin. Thrombin derived from blood component therapy will be inhibited if dabigatran activity has not been neutralised. Thus, it is important to rapidly neutralise dabigatran activity while preparing to administer blood component therapy. The challenge is to estimate an adequate idarucizumab dose to rapidly neutralise intravascular dabigatran activity. Based on earlier discussion, it can be reasonably argued that therapeutic dabigatran dosing (300 mg day−1) is associated with a serum concentration <500 ng ml−1 and 5 g of idarucizumab neutralises ∼500 ng ml−1 of dabigatran activity. Our approach is to administer an initial 5 g of idarucizumab for every 500 ng ml−1 of dabigatran activity followed by additional doses of idarucizumab based on the results of repeat Hemoclot® Thrombin Inhibitor assay (Hyphen BioMed, Neuville-sur-Oise, France) until dabigatran activity is neutralised. If the Hemoclot® Thrombin Inhibitor assay is unavailable, our approach is to administer at least 5 g of idarucizumab as an initial dose followed by additional doses of idarucizumab based on thrombin time obtained at least every 10 min until dabigatran activity is neutralised. Once initial neutralisation is achieved, blood component therapy is administered to bridge the discordance between laboratory and clinical haemostasis. The effectiveness of this treatment strategy can be assessed by serial clinical examination and the Hemoclot® Thrombin Inhibitor assay or coagulation profile at least every 6–8 h in patients with acute kidney injury or failure, or every 12 h in patients with mild to moderate renal dysfunction. Idarucizumab is very effective in neutralising intravascular dabigatran activity and correcting coagulation profile in patients with serious bleeding while on dabigatran therapy. However, there is discordance between laboratory and clinical haemostasis tests, and resurgence of dabigatran activity after initial neutralisation is to be expected. This has implications when managing patients with uncontrolled haemorrhage associated with therapeutic dabigatran use complicated by acute kidney injury or failure. When managing patients in this clinical scenario, it is important to recognise the need to rapidly neutralise intravascular dabigatran activity and administer blood component therapy. The authors declare that they have no conflicts of interest.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). As of August 27, 2019, 215 possible cases of severe pulmonary disease associated with the use of electronic cigarette (e-cigarette) products (e.g., devices, liquids, refill pods, and cartridges) had been reported to CDC by 25 state health departments. E-cigarettes are devices that produce an aerosol by heating a liquid containing various chemicals, including nicotine, flavorings, and other additives (e.g., propellants, solvents, and oils). Users inhale the aerosol, including any additives, into their lungs. Aerosols produced by e-cigarettes can contain harmful or potentially harmful substances, including heavy metals such as lead, volatile organic compounds, ultrafine particles, cancer-causing chemicals, or other agents such as chemicals used for cleaning the device (1). E-cigarettes also can be used to deliver tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, or other drugs; for example, "dabbing" involves superheating substances that contain high concentrations of THC and other plant compounds (e.g., cannabidiol) with the intent of inhaling the aerosol. E-cigarette users could potentially add other substances to the devices. This report summarizes available information and provides interim case definitions and guidance for reporting possible cases of severe pulmonary disease. The guidance in this report reflects data available as of September 6, 2019; guidance will be updated as additional information becomes available.

Dear Editor,Normally, small amounts of methemoglobin are continuously formed, and quantitatively, the most important reductive system utilizes NADH-methemoglobin reductase to maintain the proportio...

