Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning

Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy.(AU)

Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018.

Although the putative pharmacological targets of synthetic cannabinoids (SCBs) abused in "K2" and "Spice" are similar to Δ(9) -tetrahydrocannabinol (Δ(9) -THC), it remains unclear why SCB toxicity is similar yet different from marijuana. There are obvious potency and efficacy differences, but also important metabolic differences that help explain the unique adverse reactions associated with SCBs. This brief review discusses the limited research on the metabolism of the SCB JWH-018 and contrasts that with the metabolism of Δ(9) -THC.

Retained drugs in the gastrointestinal tracts of deceased victims of oral drug overdose.

CONTEXT: The extent of non-absorbed drug burden in the GI tract following overdose is unknown. Patients who present with clinical signs of toxicity may not undergo decontamination due to assumption that the drug has already been completely absorbed and because of limited scientific evidence of benefit for routine GI decontamination in poisoned patients. OBJECTIVE: The goal of this study was to assess whether people who die of an oral overdose have unabsorbed drug present in the GI tract. The secondary goal was to analyze pharmacologic characteristics of retained drugs when present. MATERIALS AND METHODS: Retrospective review of autopsy reports from 2008 to 2010, whose cause of death was determined as "intoxication" or "overdose, was performed at the Office of Chief Medical Examiner of the City of New York (OCME NYC)." Decedents of all ages were identified via electronic OCME database. Inclusion criteria were as follows: 1) cause of death "intoxication" or "overdose" noted by forensic autopsy, 2) ingestion of a solid drug formulation. RESULTS: 92 out of 1038 autopsies (9%) that met inclusion criteria had documentation of retained pill fragments, granules, paste, sludge, slurry, or whole pills in the GI tract. The most common drugs found were opioids and anticholinergics. Ninety-eight percent (98%) of the retained drugs were either modified-release preparations or drugs known to slow GI transit. Most decedents were dead on arrival; there were twelve in-hospital deaths and eleven patients died in the Emergency Department. Bupropion and venlafaxine were responsible for four deaths in those who received medical care. One person died in the ICU following bupropion ingestion. DISCUSSION AND CONCLUSION: Overdose of an oral drug that either has modified-release properties or slows GI tract motility may result in substantial unabsorbed drug burden remaining in the GI tract.

A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid.

OBJECTIVE: Synthetic cannabinoids are increasingly used in the United States as marijuana substitutes. However, reports of severe toxicity, resulting from their use, are limited. We present the case of acute cerebral infarction following synthetic cannabinoid inhalation. CASE REPORT: A 33-year-old man with no significant medical history presented at the emergency department with right-sided weakness and aphasia. He had smoked a synthetic cannabinoid (SC) product called "WTF" prior to the onset of symptoms. Physical examination showed right hemiparesis, dysarthria, and aphasia. Laboratory evaluation, electrocardiography, and computed tomography (CT) of the head were unremarkable. Following administration of intravenous tissue plasminogen activator, his symptoms improved. A repeat head CT showed acute infarction in the left insular cortex. His hypercoagulability panel was unremarkable, and the patient was discharged neurologically intact. Urine toxicology results were unremarkable. Analysis of the product by gas chromatography-mass spectrometry (GC-MS) procedure confirmed the presence of a synthetic cannabinoid known as XLR-11. CONCLUSION: XLR-11 has previously been associated with acute kidney injury in humans. However, there are no reports of it causing acute cerebral ischemic events. The close temporal association between XLR-11 inhalation and his stroke is concerning. Acute cerebral infarction may occur after XLR-11 use in healthy patients.

Effects of hydroxocobalamin on carboxyhemoglobin measured under physiologic and pathologic conditions.

