Local anesthetic systemic toxicity.

PURPOSE: The practice of regional anesthesia has been revitalized of late with the popularization of ultrasound-guided techniques. Advocates must be vigilant for the effects of unintentionally high blood levels of local anesthetic. Systemic local anesthetic toxicity, though rare, is a potentially devastating occurrence. This narrative review summarizes the effects of local anesthetic toxicity. We highlight how these toxic effects have motivated the search for a safe and long-acting local anesthetic. We outline current prevention and treatment options and appraise an emerging therapy in light of unfolding evidence. SOURCES: A search of the English language literature was conducted using the PubMed database from the National Library of Medicine. Bibliographies of retrieved articles were used to retrieve additional articles. PRINCIPAL FINDINGS: The advent of multiple safety steps has led to a dramatic reduction in the incidence of local anesthetic toxicity over the past 30 years. Rising plasma levels of local anesthetic lead to a progressive spectrum of neurological and cardiac effects. Seizure activity may herald the onset of myocardial depression and ventricular arrhythmias that are often refractory to treatment. In addition to specific measures, such as lipid emulsion therapy, general supportive measures are warranted, for example, Advanced Life Support Guidelines. CONCLUSION: Vigilance during the performance of regional anesthesia and immediate intervention at the earliest sign of toxicity improve the chances of successful treatment.

Late intravascular migration of a previously well functioning labour epidural catheter.

Intravascular epidural catheters may result in insufficient labour analgesia or can produce potentially lethal complications following an epidural top-up. We report a case of a previously well functioning epidural catheter positioned epidurally using a combined spinal epidural anaesthesia technique, which subsequently was found to be intravascular. The literature is reviewed.

The nonerythropoietic component of early bilirubin.

The early labeled bilirubin consists of two primary components. The more rapidly synthesized of the two is independent of erythropoiesis (nonerythropoietic), whereas the second fraction is related to red cell production (erythyropoietic). The present studies concern the origin of the nonerythropoietic component. The nonerythropoietic, early labeled bilirubin was studied in bile fistula rats with (delta ALA)-4-(14)C delta aminolevulinic acid and glycine-2-(14)C as precursors. That nephrectomy did not reduce the size of this component despite the large and rapidly turning over pool of renal heme suggests that this pool may be of minor importance in its production. Intoxication with lead to a level that reduced hepatic heme synthesis was associated with a decrease in early bilirubin formation. The synthesis of this bilirubin was assessed in animals with phenobarbital-induced heme protein and cycloheximide-suppressed protein synthesis. Rats pretreated with phenobarbital at a dose level of 60 mg/kg with induction of cytochrome P-450 synthesis showed a minor increase in early labeling when glycine-2-(14)C but not when delta ALA-4-(14)C was used as precursor. Rats given cycloheximide at a dose level that markedly reduced hepatic protein and cytochrome P-450 synthesis but allowed heme synthesis to continue at 60% of its pretreatment level synthesized normal or increased amounts of early bilirubin from delta ALA-4-(14)C. Allylisopropylacetamide intoxication caused little change in early bilirubin formation, whereas aminotriazole given at a time after maximal hepatic heme labeling produced a small but significant increase in the appearance of labeled bilirubin. These findings indicate that early bilirubin production is little influenced by increased hepatic porphyrin synthesis or by changes in the rapidly turning over heme protein P-450. A minimal increase attends catalase inactivation by aminotriazole. Normal or increased synthesis takes place in the presence of suppression of protein synthesis. This finding suggests that the nonerythropoietic early bilirubin may itself consist of two subcomponents. The first of these may arise from free tissue heme or its precursors, and the second may derive from the turnover of the heme proteins. The first subcomponent may serve as a regulatory mechanism for the removal of heme synthesized in excess of its protein acceptor. A composite scheme is proposed for the origin of the total early bilirubin from heme compartments in tissue and marrow.

