Yael Lurie

Lessepsian migration and tetrodotoxin poisoning due to Lagocephalus sceleratus in the eastern Mediterranean

BACKGROUND The Suez Canal permits migration of fish from the Indo-Pacific Ocean to the Mediterranean Sea. This phenomenon (Lessepsian migration) has enabled poisonous fish species to colonize the Mediterranean Sea. OBJECTIVE To report clinical tetrodotoxin poisoning after consumption of the Lessepsian immigrant fish Lagocephalus sceleratus caught on the Israeli coast of the eastern Mediterranean. CASE SERIES Thirteen patients aged 26-70years were admitted after consuming L. sceleratus. Signs of toxicity appeared within 1h. The main manifestations included vomiting, diarrhea, headache, paraesthesias, slurred speech, muscle weakness, dyspnea, hypertension, tachycardia, respiratory arrest, seizures and coma. Treatment was supportive, including mechanical ventilation (two patients). Patients recovered within 4days. All fish were identified as L. sceleratus, a species known to contain tetrodotoxin. DISCUSSION The diagnosis of tetrodotoxin poisoning was suggested by typical clinical manifestations together with temporal proximity to consumption of tetrodotoxin-containing fish. To the best of our knowledge, this is the first case series of tetrodotoxin poisoning reported from the eastern Mediterranean and due to L. sceleratus. Man made disruption of the ecological balance has resulted in the spread of tetrodotoxin-containing fish from the Indo-Pacific region to the Mediterranean Sea. Increased awareness is required to identify tetrodotoxin poisoning in an atypical fauna.

Warfarin and vitamin K intake in the era of pharmacogenetics.

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 microM* minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.

Mushroom poisoning from species of genus Inocybe (fiber head mushroom): a case series with exact species identification

Background. Many species of the genus Inocybe (family Cortinariaceae, higher Basidiomycetes) are muscarine-containing mycorrhizal mushrooms, ubiquitous around the world. The few published reports on the poisonous Inocybe mushrooms are often limited by the inadequate identification of the species. The clinical course of patients with typical muscarinic manifestations, in whom Inocybe spp. was unequivocally identified, is reported. Case series. Between November 2006 and January 2008 14 consecutive patients with typical muscarinic syndrome after mushroom ingestion were recorded. The clinical manifestations included combinations of nausea, vomiting, diarrhea, abdominal pain, hypersalivation, diaphoresis, tachycardia, bradycardia, hypotension, lacrimation, blurred vision, miosis, tremor, restlessness, flushing, and syncope. Time to onset of toxicity ranged between 15 min and 2 h after consumption, 5 h in one patient. Treatment was supportive, including intravenous fluids, antiemetics, and 1 mg atropine intravenously. Full recovery ensued within 12 h. In all the cases, an expert mycologist unequivocally identified the leftovers of the consumed mushrooms as Inocybe fastigiata, Inocybe geophylla, and Inocybe patouillardii. Conclusion. In this case series of patients who ingested identified muscarine-containing mushrooms supportive treatment and atropine resulted in recovery in all cases.

The role of chest and abdominal computed tomography in assessing the severity of acute corrosive ingestion

Abstract Context. Corrosive substance ingestion is a toxicological emergency with relatively high mortality requiring rational surgical decisions. Objective. Evaluate the role of chest and abdominal computed tomography (CT) in assessing the severity of acute corrosive ingestion. Methods. A retrospective study of adults admitted due to corrosive ingestion, who underwent gastrointestinal endoscopy and CT within 48 h of admission. Endoscopy findings were graded as 0, 1, 2a, 2b, 3a, and 3b (Zargars criteria), CT findings were graded as 0, 1, 2, and 3. For each patient endoscopy and CT grades were compared, and sensitivity and specificity for predicting mortality or emergency laparotomy were calculated. Results. Twenty-three patients were included, aged 18–87 years; seven underwent emergency laparotomy, five died. Endoscopy grading was higher than CT grading in 14 patients (66%). The sensitivities of endoscopy grades 2b and 3 to predict mortality and emergency laparotomy were 1 and 0.8, respectively; the specificities were 0.38 and 0.37, respectively. The sensitivities of CT grade 3 to predict mortality and emergency laparotomy were 0.4 and 0.28, respectively; the specificities were 0.94 and 0.93, respectively. Three patients had pulmonary infiltrates on CT but not on chest X-ray. Discussion. CT tends to underestimate the severity of corrosive ingestion compared with endoscopy. It has lower sensitivity and higher specificity than endoscopy in predicting major outcome. CT can provide important information on lung injury, and when endoscopy cannot be completed. Conclusion. CT should not be the only basis for surgical decisions during the initial phase of acute corrosive ingestions.

Pediatric cinnarizine overdose and toxicokinetics.

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel–blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t1/2 = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel–blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.

