Current Awareness in Clinical Toxicology Editors: Damian Ballam MSc and Allister Vale MD September 2015 CONTENTS General Toxicology 7 Metals 35 Management 17 Pesticides 37 Drugs 20 Chemical Warfare 39 Chemical Incidents & 30 Plants 40 Pollution Chemicals 31 Animals 40 CURRENT AWARENESS PAPERS OF THE MONTH A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose Curtis RM, Sivilotti MLA. Clin Toxicol 2015; online early: doi: 10.3109/15563650.2015.1077968: Context Risk prediction following acetaminophen (paracetamol, APAP) overdose is based on serum APAP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels. One recently proposed risk stratification tool, the APAPxAT multiplication product, uses either AST or ALT, whichever is higher, yet their interrelation is not well known following APAP- induced hepatic injury. Objective To describe the kinetics of AST and ALT release into and disappearance from the circulation following APAP overdose. Materials and Methods An observational case series of adult patients with peak AST or ALT > 100 IU/L attributable Current Awareness in Clinical Toxicology is produced monthly for the American Academy of Clinical Toxicology by the Birmingham Unit of the UK National Poisons Information Service, with contributions from the Cardiff, Edinburgh, and Newcastle Units. The NPIS is commissioned by Public Health England 2 to APAP toxicity. Cases were identified by electronic search of hospital laboratory database and by discharge diagnosis corroborated by structured explicit medical record review. Results Of 68 cases identified (mean age (SD): 39 (18) years, 63% female, and 21% ethanol co- ingested), 28 (41%) developed hepatotoxicity (peak AST or ALT > 1000 IU/L), 28 (41%) coagulopathy (international normalized ratio or INR > 2), and 21 (31%) both. Three patients (4%) were transferred for liver transplantation and ultimately six (8.8%) died. Serum AST and ALT activity rose in a closely aligned 1:1 AST:ALT ratio, but fell at distinctly different rates: AST activity fell with a half-life (interquartile range [IQR]) of 15.1 (12.2, 19.4) hours, and ALT 39.6 (32.9, 47.6) hours. Using an aminotransferase falling to below 50% of peak as the basis for discontinuing acetylcysteine would have resulted in antidotal treatment being stopped 24 (IQR: 9.6, 40) hours earlier (and in no cases later) using AST rather than ALT. Only six patients had an AST:ALT ratio greater than 2:1 at the time of acetylcysteine administration; of these six, four died and one survivor developed coagulopathy. Discussion AST and ALT release into the circulation appears tightly linked and numerically similar, except in the sickest patients. Once the aminotransferases peak, AST returns to baseline more quickly. Conclusion Either AST or ALT can be used for early risk stratification tools when only one is known. Any criterion for N-AC discontinuation should be based on the decline of AST rather than ALT, with a potential benefit measured in days. Full text available from: http://www.tandfonline.com/doi/abs/10.3109/15563650.2015.1077968 Phencyclidine analog use in Sweden–intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project Bäckberg M, Beck O, Helander A. Clin Toxicol 2015; online early: doi: 10.3109/15563650.2015.1079325: Background 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for the dissociative substance PCP ("Angel dust"), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP and/or 4-MeO-PCP within the STRIDA project. Study design Observational case series of consecutive patients with self-reported or suspected exposure to new psychoactive substances (NPS) and who require hospital care. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS analysis was performed by multicomponent liquid chromatographic–tandem mass spectrometric (LC–MS/MS) and LC–high-resolution MS (LC–HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. 3 Results The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for 3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14–55 (median: 26) years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood pressure = 140 mmHg; 7 cases), tachycardia (= 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation, dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1–2 days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy, 49% of the patients were treated with benzodiazepines and/or propofol. Conclusion Laboratory analysis constitutes an important basis for the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4- MeO-PCP resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS, poly-substance use was found to be common. Full text available from: http://www.tandfonline.com/doi/abs/10.3109/15563650.2015.1079325 Disproportionate effect on child admissions of the change in MHRA guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland Narayan H, Thomas SH, Eddleston M, Dear JW, Sandilands E, Bateman DN. Br J Clin Pharmacol 2015; online early: doi: 10.1111/bcp.12779: Abstract and full text available from: http://dx.doi.org/10.1111/bcp.12779 Paracetamol overdose in Hong Kong: is the 150-treatment line good enough to cover patients with paracetamol-induced liver injury? Chan STB, Chan CK, Tse ML. Hong Kong Med J 2015; online early: doi: 10.12809/hkmj144481: Abstract and full text available from: http://dx.doi.org/10.12809/hkmj144481 Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new Eddleston M, Chowdhury FR. Br J Clin Pharmacol 2015; online early: doi: 10.1111/bcp.12784: Abstract and full text available from: http://dx.doi.org/10.1111/bcp.12784 4 Long-acting anticoagulant rodenticide (superwarfarin) poisoning: a review of its historical development, epidemiology, and clinical management King N, Tran M-H. Transfus Med Rev 2015; online early: doi: 10.1016/j.tmrv.2015.06.002: Abstract and full text available from: http://dx.doi.org/10.1016/j.tmrv.2015.06.002 Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double- blind phase 1 trial Glund S, Stangier J, Schmohl M, Gansser D, Norris S, Van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J. Lancet 2015; 386: 15-21. Abstract and full text available from: http://dx.doi.org/10.1016/S0140-6736(15)60732-2 Aminocaproic acid and tranexamic acid fail to reverse dabigatran-induced coagulopathy Levine M, Huang M, Henderson SO, Carmelli G, Thomas SH. Am J Ther 2015; online early: doi: 10.1097/MJT.0000000000000216: Abstract and full text available from: http://dx.doi.org/10.1097/MJT.0000000000000216 Calcium channel and beta-blocker antagonist antidotes and adjunct therapies Graudins A, Lee HM, Druda D. Br J Clin Pharmacol 2015; online early: doi: 10.1111/bcp.12763: Abstract and full text available from: http://dx.doi.org/10.1111/bcp.12763 Buprenorphine infrequently found in fatal overdose in New York City Paone D, Tuazon E, Stajic M, Sampson B, Allen B, Mantha S, Kunins H. Drug Alcohol Depend 2015; online early: doi: 10.1016/j.drugalcdep.2015.08.007: Abstract and full text available from: http://dx.doi.org/10.1016/j.drugalcdep.2015.08.007 Role of extracorporeal membrane oxygenation in aluminum phosphide poisoning-induced reversible myocardial dysfunction: a novel therapeutic modality Mohan B, Gupta V, Ralhan S, Gupta D, Puri S, Wander GS, Singh B. J Emerg Med 2015; online early: doi: 10.1016/j.jemermed.2015.06.071: Abstract and full text available from: http://dx.doi.org/10.1016/j.jemermed.2015.06.071 5 Acute toluene intoxication-clinical presentation, management and prognosis: a prospective observational study Camara-Lemarroy CR, Rodríguez-Gutiérrez R, Monreal-Robles R, González-González JG. BMC Emerg Med 2015; 15: 19. Abstract and full text available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539858/ Reversible oligohydramnios in the second trimester of pregnancy in two patients with long-term diclofenac exposure Scherneck S, Schöpa FL, Entezami M, Kayser A, Weber-Schoendorfer C, Schaefer C. Reprod Toxicol 2015; 58: 61-4. Abstract and full text available from: http://dx.doi.org/10.1016/j.reprotox.2015.08.002 Epidemiology of ciguatera in Florida Radke EG, Reich A, Morris JG, Jr.