Dermatitis por Paederus. Acerca de tres casos / Paederus dermatitis. About three cases

Resumen La "dermatitis por Paederus", es una dermatitis vesicante secundaria al contacto con coleópteros de este género. Se describen más de 600 especies de Paederus, con predominio en áreas tropicales y subtropicales, varias de ellas se asocian a dermatitis. Al ser apretado o aplastado contra la piel, la hemolinfa que contiene paederina, lesiona la epidermis, por medio del bloqueo de la mitosis de células epiteliales basales y células suprabasales. Se exponen tres casos clínicos dermatológicos con lesiones características compatibles con "dermatitis por Paederus". Se realiza además una revisión bibliográfica sobre el tema, a fin de exponer los puntos más importantes de esta patología de gran interés médico y que representa en muchas ocasiones desafíos diagnósticos.

Summary "Paederus dermatitis" is a vesicant dermatitis secondary to contact with this beetle. There are more than 600 species of Paederus described, with a predominance in tropical and subtropical areas, some of these are associated with dermatitis. When they are pressed or crushed against the skin, releases secretions with pederin, that causes an injury in the epidermis, by mitosis blocking of basal and suprabasal epithelial cells. This article describes three dermatological clinical cases with charac-teristic lesions compatible with "Paederus dermatitis". In addition a bibliographic review is presented in order to expose the most important points of this medical interest pathology, that frequently represents diagnostic challenges.

Infrared image monitoring of local anesthetic poisoning in rats.

BACKGROUND AND OBJECTIVES: To evaluate the thermographic predictive value of local anesthetic poisoning in rats that indicates the early recognition of thermal signs of intoxication and enable the immediate start of advanced life support. METHODS: Wistar rats underwent intraperitoneal injection of saline and ropivacaine; they were allocated into pairs, and experiments performed at baseline and experimental times. For thermography, central and peripheral compartment were analyzed, checking the maximum and average differences of temperatures between groups. Thermographic and clinical observations were performed for each experiment, and the times in which the signs of intoxication occurred were recorded. In the thermal analysis, the thermograms corresponding to the times of interest were sought and relevant data sheets extracted for statistical analysis. RESULTS: Basal and experimental: the display of the thermal images at times was possible. It was possible to calculate the heat transfer rate in all cases. At baseline it was possible to see the physiology of microcirculation, characterized by thermal distribution in the craniocaudal direction. It was possible to visualize the pathophysiological changes or thermal dysautonomias caused by intoxication before clinical signs occur, characterized by areas of hyper-radiation, translating autonomic nervous system pathophysiological disorders. In animals poisoned by ropivacaine, there was no statistically significant difference in heat transfer rate at the experimental time. CONCLUSIONS: The maximum temperature, medium temperature, and heat transfer rate were different from the statistical point of view between groups at the experimental time, thus confirming the systemic thermographic predictive value.

The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement.

OBJECTIVE: Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro(TM), a dietary supplement used for weight loss and/or muscle building. METHODS: Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. RESULTS: From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required "new dietary ingredient" notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. CONCLUSIONS: Vigilant surveillance is required for adverse events linked to the use of dietary supplements.

Cycloplegics and mydriatics. Tolerance, habituation, and addiction to topical administration.

A patient had tolerance, habituation, and addiction to the topical use of a combination of cyclopentolate hydrochloride and tropicamide. He also developed a blotchy, diffuse epithelial keratitis that disappeared when the drugs were discontinued.

Blood investigation in a fatality involving the veterinary drug T-61.

A case involving an acute fatality resulting from self-administration of about 30 mL of T-61, a euthanasia solution, consisting of a mixture of embutramide, mebezonium, and tetracaine, in a 58-year-old veterinarian is presented. Forensic investigations consisted of an external body examination, during which 5 mL of fluorinated femoral blood was collected. Embutramide and tetracaine were quantitated using gas chromatography coupled to mass spectrometry after extraction with chloroform/isopropanol/n-heptane (50:17:33, v/v) at pH 9.5 and separation on an HP5-MS capillary column. Mebezonium was quantitated using liquid chromatography coupled to mass spectrometry after ion-pair extraction (saturated KI solution) with methylene chloride at pH 5.4 and separation on a 5-mm Nucleosil C18 column. Blood concentrations were 43.0, 6.5, and 0.21 mg/L for embutramide, mebezonium, and tetracaine, respectively. No other drugs, including ethanol, were detected.

A rapid and sensitive high-performance liquid chromatography method for determination of embutramide (a Tanax or T61 component) in human blood with photodiode-array UV detection.

