Timothy J. Wiegand

Cardiac conduction disturbance after loperamide abuse

Abstract Context. Prescription opioid abuse is a major public health concern and an ongoing epidemic in the United States. Loperamide is a widely available and inexpensive over-the-counter antidiarrheal with peripheral mu-opioid receptor activity. Online resources discuss the use of loperamide for the amelioration of withdrawal symptoms or recreational abuse. We describe the clinical course of 5 patients abusing loperamide, 3 of whom had life-threatening cardiac arrhythmias. Methods. In this observational case series, patients with cardiac arrhythmias or history of loperamide abuse with cardiac arrhythmias were identified; 5 patients were identified and 4 of the 5 patients were seen directly at the bedside. Clinical profile and outcome of patients is reported. Results. We report 5 patients with history of loperamide abuse; 3 of the 5 patients had life-threatening cardiac arrhythmias. One of the patients experienced a second life-threatening arrhythmia after he resumed loperamide abuse. Loperamide levels were obtained in 4 of the 5 patients and were at least one order of magnitude greater than therapeutic concentrations. Discontinuation of loperamide resulted in complete resolution of cardiac conduction disturbances. Conclusion. This case series describes several patients with cardiac conduction abnormalities and life-threatening ventricular arrhythmias temporally related to loperamide abuse. With the recent efforts to restrict the diversion of prescription opioids, increasing abuse of loperamide as an opioid substitute may be seen. Toxicologists should be aware of these risks and we urge all clinicians to report such cases to FDA Medwatch®.

Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup.

Background:Metformin toxicity, a challenging clinical entity, is associated with a mortality of 30%. The role of extracorporeal treatments such as hemodialysis is poorly defined at present. Here, the Extracorporeal Treatments In Poisoning workgroup, comprising international experts representing diverse professions, presents its systematic review and clinical recommendations for extracorporeal treatment in metformin poisoning. Methods:A systematic literature search was performed, data extracted, findings summarized, and structured voting statements developed. A two-round modified Delphi method was used to achieve consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Anonymized votes and opinions were compiled and discussed. A second vote determined the final recommendations. Results:One hundred seventy-five articles were identified, including 63 deaths: one observational study, 160 case reports or series, 11 studies of descriptive cohorts, and three pharmacokinetic studies in end-stage renal disease, yielding a very low quality of evidence for all recommendations. The workgroup concluded that metformin is moderately dialyzable (level of evidence C) and made the following recommendations: extracorporeal treatment is recommended in severe metformin poisoning (1D). Indications for extracorporeal treatment include lactate concentration greater than 20 mmol/L (1D), pH less than or equal to 7.0 (1D), shock (1D), failure of standard supportive measures (1D), and decreased level of consciousness (2D). Extracorporeal treatment should be continued until the lactate concentration is less than 3 mmol/L (1D) and pH greater than 7.35 (1D), at which time close monitoring is warranted to determine the need for additional courses of extracorporeal treatment. Intermittent hemodialysis is preferred initially (1D), but continuous renal replacement therapies may be considered if hemodialysis is unavailable (2D). Repeat extracorporeal treatment sessions may use hemodialysis (1D) or continuous renal replacement therapy (1D). Conclusion:Metformin poisoning with lactic acidosis appears to be amenable to extracorporeal treatments. Despite clinical evidence comprised mostly of case reports and suboptimal toxicokinetic data, the workgroup recommended extracorporeal removal in the case of severe metformin poisoning.

Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose

Abstract Background. Lipid emulsion is gaining popularity as an antidote for lipophilic drug overdose, and is generally considered safe at doses recommended for antidotal therapy. We report a case of asymptomatic pancreatitis following extended infusion lipid emulsion. Case report. A 14-year-old female presented to the emergency department actively seizing after ingesting 9 g of bupropion and unknown amounts of hydroxyzine and citalopram. She was intubated for airway protection, and gastrointestinal decontamination was performed with activated charcoal. She was treated with potassium and magnesium for a prolonged QT interval and sodium bicarbonate for metabolic acidosis and QRS complex widening. Upon transfer to the pediatric intensive care unit, she seized again, became hypotensive, and developed a junctional cardiac rhythm. A lipid emulsion bolus was recommended which improved her hypotension and conduction abnormalities. The lipid emulsion was continued for several hours and she received a total dose of 46 mL/kg in less than 12 h. She developed lipemia, which interfered with laboratory analysis, a severe elevation in her triglycerides, as well as a mild pancreatitis that resolved over several days, although she was asymptomatic. Case discussion. Large doses of lipid emulsion may result in lipemia, severe hypertriglyceridemia, interference in laboratory analyses, and pancreatitis. This is the third reported adverse event due to lipid emulsion therapy used for overdose.

Massive acetaminophen ingestion with early metabolic acidosis and coma: treatment with IV NAC and continuous venovenous hemodiafiltration.

