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.

Caustics are common in household and industrial products, and, when ingested, they can pose a significant public health risk. Caustic exposures in adults typically present in the setting of occupational exposure or suicide attempt; exposures in children occur most often by unintentional ingestion. Caustics cause local damage upon contact with tissue surfaces and can lead to systemic toxicity. Endoscopy is recommended in all intentional ingestions (and many unintentional ingestions) to grade injury severity, determine treatment options, and assess prognosis; however, it is generally best performed within 24 hours post ingestion to avoid risk of perforation. Radiography and computed tomography may also be used to visualize injury in certain cases. This review examines the pathophysiology of caustic exposures, their clinical presentations, and the most current evidence on recommendations for decontamination, surgical consult, treatment, and disposition.

Background: ASA poisoning remains a significant public health threat with upwards of 20,000 exposures annually in the US and morbidity/mortality rates of up to 25%. Objectives: In order to facilitate targeted treatment to lower these rates, we aimed to establish early predictors of severe in-hospital outcomes in ED patients presenting with ASA poisoning. Methods: This was a secondary data analysis of ASA overdoses from a prospective cohort study of suspected acute drug overdoses at two urban university teaching hospitals from 2009-2013. Patients were enrolled consecutively and were considered eligible for inclusion based on clinical suspicion of ASA ingestion. Children (<18) and alternate diagnoses were excluded. Demographics, clinical parameters, serum ASA concentrations, treatment modalities and death/admission rate were collected from the medical record. Severe outcome was defined as a composite occurrence of any of the following: acidemia (pH<7.3 or bicarbonate<16mEq/L), hemodialysis, or death. Results: 48 patients met inclusion criteria, with 43.8% male, median age 32, mean initial ASA concentration 28.1, and 10 (21%) classified as severe outcome. There were two deaths, neither of whom received hemodialysis. Patients were treated with sodium bicarbonate in onethird of cases, while 54.2% received activated charcoal and 64.6% were admitted. Univariate analysis indicated that age, respiratory rate (RR), creatinine, lactate, coma, and presence of co-ingestions were significantly associated with severe outcome, while ASA alone had no association. However, when adjusted for serum ASA concentration, only age (OR 1.02 per additional year, 95%CI 1.0-1.1), RR (1.09 per additional breath/min, 95%CI 1.03-1.15), creatinine (2.8 per additional mg/dL 95%CI 1.1-7.1), and co-ingestions (OR 6.4, 95%CI 2.3-17.8) were independent predictors of severe outcome. Conclusion: Age, RR, creatinine, and co-ingestions are predictive of severe outcome in ED patients with acute ASA poisoning, while serum ASA concentration alone is not. Despite the severity of these cases, only one-third received sodium bicarbonate, suggesting potential barriers to administration which require further study

Background: Adverse cardiovascular events (ACVE) complicate up to 16.9% of hospitalizations for acute drug overdose. We previously derived a risk prediction rule for ACVE in these patients with 97.1% negative predictive value. Objectives: Our aim was to internally validate the ACVE rule test characteristics. Methods: This prospective cohort study was conducted over 17 months (2012-14) at 2 urban teaching hospitals. Patients were adults with suspected acute drug overdose enrolled from the ED. The study outcome, ACVE, was defined as any of the following: myocardial injury (elevated troponin I), shock (requiring vasopressors), ventricular dysrhythmia (VT/VF/TdP), or cardiac arrest (pulseless requiring CPR). The rule included any of these 3 factors: (1) prior cardiac disease (CAD or CHF); (2) QTc > 500ms; (3) initial serum bicarbonate < 20 mmol/L. Sample size was predetermined in order to produce test characteristics with 95% CI widths <5%; we calculated the need to analyze 900 patients. Results: There were 1,457 patients screened, of whom 552 were excluded (185 non-drug overdose, 145 pediatrics, 111 missing data, 110 alternate diagnosis, 1 chronic), leaving 905 for analysis (mean age, 41 years; female, 44%; suicidal, 40%). ACVE occurred in 65 (7.2%, CI 5.6- 9.1) patients (myocardial injury, 44; shock, 31; dysrhythmia, 16; cardiac arrests, 17) and there were 16 (1.8%, CI 0.9-2.6) deaths. The multivariable model adjusting for the previously derived risk factors, controlling for age, confirmed the following independent predictors of ACVE: QTc >500 msec (OR 5.5, CI 2.8-10.9), bicarbonate <20 mmol/L (OR 2.7, CI 1.5-4.9), and prior cardiac disease (OR 39.5, CI 17.9-87). The validated prediction rule had 75.4% (CI 63.1-85.2) sensitivity, 82.3% specificity (CI 79.9-85.1), and 97.8% negative predictive value (CI 96.4- 98.7). The presence of 2 or more risk factors had 51.5% positive predictive value (CI 34.5-68.6). Conclusion: The risk prediction rule for ACVE in patients with acute drug overdose performed with slightly improved sensitivity and negative predictive value in the validation cohort. External validation in distinct patient populations and clinical settings remains warranted

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.

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.