Tanax or T61 is an euthanasia solution commonly used in veterinary medicine. Embutramide is one of the three components. In accidental intoxication, suicide, or suicide attempt, the determination of embutramide is needed to confirm the hypothesis of intoxication. Because the amount of sample is sometimes limited in forensic cases, a new rapid and sensitive high-performance liquid chromatography method using only 0.1 mL of blood has been developed with liquid-liquid extraction. The eluate was monitored with a photodiode-array detector with a fixed wavelength at 273 nm. The method provided extraction recoveries greater than 83%. The detection limit was 0.2 mg/L, and the limit of quantitation was 0.6 mg/L. The linearity of standards was excellent (r > 0.997). Intra- and interday precisions were acceptable with a coefficient of variation

Hepatotoxicity of N, N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61.

1. We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia product T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61. 2. Serum concentrations of DMF were high as compared with values published on occupational exposure. 3. The patient showed only a transient increase in liver enzymes with eventually a full recovery. 4. The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity. 5. Four series of randomized, controlled and double-blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindividual variations in the effect of DMF. 6. We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experiments.

Fluoroacetamide (1081) oisoning in wild birds.

An outbreak of poisoning in four greylag geese (Anser anser) and 35-45 teal (Anas crecca) is described. Laboratory findings led to the conclusion that a wheat bait containing the rodenticide fluoracetamide (1081) caused the poisoning. Circumstantial evidence incriminated fluoracetamide as the cause of death in white-fronted geese (Anser albifrons), mallards (Anas platyrhynchos), and chukars (Alectoris chukar).

Experiments on direct and secondary poisoning by fluoroacetamide (1081) in wildlife and domestic carnivores.

Fluoroacetamide (1081 or F.A.A) is used in Israel for field rodent control. Experiments on direct and secondary, short and long term poisoning caused by 1081 were carried out. Mongoose (Herpestes ichneumon), hyena (Hyaena hyaena), cats and dogs were susceptible. Barn owls (Tyto alba), buzzards (Buteo buteo) and black kites (Milvus m. migrans) were markedly resistant. Barn owls tolerated total direct poisoning ranging from 6.8 to 10.9, and a final dose ranging from 0.8 to 2.0 mg/kg. In secondary poisoning, total doses ranging from 1.7 to 7.1, and final doses ranging from 0.2 to 1.3 mg/kg were tolerated. Buzzards tolerated total direct poisoning ranging from 6 to 12.0, and final doses ranging from 0.7 to 1.3 mg/kg. In secondary poisoning, doses ranging from 0.8 to 10.3 and final doses ranging from 0.2 to 2.4 mg/kg were tolerated. One black kite tolerated a total direct dose of 6.1 and final dose of 0.7 mg/kg, another survived a total dose of 2.3 and final dose of 0.2 mg/kg in secondary poisoning. A small-scale secondary poisoning experiment on two Palestine vipers (Vipera palestinae), a Syrian black snake (Coluber jugularis) and two Montpellier snakes (Malpolon monspessulanus) indicated that these species were resistant to total doses ranging from 0.1 to 3.2 and final doses of 0.1 to 0.8 mg/kg.

[Coma due to an overdose of valnoctamide]. / Coma door overdosering van valnoctamide.

We report a 27-year-old man, who became comatose after autopoisoning with a high dose of valnoctamide. He was mechanically ventilated for 12 hours and survived without serious side effects. Valnoctamide blood levels were monitored in order to study the pharmacokinetics of oral overdosing of this drug. Serum half-time levels appeared to be approximately 15 hours.

Distribution of embutramide and mebezonium iodide in a suicide after tanax injection.

Tanax is a veterinary formulation for euthanasia comprising embutramide, mebezonium iodide and tetracaine. A 37-year-old female was found dead on her bed, with three empty used syringes and a bottle of Tanax beside her body. Three needle puncture marks were observed on the body. The aim of this study was to evaluate the distribution of embutramide and mebezonium iodide in different biological matrices (femoral and cardiac blood, liver, muscle and vitreous humor) using a chromatographic method for the simultaneous determination of the two drugs. A direct and sensitive liquid chromatography-tandem mass spectrometry method was developed in multiple reaction monitoring mode with positive ionization. Lidocaine was used as an internal standard. Limits of detection and quantitation of 0.01 and 0.05 mg/L, respectively, were reached for both compounds. Embutramide levels ranged from 2.74 mg/L in vitreous humor to 5.06 mg/L in femoral blood, while mebezonium iodide was found at widely differing concentrations (ranging from 2.80 mg/kg in muscle to 24.80 mg/kg in liver). The chromatographic method developed for this study provides a very simple and sensitive means for the simultaneous determination of embutramide and mebezonium iodide, the emetic concentrations of which were consistent with suicides reported in the literature.