Ideas and Opinions1 January 2019Nerve Agent Incidents and Public Health PreparednessArthur Chang, MD, MS, Jerry Thomas, MD, Rudolph Johnson, PhD, Susan E. Gorman, PharmD, MS, Josh Schier, MD, MPH, and Luke Yip, MDArthur Chang, MD, MSNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Search for more papers by this author, Jerry Thomas, MDNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Search for more papers by this author, Rudolph Johnson, PhDNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Search for more papers by this author, Susan E. Gorman, PharmD, MSOffice of Public Health Preparedness and Response, Centers for Disease Control and Prevention, Atlanta, Georgia (S.E.G.)Search for more papers by this author, Josh Schier, MD, MPHNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Search for more papers by this author, and Luke Yip, MDNational Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-2428 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Recent use of nerve agents (NAs) by terrorists and assassins exposes the need for public health responders and medical preparedness personnel to work together (1). Health care providers might find themselves at the scene of such an attack. Would the involvement of an NA be recognized? What should be done immediately to assess the situation, treat the victims, protect others and oneself, and alert appropriate health officials? These are essential questions a health care provider in the vicinity of an attack might face. We provide an overview of key clinical and public health concerns related to this topic for health ...References1. Vale JA, Marrs TC OBE, Maynard RL CBE. Novichok: a murderous nerve agent attack in the UK. Clin Toxicol (Phila). 2018;56:1093-7. [PMID: 29757015] doi:10.1080/15563650.2018.1469759 CrossrefMedlineGoogle Scholar2. Wiener SW, Hoffman RS. Nerve agents: a comprehensive review. J Intensive Care Med. 2004;19:22-37. [PMID: 15035752] CrossrefMedlineGoogle Scholar3. Leikin JB, Thomas RG, Walter FG, Klein R, Meislin HW. A review of nerve agent exposure for the critical care physician. Crit Care Med. 2002;30:2346-54. [PMID: 12394966] CrossrefMedlineGoogle Scholar4. Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank's Toxicologic Emergencies. 10th ed. New York: McGraw-Hill; 2015. Google Scholar5. Ciottone GR. Toxidrome recognition in chemical-weapons attacks. N Engl J Med. 2018;378:1611-20. [PMID: 29694809] doi:10.1056/NEJMra1705224 CrossrefMedlineGoogle Scholar6. Marrs TC. The role of diazepam in the treatment of nerve agent poisoning in a civilian population. Toxicol Rev. 2004;23:145-57. [PMID: 15862082] CrossrefMedlineGoogle Scholar7. Skinner C, Thomas J, Johnson R, Kobelski R. Medical toxicology and public health—update on research and activities at the Centers for Disease Control and Prevention, and the Agency for Toxic Substances and Disease Registry: introduction to the Laboratory Response Network-Chemical (LRN-C). J Med Toxicol. 2009;5:46-9. [PMID: 19191216] CrossrefMedlineGoogle Scholar8. Centers for Disease Control and Prevention. Strategic national stockpile: CHEMPACK. 2018. Accessed at www.cdc.gov/phpr/stockpile/chempack.htm on 30 July 2018. Google Scholar9. Barbera JA, Yeatts DJ, Macintyre AG. Challenge of hospital emergency preparedness: analysis and recommendations. Disaster Med Public Health Prep. 2009;3:S74-82. [PMID: 19491592] doi:10.1097/DMP.0b013e31819f754c CrossrefMedlineGoogle Scholar10. BBC News. Russian spy poisoning: what we know so far. 8 October 2018. Accessed at www.bbc.com/news/uk-43315636 on 18 October 2018. Google Scholar Author, Article, and Disclosure InformationAffiliations: National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (A.C., J.T., R.J., J.S., L.Y.)Office of Public Health Preparedness and Response, Centers for Disease Control and Prevention, Atlanta, Georgia (S.E.G.)Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-2428.Corresponding Author: Arthur Chang, MD, MS, Emergency Management, Radiation and Chemical Branch, Division of Environmental Health Science and Practice, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Highway NE, F60, Atlanta, GA 30341; e-mail, [email protected]gov.Current Author Addresses: Drs. Chang, Thomas, Johnson, Schier, and Yip: National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Atlanta, GA 30341.Dr. Gorman: Centers for Disease Control and Prevention, 1600 Clifton Road, MS D-08, Atlanta, GA 30333.Author Contributions: Conception and design: A. Chang, J. Thomas, R. Johnson, S.E. Gorman, J. Schier, L. Yip.Drafting of the article: A. Chang, J. Thomas, R. Johnson, S.E. Gorman, J. Schier, L. Yip.Critical revision of the article for important intellectual content: A. Chang, J. Thomas, R. Johnson, S.E. Gorman, J. Schier, L. Yip.Final approval of the article: A. Chang, J. Thomas, R. Johnson, S.E. Gorman, J. Schier, L. Yip.This article was published at Annals.org on 18 December 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byIntramuscularly administered A1 adenosine receptor agonists as delayed treatment for organophosphorus nerve agent-induced Status Epilepticus 1 January 2019Volume 170, Issue 1Page: 59-61KeywordsCholinergicsEnvironmental healthFasciculationsHealth care providersNervesOpioidsPrevention, policy, and public healthResearch laboratoriesRisk managementSigns and symptoms ePublished: 18 December 2018 Issue Published: 1 January 2019 PDF downloadLoading ...

