Brent W. Morgan

Acute Metformin Overdose: Examining Serum pH, Lactate Level, and Metformin Concentrations in Survivors Versus Nonsurvivors: A Systematic Review of the Literature

STUDY OBJECTIVE Metformin is known to cause potentially fatal metabolic acidosis with an increased lactate level in both overdose and therapeutic use. No association between mortality and serum pH, lactate level, or metformin concentrations, though intuitive, has yet been described. This systematic literature review is designed to evaluate the association between mortality and serum pH, lactate level, and metformin concentrations in acute metformin overdose. METHODS We reviewed the literature by using the MEDLINE, EMBASE, CINAHL, and TOXNET databases for cases of metformin overdose with documented mortality data and values of serum pH, lactate level, and metformin concentrations. When available, patient age, patient sex, and whether patients received intravenous sodium bicarbonate therapy or hemodialysis were also analyzed. Cases meeting inclusion criteria were analyzed to determine whether a difference in distribution of nadir serum pH, peak serum lactate level, or peak serum metformin concentrations existed between overdose survivors and nonsurvivors. RESULTS We identified 10 articles that had 1 or more cases meeting our inclusion criteria. In total, there were 22 cases of metformin overdose (5/22 died) that met inclusion criteria. No intentional overdose patients died whose serum pH nadir was greater than 6.9, maximum lactate concentration less than 25 mol/L, or maximum metformin concentration less than 50 microg/mL (therapeutic range 1 to 2 microg/mL). Intentional overdose patients with a nadir serum pH less than 6.9 had 83% mortality (5/6), those with lactate concentration greater than 25 mmol/L had 83% mortality (5/6), and those with metformin concentration greater than 50 microg/mL had 38% mortality (5/12). Nadir serum pH and peak serum lactate and metformin concentration distributions in survivors and nonsurvivors revealed that survivors had a median nadir pH of 7.30, interquartile range (IQR) 7.22, 7.36; nonsurvivors, a median nadir pH of 6.71, IQR 6.71, 6.73; survivors, a median peak lactate level of 10.8 mmol/L, IQR 4.2, 12.9; nonsurvivors, a median peak lactate level of 35.0 mmol/L, IQR 33.3, 39.0; survivors, a median peak metformin level of 42 microg/mL, IQR 6.6, 67.6; and nonsurvivors, a median peak metformin level of 110 microg/mL, IQR 110, 110. CONCLUSION No cases of acute metformin overdose meeting the studys inclusion criteria were found in which patients with a nadir serum pH greater than 6.9, peak serum lactate concentrations less than 25 mmol/L, or peak serum metformin concentrations less than 50 microg/mL died. Patients with acute metformin overdose who died had much lower serum pH nadirs and much higher peak serum lactate and metformin concentrations than those who survived.

Opioid Prescribing in a Cross Section of US Emergency Departments

STUDY OBJECTIVE Opioid pain reliever prescribing at emergency department (ED) discharge has increased in the past decade but specific prescription details are lacking. Previous ED opioid pain reliever prescribing estimates relied on national survey extrapolation or prescription databases. The main goal of this study is to use a research consortium to analyze the characteristics of patients and opioid prescriptions, using a national sample of ED patients. We also aim to examine the indications for opioid pain reliever prescribing, characteristics of opioids prescribed both in the ED and at discharge, and characteristics of patients who received opioid pain relievers compared with those who did not. METHODS This observational, multicenter, retrospective, cohort study assessed opioid pain reliever prescribing to consecutive patients presenting to the consortium EDs during 1 week in October 2012. The consortium study sites consisted of 19 EDs representing 1.4 million annual visits, varied geographically, and were predominantly academic centers. Medical records of all patients aged 18 to 90 years and discharged with an opioid pain reliever (excluding tramadol) were individually abstracted by standardized chart review by investigators for detailed analysis. Descriptive statistics were generated. RESULTS During the study week, 27,516 patient visits were evaluated in the consortium EDs; 19,321 patients (70.2%) were discharged and 3,284 (11.9% of all patients and 17.0% of discharged patients) received an opioid pain reliever prescription. For patients prescribed an opioid pain reliever, mean age was 41 years (SD 14 years) and 1,694 (51.6%) were women. Mean initial pain score was 7.7 (SD 2.4). The most common diagnoses associated with opioid pain reliever prescribing were back pain (10.2%), abdominal pain (10.1%), and extremity fracture (7.1%) or sprain (6.5%). The most common opioid pain relievers prescribed were oxycodone (52.3%), hydrocodone (40.9%), and codeine (4.8%). Greater than 99% of pain relievers were immediate release and 90.0% were combination preparations, and the mean and median number of pills was 16.6 (SD 7.6) and 15 (interquartile range 12 to 20), respectively. CONCLUSION In a study of ED patients treated during a single week across the country, 17% of discharged patients were prescribed opioid pain relievers. The majority of the prescriptions had small pill counts and almost exclusively immediate-release formulations.

