Faculty Bibliography

OBJECTIVE: Loperamide, a non-prescription anti-diarrheal agent, is a peripheral mu-opioid receptor agonist that is excluded from the blood-brain barrier by p-glycoprotein at therapeutic doses. Overdoses of loperamide penetrate the central nervous system (CNS), leading to abuse. We report cardiac conduction abnormalities and dysrhythmias after ingestion of a recreational supra-therapeutic dose of loperamide confirmed with an elevated blood loperamide concentration. CASE DETAILS: A 48-year-old woman with a history of alcohol and benzodiazepine abuse presented to the emergency department (ED) with somnolence, weakness and slurred speech. She was taking 20 to 40 tablets of 2 mg loperamide 1-2 times/day for weeks along with clonazepam and whiskey. Vital signs were: blood pressure (BP), 124/90 mmHg; heart rate (HR), 88/min; respiratory rate(RR), 20/min; T, 36.9 degrees C; O2 saturation 100% on room air (RA). Glucose was 6.4 mmol/L. Electrocardiogram (ECG) had a ventricular rate of 58/min, QRS 164 ms, QT 582 ms with no discernable p-waves. Lactate was 3.5 mmol/L and potassium was 6.2 mEq/L. Labs were notable for an anion gap of 20 mEq/L, ethanol of 3.9 mmol/L, creatinine of 2.3 mg/dL and loperamide concentration of 210 ng/mL (average therapeutic plasma concentration 1.2 ng/mL). She became hypotensive, but responded to fluids. Following treatment for hyperkalemia with calcium, insulin, dextrose, and hypertonic sodium bicarbonate a repeat ECG had a ventricular rate of 66/min, QRS 156 ms, and QT 576 ms. Magnesium was given and pacer pads were placed. During the infusion of magnesium, her BP fell to 92/58 mmHg with a HR of 54/min, RR 14/min, O2 saturation of 97% on RA so the infusion was stopped. The ECG after the magnesium infusion had a ventricular rate of 51/min, QRS of 134 ms, and QT 614 ms. In the ICU she had multiple runs of non-sustained ventricular tachycardia that did not require therapy. Over the next 48 h she improved and was transferred to a floor bed. On day four of hospitalization the patient left against medical advice. At that time, her ECG showed sinus tachycardia with a heart rate 114/min, QRS 82 ms, QT 334 ms. DISCUSSION: Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing. A blood loperamide concentration of 210 ng/mL is among the highest concentrations reported. Supra-therapeutic dosing of loperamide is promoted on multiple drug-use websites and online forums as a treatment for opioid withdrawal, as well as for euphoric effects. With the current epidemic of prescription opioid abuse, toxicity related to loperamide, an opioid agonist that is readily available without a prescription is occurring more frequently. It is important for clinicians to be aware of the potentially life-threatening toxicity related to loperamide abuse in order to provide proper diagnosis, management and patient education.

BACKGROUND: The use of intravenous lipid emulsion (ILE) therapy for the treatment of lipophilic drug toxicity is increasing. Despite this, the evidence for its effect in non-local anesthetic toxicity remains sparse. Furthermore, many case reports describe ILE use for substances in which no clear efficacy data exists. The American Academy of Clinical Toxicology established a lipid emulsion workgroup. The aim of this group is to review the available evidence regarding the effect of ILE in non-LA drug poisoning and develop consensus-based recommendations on the use of this therapy. METHODS: A systematic review of the literature was performed to capture articles through 15 December 2014. Relevant articles were determined based upon a predefined methodology. Articles involving pre-treatment experiments, pharmacokinetic studies not involving toxicity, and studies not addressing antidotal use of ILE met pre-defined exclusion criteria. Agreement of at least two members of the subgroup was required before an article could be excluded. RESULTS: The final analysis included 203 articles: 141 for humans and 62 for animals. These include 40 animal experiments and 22 case reports involving animal toxicity. There were three human randomized control trials (RCT): one RCT examined ILE in TCA overdose, one RCT examined ILE in various overdoses, and one study examined ILE in reversal of sedation after therapeutic administration of inhaled anesthesia. One observational study examined ILE in glyphosate overdose. In addition, 137 human case reports or case series were identified. Intravenous lipid emulsion therapy was used in the management of overdose with 65 unique substances. CONCLUSIONS: Despite the use of ILE for multiple substances in the treatment of patients with poisoning and overdose, the effect of ILE in various non-local anesthetic poisonings is heterogenous, and the quality of evidence remains low to very low.

BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, we present our results for digoxin. METHODS: After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. RESULTS: Out of 435 articles screened, 77 met inclusion criteria. Only in-vitro, animal studies, case reports and case series were identified yielding a very low quality of evidence for all recommendations. Based on data from 84 patients, including six fatalities, it was concluded that digoxin is slightly dialyzable (level of evidence = B), and that ECTR is unlikely to improve the outcome of digoxin-toxic patients whether or not digoxin immune Fab (Fab) is administered. Despite the lack of robust clinical evidence, the workgroup recommended against the use of ECTR in cases of severe digoxin poisoning when Fab was available (1D) and also suggested against the use of ECTR when Fab was unavailable (2D). CONCLUSION: ECTR, in any form, is not indicated for either suspected or proven digoxin toxicity, regardless of the clinical context, and is not indicated for removal of digoxin-Fab complex.

BACKGROUND: Novel psychoactive substances (NPS) are emerging at an unprecedented rate. Likewise, prevalence of use and poisonings has increased in recent years. OBJECTIVE: To compare characteristics of NPS exposures and non-NPS-drug-related exposures and to examine whether there are differences between exposures involving synthetic cannabinoid receptor agonists (SCRAs) and other NPS. METHODS: Poison control center data from the five counties of New York City and Long Island were examined from 2011-2014. We examined prevalence and characteristics of NPS exposures (classified as intentional abuse) and compared characteristics of cases involving SCRAs and other NPS. RESULTS: Prevalence of NPS exposures was 7.1% in 2011, rising to 12.6% in 2014. Most exposures (82.3%) involved SCRA use. The second and third most prevalent classes were phenethylamines/synthetic cathinones ("bath salts"; 10.2%) and psychedelic phenethylamines (4.3%). Compared to other drug-related exposures (i.e. involving licit and illicit drugs), those who used NPS were more likely to be younger, male, and to have not co-used other drugs (ps < 0.001). SCRA exposures increased sharply in 2014 and the mean age of users increased over time (p < 0.01). Females exposed to SCRAs were younger than males (p < 0.001), and in 2014, individuals exposed to SCRAs were more likely to report concomitant use of alcohol than users of other NPS (p = 0.010). Users of other NPS were more likely than SCRA users to report concomitant use of ecstasy/3,4-methylenedioxymethamphetamine (MDMA)/"Molly" (p < 0.001). CONCLUSION: Exposures reported to the poison center that involve NPS are increasing and the majority involve SCRAs. These findings should inform prevention and harm reduction approaches.

Context Although the clinical use of intravenous lipid emulsion therapy for the treatment of lipophilic drug toxicity is increasing, the focus of most publications is on outcome in laboratory animals or in patients. An unintended consequence of intravenous lipid emulsion is the creation of extremely lipemic blood, which may interfere with the laboratory analysis or interpretation of common analytes. Objective The American Academy of Clinical Toxicology has established a lipid emulsion workgroup to review the evidence and produce recommendations on the use of this novel therapy for drug toxicity. The aim of this subgroup is to review the available evidence regarding the effect of intravenous lipid emulsion on common laboratory testing, which often forms the basis of the appraisal of the balance between benefits and potential adverse events. Methods We performed a comprehensive review of the literature. Relevant articles were determined based upon a predefined methodology. Package inserts of manufacturers' assays were collected. Article inclusion required that the article met predefined inclusion criteria with the agreement of at least two members of the subgroup. Results We included thirty-six articles in the final analysis. Evaluation of the reviewed analytes revealed heterogeneity with regards to the assessment of the effect of intravenous lipid emulsion in terms of consistency and magnitude of effect across the different analytic platforms. Conclusions The measurements of a number of common analytes can be markedly affected by the lipemia produced by lipid emulsions such that they cannot always be interpreted in the way that most physicians use this information in typical clinical situations. In fact, a lack of appreciation of this effect may lead to unintentional treatment errors. Because the effect of the lipemia produced is dependent on the reagents and laboratory platform used, it would be useful for all future reports to clearly document sample handling, reagents and laboratory platform used, as well as any procedures employed to reduce the lipid content.

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.