We appreciate the contribution by Henstra et al. on the relationship between plasma ibogaine and noribogaine concentrations following ingestion of “ibogaine capsules” purchased over the internet [1]. However, “ibogaine capsules”, “toxicokinetics”, and their statement “ibogaine and noribogaine both are an agonist of the opioid receptor” deserve further discussion. The actual composition of the “ibogaine capsules” (e.g., Tabernanthe iboga extract, powdered root bark, or ibogaine hydrochloride) and the formulation and purity of its content are important when informing on ibogaine pharmacokinetics QTc prolongation, and dysrhythmias. The actual amount of ibogaine is likely suspect when dealing with extract or powdered root bark and in the case of ibogaine hydrochloride its purity needs to be verified. Thus, the total amount of ibogaine ingested by this patient may not have been 1400mg or within the “therapeutic” dose, which is often a single oral dose 10–30mg/kg. Depending on the composition of the “ibogaine capsules”, constituents of the extract or powered root bark and impurities or contaminants in ibogaine hydrochloride may have contributed to the cardiac adverse events in a drug addict with a suspect pristine medical history following “therapeutic” ibogaine dosing. Let us say the “ibogaine capsules” contained pure ibogaine hydrochloride and this patient ingested 1400mg ibogaine resulting in maximum plasma ibogaine and noribogaine concentrations 1.45mg/L (12.7 h) and 0.569mg/L (98 h), respectively. This is in contrast to study subjects and cocainedependent patients who were administered oral ibogaine in “therapeutic” doses. The maximum whole blood ibogaine concentrations in study subjects were 0.818–1.128mg/mL at 4 h following 20mg/kg of ibogaine and noribogaine concentrations were 0.508–0.706mg/L at 24 h post-dose [2]. In cocaine-dependent patients, who received 500–1000mg of ibogaine, their maximum whole blood ibogaine concentrations were 0.600–1.25mg/L at 4 h post-dose and noribogaine concentrations were 0.750–1.25mg/L at approximately 6 h post-dose [3]. The reason(s) for the observed difference in “peak” and time to “peak” ibogaine and noribogaine concentrations between this patient, study subjects, and cocainedependent patients following “therapeutic” ibogaine dosing is unclear and requires reconciliation. The putative mu-opioid receptor agonist activity of ibogaine or noribogaine to explain its effectiveness in opioid withdrawal is challenged by observations that include ibogaine does not behave as a mu-opioid agonist in assays with isolated smooth muscle preparations and ibogaine and noribogaine, unlike mu-opioid agonists, do not by themselves have antinociceptive effects [4]. In addition, there are findings to suggest ibogaine acts at the level of second messenger signal transduction to enhance the functional activity of mu-opioid receptors independent of direct agonist interaction at opioid receptors. Both ibogaine and noribogaine appear to potentiate morphine-induced inhibition of adenylate cyclase in vitro with opioid receptors already maximally occupied by morphine and did not affect adenylate cyclase in the absence of morphine. This may also explain the finding that ibogaine inhibited the development of tolerance to the antinociceptive effect of morphine in mice without by itself affecting nociception.