CONTEXT: Pre-hospital administration of hydroxocobalamin (B12a) is used for empiric treatment of cyanide poisoning because cyanide poisoning is difficult to identify and requires immediate treatment. B12a interferes with the accuracy of several blood laboratory tests. This study aimed to explore how B12a affects carboxyhemoglobin (COHb) measurements in human blood at both physiologic and pathologic COHb levels. METHODS: Several clinically relevant concentrations of B12a were added to human blood samples containing physiologic (∼ 3%) and pathologic (30% and 50%) COHb levels. We then measured the COHb levels of the samples using two different co-oximeters, the Radiometer ABL 700 and the Rapidpoint 500, and compared to their actual baseline COHb levels. RESULTS: B12a had minimal effects on the COHb measured at both physiologic and pathologic levels when measured on the Radiometer. In contrast, the Rapidpoint B12a caused a dose-dependent decrease in the COHb measured, especially of pathologic COHb levels (∼ 30 and 50%). CONCLUSION: The magnitude of B12a interference on measured COHb is dependent upon the specific co-oximeter used, the actual COHb level and the serum B12a concentration. These errors may potentially influence clinical decision making and thus affect patient outcomes. Our findings emphasize the importance of measuring COHb levels on blood samples collected prior to B12a administration.

Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup.

BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). METHODS: After a systematic review of the literature, a subgroup selected and reviewed the articles and summarized clinical and toxicokinetic data in order to propose structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Following discussion, a second vote determined the final recommendations. RESULTS: Twenty-four articles (1 randomized controlled trial, 1 observational study, 2 pharmacokinetic studies, and 20 case reports or case series) were identified, yielding an overall very low quality of evidence for all recommendations. Clinical data on 135 patients and toxicokinetic data on 54 patients were analyzed. Twenty-three fatalities were reviewed. The workgroup agreed that N-acetylcysteine (NAC) is the mainstay of treatment, and that ECTR is not warranted in most cases of APAP poisoning. However, given that APAP is dialyzable, the workgroup agreed that ECTR is suggested in patients with excessively large overdoses who display features of mitochondrial dysfunction. This is reflected by early development of altered mental status and severe metabolic acidosis prior to the onset of hepatic failure. Specific recommendations for ECTR include an APAP concentration over 1000 mg/L if NAC is not administered (1D), signs of mitochondrial dysfunction and an APAP concentration over 700 mg/L (4630 mmol/L) if NAC is not administered (1D) and signs of mitochondrial dysfunction and an APAP concentration over 900 mg/L (5960 mmol/L) if NAC is administered (1D). Intermittent hemodialysis (HD) is the preferred ECTR modality in APAP poisoning (1D). CONCLUSION: APAP is amenable to extracorporeal removal. Due to the efficacy of NAC, ECTR is reserved for rare situations when the efficacy of NAC has not been definitively demonstrated.

Chronic hematuria and abdominal pain.

An 18-year-old Asian woman with a history of substance abuse presented to the Emergency Department with right-sided abdominal pain and hematuria of several months duration. Physical examination revealed right upper quadrant and suprapubic tenderness. Liver function tests were normal. Urinalysis showed: large blood, 30-50 red blood cells/high-powered field, and no bacteria. She underwent a CT of the abdomen and pelvis following oral and intravenous contrast.

Hemodialysis clearance of glyphosate following a life-threatening ingestion of glyphosate-surfactant herbicide.

CONTEXT: Ingestion of glyphosate-surfactant herbicides (GlySH) can result in acute kidney injury, electrolyte abnormalities, acidosis, cardiovascular collapse, and death. In severe toxicity, the use of hemodialysis is reported, but largely unsupported by kinetic analysis. We report the dialysis clearance of glyphosate following a suicidal ingestion of a glyphosate-containing herbicide. CASE DETAILS: A 62-year-old man was brought to the emergency department (ED) 8.5 h after drinking a bottle of commercial herbicide containing a 41% solution of glyphosate isopropylamine, in polyoxyethyleneamine (POEA) surfactant and water. He was bradycardic and obtunded with respiratory depression necessitating intubation and mechanical ventilation. Initial laboratory results were significant for the following: pH, 7.11; PCO2, 64 mmHg; PO2, 48 mmHg; potassium, 7.8 mEq/L; Cr 3.3, mg/dL; bicarbonate, 22 mEq/L; anion gap, 18 mEq/L; and lactate, 7.5 mmol/L. Acidosis and hyperkalemia persisted despite ventilation and fluid resuscitation. The patient underwent hemodialysis 16 h post ingestion, after which he demonstrated resolution of acidosis and hyperkalemia, and improvement in clinical status. Serum glyphosate concentrations were drawn prior to, during, and after hemodialysis. The extraction ratio and hemodialysis clearance were calculated to be 91.8% and 97.5 mL/min, respectively. DISCUSSION: We demonstrate the successful clearance of glyphosate using hemodialysis, with corresponding clinical improvement in a patient with several poor prognostic factors (advanced age, large volume ingested, and impaired consciousness). The effects of hemodialysis on the surfactant compound are unknown. Hemodialysis can be considered when severe acidosis and acute kidney injury complicate ingestion of glyphosate-containing products.