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®.

Selenium Toxicity: A Case of Selenosis Caused by a Nutritional Supplement

Background: Selenium is a nonmetal element that serves vital roles in normal physiologic function. Substantial toxicity can occur with excessive selenium consumption. In March 2008, the U.S. Food and Drug Administration (FDA) announced that it had received reports of adverse reactions to over-the-counter liquid nutritional supplements marketed as Total Body Formula and Total Body Mega Formula (distributed by Total Body Essential Nutrition, Atlanta, Georgia) (1). A voluntary recall of these products was implemented. In May 2008, the FDA found substantially elevated selenium levels and modestly elevated chromium levels in the products (2).

Ethylene Glycol Ingestion Resulting in Brainstem and Midbrain Dysfunction

Introduction: Ethylene glycol toxicity has produced central nervous system abnormalities including coma, cerebral edema, and cranial nerve dysfunction. Case Report: A 26-year-old male developed widespread brainstem and midbrain dysfunction with corresponding cranial computed tomography findings after ingesting ethylene glycol. The computed tomography scan which was obtained 3 days after ethylene glycol ingestion showed low density areas in the basal ganglia, thalami, midbrain, and upper pons. The neurologic findings in our patient reflected dysfunction of all the areas of hypodensity on the cranial computed tomography scan. A magnetic resonance imaging of the brain obtained 24 days after ingestion revealed bilateral putamen necrosis. The patients neurologic sequelae resolved over the following 4 months.

Case Series Of Selenium Toxicity From A Nutritional Supplement

Introduction. Selenium is an essential trace element, but can be toxic in excess. In May 2008, US FDA reported 201 individuals with adverse reactions to liquid nutritional supplements containing excess selenium and chromium resulting in the largest epidemic of selenosis in the history of the United States. Objective. To describe the clinical features, biomonitoring data of selenium levels, and the estimated total dose of selenium ingestions of nine patients with selenium toxicity who presented after use of a liquid dietary supplement with a formulation error. Methods. A retrospective observational case series was performed on nine patients presenting to our medical toxicology clinic between March 2008 and May 2008 with symptoms of selenosis after consuming a nutritional supplement. Institutional IRB approval was obtained for this case series. Results. Supplement testing revealed almost 200 times the reported amount of selenium. There were 5 males and 4 females and their ages ranged from 15 to 57 years (median 46 years, mean 44.2 years). The mean estimated cumulative dose of selenium ingested in our patients was 1.3 gram over a mean period of 37.5 days (10–60 days). In each case, the symptoms of selenium toxicity manifested within 1 week from the start of ingestion. Initial symptoms included alopecia, dystrophic fingernail changes, GI symptoms, and memory difficulties. The initial whole blood selenium concentrations ranged from 150 to 732 mcg/L (reference mean range 123–193 mcg/L) at an average of 27 days post cessation of the formula. The urinary selenium concentrations ranged from 41 to 220 mcg/g Creat (reference < 25 mcg/g Creatinine). None of the patients required more than supportive care for symptoms and none required hospitalization. Conclusion. Selenium is an essential element, which can result in significant toxicity if ingested in large amounts.