In the case report by Novak et al,1Novak J.E. Alamiri K. Yee J. Dabigatran reversal in a patient with end-stage liver disease and acute kidney injury.Am J Kidney Dis. 2018; 71: 137-141Google Scholar their use of a single idarucizumab dose and blood product therapy merits further discussion. We believe that idarucizumab dosing should be based on serial clinical assessments (eg, vital signs, hemorrhage site, and patient’s response to therapy) and a profile of clotting times at least every 6 to 8 hours (eg, ecarin clotting time, thrombin clotting time, activated clotting time, and activated partial thromboplastin time) in addition to blood component therapy, as in the clinical scenario described by Novak et al. Dabigatran is redistributed from peripheral tissues into the intravascular compartment following idarucizumab therapy.1Novak J.E. Alamiri K. Yee J. Dabigatran reversal in a patient with end-stage liver disease and acute kidney injury.Am J Kidney Dis. 2018; 71: 137-141Google Scholar, 2Simon A, Domanovits H, Ay C, et al. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran [published online ahead of print April 20, 2017]. J Thromb Haemost. https://doi.org/10.1111/jth.13706.Google Scholar, 3Quintard H. Viard D. Drici M.D. et al.Idarucizumab administration for reversing dabigatran effect in an acute kidney injured patient with bleeding.Thromb Haemost. 2017; 117: 196-197Crossref PubMed Scopus (16) Google Scholar, 4Pollack CV Jr, Reilly PA, van Ryn J, et al: Idarucizumab for dabigatran reversal - full cohort analysis [published online ahead of print July 11, 2017]. N Engl J Med. https://doi.org/10.1056/NEJMoa1707278.Google Scholar Resurgence of dabigatran activity occurs after about 6 to 8 hours in patients with acute kidney injury or kidney failure.1Novak J.E. Alamiri K. Yee J. Dabigatran reversal in a patient with end-stage liver disease and acute kidney injury.Am J Kidney Dis. 2018; 71: 137-141Google Scholar, 2Simon A, Domanovits H, Ay C, et al. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran [published online ahead of print April 20, 2017]. J Thromb Haemost. https://doi.org/10.1111/jth.13706.Google Scholar, 3Quintard H. Viard D. Drici M.D. et al.Idarucizumab administration for reversing dabigatran effect in an acute kidney injured patient with bleeding.Thromb Haemost. 2017; 117: 196-197Crossref PubMed Scopus (16) Google Scholar Dabigatran does not discriminate between endogenous or exogenous sources of thrombin. Thrombin derived from blood component therapy (eg, prothrombin complex concentrate, activated prothrombin complex concentrate, or fresh frozen plasma) will be inhibited unless dabigatran activity has been neutralized. This suggests that the effectiveness of therapy should be assessed by serial clinical assessments and a profile of clotting times at least every 6 to 8 hours, with additional blood component and idarucizumab therapy as clinically indicated. In the REVERSE-AD study, 1.8% of patients received 10 to 15 g of idarucizumab,4Pollack CV Jr, Reilly PA, van Ryn J, et al: Idarucizumab for dabigatran reversal - full cohort analysis [published online ahead of print July 11, 2017]. N Engl J Med. https://doi.org/10.1056/NEJMoa1707278.Google Scholar while its product label indicates an additional 5-g dose of idarucizumab may be considered.5PRAXBIND® (idarucizumab) injection, for intravenous use. Initial U.S. approval: 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761025lbl.pdf. Accessed August 1, 2017.Google Scholar The data for nonspecific prohemostatic agents are methodologically limited, but it is reasonable to administer blood component therapy to a patient with serious hemorrhaging due to excessive dabigatran activity based on in vitro and preclinical data.6Zhou W. Schwarting S. Illanes S. et al.Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.Stroke. 2011; 42: 3594-3599Crossref PubMed Scopus (313) Google Scholar Although the discrepancies between some of the animal data and data for humans may be due to different measured end points, these data suggest prothrombin complex concentrate and activated prothrombin complex concentrate to be more effective than fresh frozen plasma.6Zhou W. Schwarting S. Illanes S. et al.Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran.Stroke. 2011; 42: 3594-3599Crossref PubMed Scopus (313) Google Scholar In select patients, the need to establish effective hemostasis using blood component and idarucizumab therapy outweighs the potential risk for thrombotic adverse events in patients who are hemorrhaging.

We thank Helander et al for sharing their fascinating MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) cases (Br J Dermatol 2016 Dec 14. https://doi.org/10.1111/bjd.15174. [Epub ahead of print]). MT-45 is a piperazine derivative and was investigated as an opioid analgesic in the 1970s. Laboratory studies suggest its pharmacology is complex and involves opioid receptors and non-opioid targets. MT-45 has emerged on the new psychoactive substances market where it is mostly sold on the Internet. The majority of reported clinical features of MT-45 are that associated with traditional opioids (e.g., reduced level of consciousness or coma, reduced respiratory effort, oxygen saturation or cyanosis, miosis, and hearing loss) and patients often present with decreased level of consciousness and respiratory depression that responded well to naloxone treatment. This article is protected by copyright. All rights reserved.