Infrared image monitoring of local anesthetic poisoning in rats / Monitorização por imagem infravermelha da intoxicação por anestésico local em ratos

Abstract Background and objectives: To evaluate the thermographic predictive value of local anesthetic poisoning in rats that indicates the early recognition of thermal signs of intoxication and enable the immediate start of advanced life support. Methods: Wistar rats underwent intraperitoneal injection of saline and ropivacaine; they were allocated into pairs, and experiments performed at baseline and experimental times. For thermography, central and peripheral compartment were analyzed, checking the maximum and average differences of temperatures between groups. Thermographic and clinical observations were performed for each experiment, and the times in which the signs of intoxication occurred were recorded. In the thermal analysis, the thermograms corresponding to the times of interest were sought and relevant data sheets extracted for statistical analysis. Results: Basal and experimental: the display of the thermal images at times was possible. It was possible to calculate the heat transfer rate in all cases. At baseline it was possible to see the physiology of microcirculation, characterized by thermal distribution in the craniocaudal direction. It was possible to visualize the pathophysiological changes or thermal dysautonomias caused by intoxication before clinical signs occur, characterized by areas of hyper-radiation, translating autonomic nervous system pathophysiological disorders. In animals poisoned by ropivacaine, there was no statistically significant difference in heat transfer rate at the experimental time. Conclusions: The maximum temperature, medium temperature, and heat transfer rate were different from the statistical point of view between groups at the experimental time, thus confirming the systemic thermographic predictive value.

Resumo Justificativa e objetivos: Estudar o valor preditivo termográfico na intoxicação por anestésico local em ratos que efetue o reconhecimento precoce dos sinais térmicos de intoxicação e possibilite o início imediato do suporte avançado de vida. Método: Ratos Wistar foram submetidos à injeção intraperitoneal de soro fisiológico e ropivacaína, alocados aos pares, e foram feitos experimentos em tempos basal e experimental. Para o estudo termodinâmico foram analisados o compartimento central e o periférico, verificaram-se as diferenças das temperaturas máximas e médias entre os grupos. Foram feitas observações clínicas e termográficas para cada experimento e anotados os tempos em que os sinais de intoxicação ocorriam. Foram buscados na análise termográfica os termogramas correspondentes aos tempos de interesse e extraídas as planilhas de dados correspondentes, para análise estatística. Resultados: Foi possível a visibilização das imagens térmicas nos momentos basal e experimental. Foi possível calcular a taxa de transferência de calor em todos os casos. No momento basal foi possível observar a fisiologia da microcirculação, caracterizada por distribuição térmica no sentido craniocaudal. Foi possível visibilizar as alterações fisiopatológicas ou disautonomias térmicas causadas pela intoxicação antes que os sinais clínicos ocorressem, caracterizadas por áreas de hiperradiação e traduziram perturbações fisiopatológicas do Sistema Nervoso Autônomo. Nos animais intoxicados por ropivacaína houve diferença estatisticamente significativa na taxa de transferência de calor no momento experimental. Conclusões: Constatou-se que a temperatura máxima, a temperatura média e a taxa de transferência de calor foram diferentes do ponto de vista estatístico entre os grupos no momento experimental, o que corrobora o valor preditivo termográfico sistêmico.

Dimethylformamide metabolism following self-harm using a veterinary euthanasia product.

BACKGROUND: A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (DMF; T-61® or Tanax®) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent DMF. The protective role of N-acetylcysteine (NAC) administration remains debatable. MATERIAL AND METHODS: Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 h in the second). Urine was collected for the serial determination of DMF, N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC). RESULTS: Both patients developed only mild signs of liver injury. The metabolite of DMF, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of DMF and DMF metabolites were slightly slower than those reported in exposed workers. CONCLUSIONS: While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion. Further investigations of NMF and AMCC excretion, with and without NAC, would be indicated.