Methanol Toxicity in a Newborn

Background: Methanol poisoning during human pregnancy rarely has been described. We report the first human newborn with a documented methanol concentration resulting from maternal exposure. Case Report: A 28‐year‐old pregnant woman EGA 30 weeks with HIV infection and asthma presented to the emergency department in respiratory distress. She was acidotic (pH 7.17) with an anion gap of 26, and fetal bradycardia was noted. Her son was delivered by emergent C‐section (birthweight 950 g, Apgars 1 and 3) and required aggressive resuscitation. During his hospital course, acidosis (initial pH 6.9) persisted despite fluid, blood, and bicarbonate administration. His mother also had persistent metabolic acidosis despite fluids, bicarbonate, and dopamine. Results of other laboratory tests on the mother included undetectable ethanol and salicylates and an osmolar gap of 41. An ethanol drip was initiated for the mother 36 h after admission when a methanol level of 54 mg/dL was reported. When consulted on hospital day 3, our regional poison center recommended hemodialysis for the mother and administering fomepizole and testing the methanol level of the newborn (61.6 mg/dL). Because the infant developed a grade 4 intraventricular bleed, no further therapy was offered, and he died on day 4. His mother died on day 10. Conclusion: Fatal neonatal methanol toxicity can result from transplacental exposure.

Metformin overdose with a resultant serum pH of 6.59: survival without sequalae.

Metformin, widely used in the treatment of diabetes mellitus, is known to cause lactic acidosis in both therapeutic use and after an overdose. We report the case of a 40-year-old woman who claimed to have ingested between 75 and 100 grams of metformin and subsequently developed severe lactic acidosis. She eventually developed a peak serum lactate level of 40.0 mmol/L and a serum pH nadir of 6.59 and became obtunded, hypotensive, and hypothermic. After aggressive supportive therapy with mechanical ventilation, vasopressor agents, sodium bicarbonate, and hemodialysis, her metabolic derangements steadily improved and she made a complete recovery without any residual sequelae. Her admission serum metformin concentration was later determined to be 160 microg/mL (therapeutic range is 1-2 microg/mL). There are several case reports and case series describing lactic acidosis secondary to metformin ingestion, although the exact mechanism remains unclear. The overall management of metformin overdose is reviewed. This case represents the largest reported amount of ingested metformin, the lowest serum pH, and the highest serum lactate concentration in any intentional metformin overdose survivor in the literature. Despite potentially lethal metabolic derangements, such patients can survive with aggressive supportive care.

Cardiotoxicity after Massive Amantadine Overdose

IntroductionAmantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels.Case ReportsA 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient’s ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient’s hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4–5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion.ConclusionAcute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium.

Abstract Background. Medical toxicologists are frequently consulted when young patients present with delirium attributed to suspected poisoning. Medical toxicologists should be aware of non-toxicological mimics of delirium. We describe two patients ultimately diagnosed with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis for which a toxicological consultation was requested to evaluate for neuroleptic malignant syndrome (NMS). Case 1. A 21 year old male was sent from a psychiatric facility for new, worsening psychotic symptoms. He had autonomic instability, confusion, and hyper-reflexia. He was treated for NMS without improvement, and after an extensive workup was unrevealing, he was discharged home with significant cognitive dysfunction. Stored CSF later tested positive for anti-NMDAR antibodies. Case 2. A 27 year old female was sent from a psychiatric facility for a seizure and new psychiatric symptoms. She was agitated and had violent, alternating extremity flexion and extension along with autonomic instability. She was treated for NMS, rhabdomyolysis, and rabies before analysis of CSF demonstrated anti-NMDAR antibodies. Treatment included surgical resection of a suspicious ovarian cyst, steroids and IVIG, with moderate improvement. Discussion. Autoimmune syndromes of the central nervous system result from receptor dysfunction after an antibody response to extracellular or intracellular antigens, such as subunits of the NMDA receptor. The NMDA subunits NR2b and NR2a, in addition to the N-terminal region of the glycine binding NR1 subunit, have been implicated. Typical features such as memory loss, movement disorders, and hallucinations reflect the density and distribution of neuronal NDMA receptors. As young people, particularly young women, are predominantly affected, initial symptoms may be attributed to encephalopathy from drug abuse or schizophrenia. Toxicologists may be consulted as many features mimic NMS. Serum and cerebrospinal fluid can be checked for anti-NMDAR antibodies as part of a paraneoplastic or meningioencephalitis panel. Effective treatments have been described and include surgical resection and immunosuppressive medications.