Carbon monoxide exposures in New York City following Hurricane Sandy in 2012.

CONTEXT: On October 29, 2012, Hurricane Sandy made landfall and devastated New York's metropolitan area, causing widespread damage to homes and the utility infrastructure. Eight days later, snow and freezing temperatures from a nor'easter storm delayed utility restoration. OBJECTIVE: To examine carbon monoxide (CO) exposures in the 2 weeks following Hurricane Sandy. Methods. This was a retrospective review of prospectively collected, standardized, and de-identified data sets. CO exposures and poisonings identified from two electronic surveillance systems, the New York City Poison Control Center (NYCPCC) and New York City's Syndromic Surveillance Unit, were compared with CO exposures from identical dates in 2008-2011. Data collected from the poison center included exposure type, CO source, poisoning type, treatment, and outcomes. Data collected from the Syndromic Surveillance Unit cases, which were identified by CO-related chief complaints presenting to NYC hospitals, included visit date and time, and patient demographics. RESULTS: Four hundred thirty-seven CO exposures were reported to the NYCPCC, 355 from NYC callers, and the remainder from surrounding counties, which represented a significant increase when compared with CO exposures from identical dates in the preceding 4 years (p < 0.001). The total cases that were reported to the NYCPCC in 2008, 2009, 2010, and 2011 were 18, 13, 24, and 61, respectively. Excluding a single apartment fire that occurred (n = 311), the more common sources of CO were grilling indoors (26.2%) and generators (17.5%). Syndromic surveillance captured 70 cases; 6 cases were captured by both data sets. CONCLUSIONS: CO exposures following weather-related disasters are a significant public health concern, and the use of fuel-burning equipment is a clear source of storm-related morbidity and mortality. Multiple real-time epidemiologic surveillance tools are useful in estimating the prevalence of CO exposure and poisoning and are necessary to assist public health efforts to prevent CO poisoning during and after disasters.

[Emergent drugs (II): the Pharming phenomenon]. / Drogas emergentes (II): el pharming.

The use of medicines, with or without medical prescription, for recreational ends by the young population has received little attention from doctors. In the USA, one in five adolescents has used medicines for recreational purposes, and consultations in Emergency Departments for medicine abuse have exceeded those for illegal drugs. Although few data are available in Spain, such consumption is situated between 3.1 and 8.6% according to surveys. The medicines most used are dextromethorphan and methylphenidate. The former, on sale without prescription, presents a varied symptomatology, dosage and dependent metabolic action, ranging from euphoria to hallucinations. Methylphenidate, taken orally, nasally or intravenously, is used as a stimulant in substitution for cocaine and is one of the medicines most diverted onto the illicit market at the world level. In principle, other substances like modafinil and propofol present a limited incidence of non-medical use, but they have a probable abuse potential that should be borne in mind, above all in the health context. Finally, opiates like fentanyl, oxycodone and buprenorphine, with new pharmaceutical presentations, have recently become generalized in the therapeutic arsenal of many medical specialities; they are giving rise to phenomena of abuse, dependence and diversion towards the illicit market. Demands for detoxification treatment, their mixture with illegal substances, and cases of death should alert us to the abuse of these medicines.

Treating acetaminophen overdose: thresholds, costs and uncertainties.