Reliability of history of acetaminophen ingestion in intentional drug overdose patients

The objective of this study was to determine the reliability of denial of acetaminophen ingestion in intentional drug overdose patients. All intentional drug overdose patients admitted to an emergency department who were able to provide a history were included. A detailed history was obtained on names, timing and number of medications ingested, and serum acetaminophen was assayed. Multidrug ingestion was defined as the reporting of ≥2 medications. Patients were considered ‘reliable’ if they reported acetaminophen ingestion and had detectable acetaminophen levels or the other way around. Validity parameters of acetaminophen history were assessed by sensitivity, specificity and positive and negative predictive values. A total of 154 patients were included. History was significantly more reliable in patients who denied ingestion of acetaminophen (n = 107) compared with patients who reported it (n = 47; 95.3% vs 65.9%, respectively; p < 0.0001, 95% CI of the difference 17.5%—41.2%). No suicidal patient who denied both acetaminophen and multidrug ingestions had a detectable acetaminophen level (negative predictive value 1, 95% CI 0.93—1.0). It is suggested that denial of both acetaminophen and multidrug ingestions by intentional drug overdose patients after a thorough history taking can be considered reliable for acetaminophen history. In facilities with limited resources, these patients may not require routine acetaminophen screening.

Vipera Palaestinae Bite and Serum Sickness During Pregnancy

BACKGROUND Vipera palaestinae is the most common venomous snake in Israel. We report a case of V. palaestinae bite and antivenom-induced serum sickness during pregnancy and discuss the unique considerations relevant to the treatment of a pregnant woman envenomated by a snake. CASE REPORT A 46-year-old woman, G6P5, 14 weeks gestation, was admitted after a V. palaestinae bite on her right toe. On admission to the Emergency Department, physical examination included the following vital signs and findings: pulse 76 beats/min, blood pressure 90/60 mm Hg, nausea, vomiting, foot and distal leg swelling, and normal fetal monitoring. She was treated with intravenous fluids, analgesics, and V. palaestinae antivenom. Eight days later she developed serum sickness, was treated with prednisone, and fully recovered. A healthy baby was born at term, with normal examination at 2 months post-delivery. CONCLUSION To our knowledge, this is the first reported case of V. palaestinae bite complicated by antivenom-induced serum sickness during pregnancy. No adverse pregnancy outcome due to the antivenom treatment or serum sickness was observed. Careful hemodynamic, hematologic, and obstetric monitoring (including ultrasound) of pregnant snakebite victims is warranted. Antivenom administration should be considered according to published indications to prevent maternal complications and fetal compromise. Patients treated with antivenom should be followed for possible development of serum sickness.