Context. We report the extraction of acetaminophen by continuous venovenous hemodiafiltration (CVVHD) during treatment of an acute ingestion of 200 g with a peak recorded serum acetaminophen level of 1,614 mg/L (10,652 μmol/L). Case details. The patient presented with early onset of coma, metabolic acidosis, and hypotension in the absence of significant hepatic injury. In addition to N-acetylcysteine (NAC) therapy, CVVHD was performed to manage the acid–base disturbance. Flow rate, effluent volume, and serum and effluent drug concentrations were obtained at hourly intervals. During 16 h of CVVHD the acetaminophen level dropped from 1,212 to 247 mg/L. Discussion. The average clearance of acetaminophen by CVVHD was 2.53 L/h, with removal of 24 g of acetaminophen over 16 h. As NAC is effective in preventing hepatic injury after acute acetaminophen overdose, the role of dialysis or CVVHD is limited.

What is the role of lidocaine or phenytoin in tricyclic antidepressant-induced cardiotoxicity?

Introduction.Tricyclic antidepressant (TCA) poisoning is a relatively common occurrence and remains a significant cause of mortality and morbidity. Deaths from TCA toxicity are typically due to cardiovascular events such as arrhythmias and hypotension. Cardiovascular toxicity may be multifactorial. However, the primary mechanism is a TCA-induced membrane-depressant or “quinidine-like” effect on the myocardium resulting in slowing down of phase 0 depolarization of the cardiac action potential and subsequent impairment of conduction through the His-Purkinje system and myocardium. This effect is manifest as QRS prolongation on the EKG, atrioventricular (AV) block, and impairment in automaticity leading to hypotension and ventricular dysrhythmia. Primary treatment strategies include sodium bicarbonate, hypertonic saline, and correction of any conditions that may aggravate this toxicity such as acidosis, hyperthermia, and hypotension. In cases of severe TCA toxicity, administration of sodium bicarbonate may be insufficient to correct the cardiac conduction defects. Use of lidocaine or phenytoin, both Vaughan Williams Class IB antiarrhythmic agents, has been reported as an effective adjunctive therapy in cases of severe cardiotoxicity. Methods. Thirty articles of interest were identified by searching PubMed, abstracts from meetings, and the reference sections of related primary and review articles and toxicological texts. Role of lidocaine and phenytoin. Lidocaine and phenytoin also cause sodium channel blockade, but unlike Class IA or IC agents do not depress phase 0 depolarization in healthy cardiac tissue. Lidocaine and phenytoin dissociate relatively quickly from cardiac sodium channels. Sodium channels have faster recovery times after exposure to lidocaine (1–2 s) and phenytoin (0.71 s), than with some TCAs such as amitriptyline (13.6 s), but not others (e.g., imipramine at 1.6 s). In experimental models of amitriptyline poisoning, lidocaine co-administration resulted in decreased sodium channel blockade compared to amitriptyline alone. This correlated with clinical improvement, including normalization of QRS interval, improved hypotension, and decreased mortality. It is postulated that lidocaines rapid binding to the sodium channel may directly displace slower acting agents from the channel, leaving more channels unbound, and therefore be able to facilitate cardiac conduction. Phenytoin may act through a similar mechanism as lidocaine, although experimental studies suggest that it does not compete directly for the same sodium channel binding site as TCAs. Allosteric modulation of the TCA binding site may occur in the setting of phenytoin use. The evidence for using phenytoin in treating TCA-induced sodium channel blockade is less convincing than that for lidocaine. Human trials are limited to case series and, in most human exposures in which there appeared to be efficacy, the toxicity was not severe. Conclusions. Although there appears to be more evidence for the use of lidocaine than phenytoin as adjunctive treatment for TCA-associated cardiotoxicity, specific clinical indications and dosing recommendations remain to be defined. We recommend the use of lidocaine in cases in which cardiotoxicity (arrhythmias, hypotension) is refractory to treatment with sodium bicarbonate or hypertonic saline, or in which physiological derangement (e.g., severe alkalosis or hypernatremia) limits effective use of these primary strategies.