The United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) modified the indications for N-acetylcysteine therapy of acetaminophen (paracetamol) overdose in September 2012. The new treatment threshold line was lowered to 100 mg/L (662 µmol/L) for a 4 hours acetaminophen concentration from the previous 200 mg/L (1325 µmol/L). This decision has the potential to substantially increase overall costs associated with acetaminophen overdose with unclear benefits from a marginal increase in patients protected from hepatotoxicity, fulminant hepatic failure, death, or transplant. Changing the treatment threshold for acetaminophen overdose also implies that ingestion amounts previously thought not to require acetaminophen concentration measurements would need to be revised. As a result, more individuals will be sent to hospitals in order that everyone with a predicted 4 hours concentration above the 100 mg/L line will have concentrations measured and potentially be treated with N-acetylcysteine. Before others consider adopting this new treatment guideline, formal cost-effectiveness analyses need to be performed to define the appropriate thresholds for referral and treatment.

[Emergent drugs (III): hallucinogenic plants and mushrooms]. / Drogas emergentes (III): plantas y hongos alucinógenos.

An increase in the consumption of vegetable substances with a hallucinogenic effect has been observed. Some of these substances are associated with ancestral religious ceremonies, while many of them are legal or are partially regulated. Salvia divinorum is a powerful kappa receptor agonist, with dissociative and hallucinogenic properties, which start quickly and have a short duration. Kratom (Mytragyna speciosa) has mitragynine as its principal alkaloid, with stimulating effects at low doses (coke-like effect), and sedative effects (opiate-like effect) at high doses. Several deaths from its consumption have been detected. The consumption of hallucinogenic mushrooms appears in cyclic form, although there has been increase in their online offer. They are consumed in search of their hallucinogenic effects, above all those belonging to the family of psilocybes, which contain tryptamines with a hallucinogenic effect similar to LSD. Peyote (Lophophora psilocybes), a cactus rich in mescaline (trimetoxifeniletilamina), produces hallucinations of the five senses, and forms part of the religious culture of the North American Indians. Daturas, which are ubiquitous, produce anticholinergic symptoms and effects on the central nervous system (delirium, hallucinations, etc.), due to their high atropine and scopolamine content. Other substances used for their hallucinogenic effects include the drink known as ayahuasca, and seeds for preparing infusions like Ololiuqui, Morning Glory (Ipomoea violacea), Hawaian Baby Woodrose (Argyreia nervosa), Syrian Rue (Peganum harmala) and Iboga Rootbark (Tabernanthe iboga).

Health risks of using mothballs in Greater Accra, Ghana.

OBJECTIVE: Internal use of 'camphor' is a potential public health concern in Accra. We sought to identify the toxins being sold as mothballs in Greater Accra and use this information to help educate both clinicians and the public. METHODS: Mothballs are commonly sold by street and marketplace vendors in unmarked cling film-wrapped packs. Fifteen small packs of mothballs were purchased from random vendors in three major markets and six roadside stands in Greater Accra. All samples were subjected to the float test; one sample was confirmed by gas chromatography/mass spectroscopy. RESULTS: All samples sank in tap water but floated in a saturated salt solution, consistent with naphthalene. The analysed sample was identified as naphthalene. CONCLUSION: Naphthalene was most likely the primary ingredient in all the mothballs purchased for the study. Naphthalene is poorly soluble in water, and 'camphor water' is unlikely to cause harm. However, ideas about the efficacy of 'camphor' as a purification tool may lead to therapeutic misuse by analogy. A high prevalence of G6PD in the Ghanaian population may increase the risk of toxic haematologic effects from ingestion of mothballs. Mothballs known in Greater Accra as 'camphor' are likely to be predominantly naphthalene. A public awareness campaign about the health risks of mothball ingestion is planned.

Severe toxicity following synthetic cannabinoid ingestion.

OBJECTIVE: To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion. BACKGROUND: Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis. CASE REPORT: A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient's urine (200 nM) using liquid chromatography tandem mass spectrometry. DISCUSSION: Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana. CONCLUSION: Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.