Pediatric clotiapine poisoning: clinical manifestations and toxicokinetics☆☆☆

Clotiapine (clothiapine, Entumine) is a dibenzothiazepine antipsychotic drug indicated for the treatment of acute and chronic schizophrenia. Very limited data on clotiapines pharmacokinetics and on clinical manifestations and toxicokinetics of overdose exist. We report a case of pediatric clotiapine overdose with toxicokinetic evaluation. An 18month-old toddler developed stupor, miosis, and short-lived hypertension after a witnessed ingestion of 200 mg of clotiapine. Clotiapine plasma concentration 5 hours after ingestion was 128.5 ng/mL and decreased gradually to 9 ng/mL 39 hours after ingestion. Clotiapine elimination rate constant was 0.075 h (R = 0.9655); elimination half-life was 9.2 hours. The patient was treated supportively with oxygen and intravenous normal saline. He completely recovered within 39 hours after exposure, compatible with 4.2 half-lives. Central nervous systemdepressionwas also reported after therapeutic dose of clotiapine in adults. The concentration measured on admission is compatible with concentrations reported in adults treated with the high therapeutic range of clotiapine. The concentration we found is also in the range measured postmortem after multiple-drug overdose, including clotipaine, in adults. We suggest that after clotiapine ingestion, asymptomatic children be observed for at least 9 hours (1 elimination half-life) and to provide supportive treatment to symptomatic patients. Clotiapine (clothiapine, Entumine; Taro, Israel) is a dibenzothiazepine antipsychotic drug. It is indicated mainly for the treatment of acute or chronic schizophrenia [1–3] and drug withdrawal [4]. The therapeutic adult dose for acute psychosis is usually 120 to 200mg/d, up to 360mg/d [1]. It is not approved for pediatric use. Experimental studies showed clotiapine to be a noncompetitive antagonist of norepinephrine, dopamine, and histamine, and a competitive antagonist of serotonin [5]; selective affinity to subtype receptors exists [6]. There is limited information on the symptoms, pharmacokinetics, and toxicokinetics of clotiapine. We report the clinical manifestations and toxicokinetics of pediatric clotiapine overdose. An 18-month-old previously healthy boy was seen by his parents ingesting 40 mg clotiapine tablets; 5 were missing. About 2 hours later, he fell asleep; when realizing that he is not waking up, emergency medical services were called. Upon their arrival, 4 hours after ingestion, he was found to be stuporotic and reactive to pain. On admission to the ☆ The study was presented at the XXXII Congress of the European Poison Centres and Clinical Toxicologists; London, UK; May 25–June 1, 2012. ☆☆ The authors report no declarations of interest. 0735-6757/© 2016 Elsevier Inc. All rights reserved. Please cite this article as: Lurie Y, et al, Pediatric clotiapine poisoning: clini dx.doi.org/10.1016/j.ajem.2016.06.059 emergency department 41⁄2 hours after ingestion, he was still in stupor and reactive to pain, and had pin-point pupils. The vital signs were as follows: pulse, 100 beats/min; blood pressure, 130/70 mm Hg (considered hypertension as it is N95 percentile for sex and age) [7], O2 saturation, 100%; and temperature, 36.4°C. The electrocardiogram demonstrated normal sinus rhythm. Laboratory workup showed the following: hemoglobin 10.2 g/dL, pH 7.48, pO2 173mmHg (with supplemental oxygen by facemask), pCO2 29.5mmHg, andHCO3 22.3mmol/L; glucose, creatinine, blood urea nitrogen, and electrolytes were within normal limits. Urine immunoassays were negative for cannabis, opiates, amphetamine derivatives, cocaine, barbiturates, benzodiazepines, tricyclic antidepressants, and phenothiazines. The toddler was admitted to the pediatric intensive care unit. Blood pressure remained elevated for about 4 hours (125/93-116/78mmHg) and decreased thereafter to normal values. He was treated with oxygen and intravenous normal saline and completely recovered within 36 hours. Blood samples for plasma clotiapine concentration were drawn 5 hours after ingestion and then over the next 34 hours thereafter, 9 samples overall. Plasma clotiapine concentrations were measured by liquid chromatography-tandem mass spectrometry (triple quadrupole mass spectrometer, Micromaass Quattro Ultima PT, connected to an Alliance 2695 HPLC separation module; Waters, Manchester, UK). Clotiapine plasma concentration 5 hours after ingestion was 128.5 ng/mL and gradually decreased to 9 ng/mL 39 hours after ingestion (Figure). Noncompartmental analysis (Kinetica 5.1; Thermo Fisher Scientific, Waltham, MS) was used to evaluate the pharmacokinetic parameters. Clotiapine elimination rate constant (kel) was found to be 0.0751 h (R = 0.9655 for the 9 sampling points), and elimination half-life (t1⁄2) was 9.2 hours. Themain clinicalmanifestations of this pediatric clotiapine overdose were stupor, miosis, and short-lived hypertension. Elimination half-life was 9.2 hours. The patient fully recovered within 39 hours after exposure, corresponding to 4.2 elimination half-lives. Adverse effects reported in adults include tiredness, obstipation, extrapyramidal symptoms, and rash [2]. Neuroleptic malignant syndromewas reported in a child after intramuscular clotiapine administration [8]. Central nervous system depression observed in our patient is compatible with previous reports and our knowledge on antipsychotic agents. The hypertension was short lived and required no treatment. Atypical neuroleptics usually cause hypotension; hypertension was also reported, although its underlying mechanism is not fully elucidated [9]. The pharmacokinetic data on clotiapine are limited. About 25% of an oral dose is eliminated unchanged in the urine, and approximately 10% as conjugated metabolites [10]. There are no data on the peak cal manifestations and toxicokinetics, Am J Emerg Med (2016), http://

The clinical effects of the venomous Lessepsian migrant fish Plotosus lineatus (Thunberg, 1787) in the Southeastern Mediterranean Sea

Abstract Context: Plotosus lineatus is a venomous fish that has migrated from the Indo-Pacific region to the Mediterranean Sea (Lessepsian migrant). Its presence in the Mediterranean Sea was first recorded in 2002 and was observed in growing schools. Its spines contain toxins with lytic, hemolytic and edematous activities. Objective: To characterize the injuries caused by Plotosus lineatus in the Southeastern Mediterranean Sea. Methods: A prospective observational case series of consultations provided by a national Poison Center pertaining to Plotosus lineatus from 2007 to 2016. Demographic and clinical data and method of fish identification were retrieved from the medical toxicological records, and described. Results: Eighty four cases were included; the main findings are: median age 35 (range 3–80) years, 91.7% males, 51.2% fishermen, 78.6% palm injuries, 94% and 4.8% were mildly and moderately injured, respectively. Main local manifestations included pain, puncture wound, swelling, and erythema (90.5%, 70.2%, 33.3%, and 16.7%, respectively). Systemic signs were minor and infrequent (≤7.1%), including hypertension, tachycardia, vomiting, chills, and weakness. Management included wound disinfection, immersion in hot water, tetanus prophylaxis, and analgesics. No patient required hospital admission. The fish was identified mostly by the victim with the aid of the Poison Center (mainly by typical description, and a picture), and some by marine biologists. Conclusions: Plotosus lineatus is a new fish in the Southeastern Mediterranean Sea. It affects fishermen handling fishing nets, and beach hikers stepping on or holding it. Injuries caused by its spines usually result in minor effects; pain may be intense. Treatment includes disinfection, analgesics, and antitetanus and antibiotics as needed. No lethal cases were recorded, unlike exposure of animals to the venom of the Indo-Pacific species; reason is unclear. Our series illustrates the consequences of manmade disruption of ecosystem resulting in invasion of toxic species to a new environment, affecting human health.