Adulterated Cocaine and Lessons Learned from the Jake Walk Blues

The Substance Abuse and Mental Health Services Administration has posted a warning on their website and sent fliers to healthcare providers throughout the USA: Nationwide Pubic Health Alert Issued Concerning LifeThreatening Risk Posed by Cocaine Laced with Veterinary Anti-Parasite Drug. Similar reports have come out of Alberta, Canada and from Canadian public health advocacy groups—Alberta, Canada was one of the first locations where levamisoleadulterated cocaine was reported and first associated with severe health effects including death. Since consistently turning up in cocaine seizures in 2002, the amount of cocaine adulterated with levamisole has been steadily increasing. According to Drug Enforcement Agency (DEA) data levamisole was found in over 70% of all illicit cocaine as of July 2009 [1]. The amount of levamisole encountered in cocaine typically ranges from 6 to 9% of the drug by weight and according to a recent study from Seattle, Washington nearly 80% of individuals who tested positive for cocaine also tested positive for levamisole. Although it has been used historically as an immune modulator for diseases such as rheumatoid arthritis and as an adjuvant agent in anticancer therapy, levamisole is no longer approved for human use. It remains readily available, however, in pet stores throughout the USA and in Central and South America for sale as a deworming or anti-parasitic agent. A recent celebrity death brought attention to this issue. Adam Goldstein, aka DJ AM, a celebrated musician and pop DJ known for his ability to mix and blend songs together into what is referred to as ‘mashups’ was found dead in his apartment on August 28, 2009 of an apparent drug overdose. Although DJ AM was found to have oxycodone, cocaine, hydrocodone, alprazolam, and lorazepam in his system, toxicology results also included the chemical levamisole, presumed to have been present as a cocaine adulterant. Goldstein’s death, while most likely due to the combined effects of the cocaine, opioids, and benzodiazepines has created public awareness of the cocaine epidemic and drug adulteration [2]. The Annals of Internal Medicine published a report describing five cases of agranulocytosis associated with cocaine adulterated with levamisole [3] and in Alberta, where some of the first reports of levamisole appeared, over 20 confirmed or probable cases of agranulocytosis, including at least two deaths, have been reported due to adulterated cocaine as of this past August. While levamisole may cause reversible agranulocytosis in up to 20% of individuals exposed to it, the true threat to the public health is unclear. What also remains unclear is why levamisole in particular is being used as a cocaine adulterant. Reviewing similar epidemics from history may provide some insight and understanding into this current epidemic and drug adulteration or contamination in general. Jamaican ginger extract, also known as Jake, was a patent medicine with a high ethanol content that was available in the nineteenth and early twentieth century. Although not T. J. Wiegand (*) Northern New England Poison Center, Maine Medical Center, Portland, ME, USA e-mail: timothywiegand@yahoo.com

The New Kid on the Block—Incorporating Buprenorphine into a Medical Toxicology Practice

Buprenorphine represents a safe and effective therapy for treating opioid dependence, alleviating craving and withdrawal symptoms in opioid-dependent patients. Buprenorphine has a “blocking” effect against the action of other opioids at the mu-receptor, preventing not only opioid-induced euphoria, but CNS and respiratory depressant effects as well. Buprenorphine was approved for the treatment of opioid dependence in 2002 after the passage of Drug Abuse Treatment Act 2000 (DATA 2000) which allowed clinicians to treat opioid-dependent patients with specifically named opioid agonist therapies in an office setting. Buprenorphine programs reduce the prevalence of HIV and hepatitis C and reduce criminal behaviors associated with illicit drug use. Patients stabilized on buprenorphine have increased employment, enhanced engagement with social services, and better overall health and well-being.

Hypoglycemia and lactic acidosis outperform King’s College criteria for predicting death or transplant in acetaminophen toxic patients

Abstract Importance: Acetaminophen toxicity is common and is characterized by hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require hepatic transplant. While there are various criteria to predict patients who might benefit from transplant, the King’s College criteria remain one of the most widely used. However, the King’s College criteria have several limitations and do not incorporate glucose, an important marker of hepatic function. Objective: The primary objective of this study is to compare the presence of hypoglycemia, coagulopathy, and metabolic acidosis with the King’s College criteria for predicting a composite endpoint of death or transplant. Design: This study is a retrospective cohort study of adult patients admitted with a discharge diagnosis of acetaminophen-induced liver failure. Setting: The patients were admitted at one of six university-affiliated teaching hospitals in the United States. Results: A total of 334 subjects were identified who met inclusion criteria. Fifty-one subjects (15.3%) met the composite endpoint of death or transplant. Ninety-six (28.7%) subjects met the King’s College criteria for transplant. The presence of hypoglycemia increased the odds of reaching the composite endpoint by 3.39-fold. This model performed better than the King’s College criteria (pseudo R2 for the area under the curve of 0.93 vs. 0.20 for the King’s College criteria). Conclusions: The combination of hypoglycemia, coagulopathy, and lactic acidosis performed better than the King’s College criteria for predicting death or transplant.

Case Presentations from the Addiction Academy

In this article, a case-based format is used to address complex clinical issues in addiction medicine. The cases were developed from the authors’ practice experience, and were presented at the American College of Medical Toxicology Addiction Academy in 2015. Section I: Drug and Alcohol Dependence and Pain explores cases of patients with co-occurring pain and substance use disorders. Section II: Legal and Policy Issues in Substance Use Disorders highlights difficult legal and policy questions in addiction medicine. Section III: Special Populations and Addictive Disorders delves into the complexity of addiction in special populations (pregnant, pediatric, and geriatric patients).

Two Cases of Accidental Injection of Epinephrine into a Digit Treated with Subcutaneous Phentolamine Injections

Accidental injection into the digit from an epinephrine autoinjection device can cause discoloration, pain, and paresthesias. Although loss of digit is rare, treatment in the emergency department is commonly aimed at vasodilation of the affected tissue. We report two cases of accidental injection of epinephrine into the digits that were successfully treated with subcutaneous phentolamine injection with no adverse events.