Toxicology from across the pond.

Despite extensive educational and preventive efforts, fatality from poisoning is a growing public health concern. While strategies to reduce fatal unintentional poisoning in children have been largely successful, growing numbers of deaths from suicidality and substance abuse present unique challenges to the public health system. This paper explores three areas where new approaches hope to mitigate major causes of poison-related fatality. Included in this discussion are bystander naloxone for opioid overdose, a reconsideration of the optimal dose of N-acetylcysteine therapy and intravenous fat emulsion (lipid rescue) therapy for cardiovascular toxins. These innovative approaches are designed to challenge dogma and provide a stimulus for individualised clinical care.

Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity.

Some experimental models suggest that the use of pralidoxime in carbamate toxicity is deleterious. Although pretreatment with atropine minimizes the adverse effect of pralidoxime reported in these models, concerns over the risks of pralidoxime in humans with carbamate poisoning continue. We present a unique case of carbamate toxicity treated successfully with pralidoxime alone. An 80-year-old woman with Alzheimer's dementia presented to the emergency department with 3-4 days of lightheadedness, vomiting, diarrhea, and bilateral lower extremity muscle pain. Extensive review of systems was otherwise negative. Her vital signs were BP, 207/85 mmHg; pulse, 101 beats/min; rectal temperature, 36.6( degrees )C; respirations, 18/min; and SpO(2), 95% breathing room air. Her bedside glucose measurement was 6.7 mmol/L. Physical examination revealed a confused, diaphoretic, ill-appearing woman with miosis and fasciculations of the tongue, eyelids, gastrocnemius and quadriceps bilaterally. The heart, lung, abdominal and head, eyes, ears, nose and throat examinations were otherwise unremarkable. Nine 5-cm(2) rivastigmine patches (9.5 mg/24-hour) were found adherent to her torso and lower extremities. The patches were immediately removed and underlying skin cleansed with soap and water. Laboratory values including complete blood count, basic metabolic panel, calcium, magnesium, phosphorus, troponin, coagulation studies and urinalysis were unremarkable. Due to the absence of pulmonary muscarinic findings, no atropine was administered. However, 1 g of pralidoxime was administered intravenously over 30 min to treat fasciculations. Within 30 min of this treatment, there was significant improvement in symptoms and resolution of fasciculations. She was admitted to the hospital, required no further pralidoxime therapy and was discharged after 3 days. Rivastigmine is a reversible (carbamate) cholinesterase inhibitor used to treat dementia. In overdose, cholinergic crisis is expected and in this case was precipitated by patch overuse. We believe there was a causal relationship between pralidoxime administration and the prompt resolution of symptoms and fasciculations. This case of apparently safe and effective pralidoxime use without concomitant atropine administration in a patient with carbamate toxicity reinforces recent data demonstrating the potential safety of pralidoxime in carbamate toxicity.

Adverse effects associated with arginine alpha-ketoglutarate containing supplements.

The athletic performance supplement industry is a multibillion-dollar business and one popular category claims to increase nitric oxide (NO) production. We report three patients presenting to the emergency department with adverse effects. A 33-year-old man presented with palpitations, dizziness, vomiting, and syncope, after the use of NO(2) platinum. His examination and electrocardiogram (ECG) were normal. The dizziness persisted, requiring admission overnight. A 21-year-old man with palpitations and near syncope had used a "nitric oxide" supplement. He was tachycardic to 115 bpm with otherwise normal examination. Laboratory values including methemoglobin, and ECG were unremarkable. He was treated with 1 L of saline with no change in heart rate. He was admitted for observation. A 24-year-old man presented after taking NO-Xplode with palpitations and a headache. His examination, laboratory values, and ECG were normal. He was discharged. The purported active ingredient in these products is arginine alpha-ketoglutarate (AAKG), which is claimed to increase NO production by supplying the precursor L-arginine. The symptoms could be due to vasodilation from increased levels of NO, though other etiologies cannot be excluded. AAKG containing supplements may be associated with adverse effects requiring hospital admission.