Week 14: Quarterly Tox Rounds

Bupropion can induce seizures even at therapeutic levels. Other adverse effects include tachycardia, tremulousness, hallucinations, and QRS prolongation. Cyclic antidepressants (amitriptyline), SSRIs (fluoxetine), and monoamine oxidase inhibitors (phenelzine) can also cause seizures but less frequently than bupropion and usually with other symptoms of serious intoxication, such as central nervous system depression or QRS prolongation. Delayed seizures are seen with Bupropion overdose especially the extended release formulation.

Abstract about seizure with bupropion.

LITFL Bupropion 

This patient has significant valproic acid (VPA) toxicity, as evidenced by altered mental status, elevated VPA level, and hyperammonemia. Valproic acid is used to treat seizures, migraines, and mood disorders. The range of therapeutic concentration for VPA is 50–100 mg/L. In the setting of overdose, CNS depression, encephalopathy, metabolic acidosis, hepatoxicity, pancreatitis, renal failure, and pancytopenia may occur. Hyperammonemia is caused by depletion of L-carnitine and acetyl CoA, which inhibits the urea cycle. L-carnitine administration can improve these metabolic abnormalities and is the treatment of choice for severe VPA overdose. Serial VPA and ammonia concentrations should be obtained.

Activated charcoal (A) binds VPA effectively, and multiple dose-activated charcoal can be of utility due to enterohepatic recirculation; however, the patient in this scenario ingested valproic acid 24 hours prior to presentation, thus limiting the potential benefit of activated charcoal. Additionally, the patient is lethargic and vomiting, so charcoal administration is potentially harmful in the setting of an unprotected airway. Hemodialysis (B) and hemoperfusion can be of utility for very large VPA overdoses with significant acidosis and renal failure. The patient in this scenario has normal renal function and normal pH. Although VPA is an acid, urinary alkalinization (D) does not increase urinary excretion and is not indicated. Whole-bowel irrigation with polyethylene glycol electrolyte solution (E) can be of utility if a delayed or extended-release product is ingested. Once again, the utility of this therapy is limited 24 hours postingestion and requires a secure airway.

Indications for Multi-Dose Activated Charcoal

Neuroleptic malignant syndrome (NMS) a life-threatening condition characterized by muscle rigidity, autonomic instability, altered mental status, and hyperthermia that occurs soon after initiation or dose adjustment of adopaminergic or antipsychotic drug. This patient was likely started on an antipsychotic mediation when he was diagnosed with schizophrenia. Other risk factors for the development of NMS include high dosage, high-potency antipsychotic medications, parenteral formulation, dehydration, preceding psychomotor agitation, and previous episodes of NMS. The diagnosis is made when a patient develops severe muscle rigidity and hyperthermia while taking a neuroleptic or antipsychotic medication and develops two or more of the following symptoms: diaphoresis, dysphagia, tremor, incontinence, altered mental status, tachycardia, mutism, hypertension or labile blood pressure, rhabdomyolysis, leukocytosis and symptoms are not caused by another substance, neurologic, medical or psychological disorder.

A) The patient in the question stem is suffering from cocaine induced chest pain. The EKG demonstrates left ventricular hypertrophy, R wave in aVL >11mm, with strain pattern in I and aVL. Given the active chest pain, in the absence of ST-segment elevation, immediate treatment involves supportive care and serial troponin/ECGs.

B) There is no ST-segment elevation to indicate thrombolytics

C) There is no ST-segment elevation to indicate percutaneous coronary intervention

D) There is no evidence the patient is suffering from an aortic dissection and would thus not require further imaging.

.Phenytoin has delayed and erratic gastrointestinal absorption; therefore, multiple-dose activated charcoal can be of utility for phenytoin overdose. Phenytoin has also been known to form concretions in the intestinal tract. In fact, phenytoin levels may continue to rise for days after ingestion. Phenytoin is bound by activated charcoal; charcoal should be administered to patients with a secure airway. Multiple-dose activated charcoal can be administered every two to four hours (provided the patient has active bowel sounds) to minimize drug absorption and decrease the half-life of phenytoin. The most common manifestations of phenytoin toxicity include nystagmus, somnolence, dizziness, gastrointestinal disturbances, and headache.

Cardiac toxicity (A) occurs almost exclusively with intravenous preparations of phenytoin. Even though phenytoin is a sodium channel blocker with Vaughan-Williams class 1B antiarrhythmic effects, cardiotoxic manifestations are largely attributed to diluents (i.e., propylene glycol and ethanol) used in the IV formulation. Clinical manifestations include hypotension and (somewhat paradoxically) dysrhythmias, which can lead to cardiovascular collapse and death. These effects are rarely observed with the oral formulation due to the lack of diluent. Phenytoin is highly protein bound. Because dialysis (B) can remove only free, unbound phenytoin, it is of limited utility in the setting of an overdose. Significant cardiovascular toxicity generally occurs at infusion rates (D) of greater than 50 mg/min (not 25 mg/min); therefore, higher infusion rates are not recommended. Cardiovascular toxicity from phenytoin appears to be a dose- and rate-related phenomenon.

Note, phenytoin may not reflect free drug concentrations. This is important because phenytoin, in general, is highly protein bound, and only free drug exerts pharmacologic effects. Free phenytoin concentrations can be elevated in states of low albumin (even with a normal total phenytoin level). In these cases, free levels should be monitored. Patients at risk for having decreased protein-binding capacity include the elderly, neonates, patients with liver disease or uremia, or patients taking medications that would displace phenytoin from albumin. The normal range for total phenytoin levels is 10–20 mg/L, whereas free concentrations should be between 1.0 and 2.1 mg/L.

.The boy has signs and symptoms consistent with opioid ingestion. Methadone ingestion can manifest with the classic opioid toxidrome of respiratory depression, sedation, and miosis. Signs of more severe toxicity can include bradycardia, hypotension, and hypothermia. Methadone has been associated with a prolonged QTc interval and risk of torsades de pointes. Patients with significant respiratory or CNS depression should be treated with naloxone, which is a mu receptor antagonist. Because the half-life of methadone is longer than naloxone, patients can require multiple doses of naloxone. Also, serial ECGs are needed to monitor for the development of a prolonged QTc interval. If a patient does develop a prolonged QTc, management includes close cardiac monitoring, repletion of electrolytes, and having magnesium readily available should the patient develop torsades de pointes.

Clonidine (A) toxicity manifests as lethargy, miosis, and bradycardia. Although, findings may be similar to opioid overdose, QTc interval prolongation and torsades de pointes are typically only seen with opioid overdose. Propanolol (C) toxicity causes bradycardia and hypotension that typically develops within six hours of ingestion. Heart block and hypoglycemia may also be seen. Clinical manifestations of salicylate (D) toxicity include nausea, vomiting, diaphoresis, and tinnitus. Moderate cases can manifest as tachypnea, tachycardia, and altered mental status.

This patient presents with Wernicke syndrome, a clinical diagnosis that can be corroborated by improvement of symptoms after thiamine administration. Wernicke’s encephalopathy is a medical emergency with a high mortality rate (10-20%). Unfortunately, it often goes unrecognized. Diagnosis requires two of the following criteria: 1) dietary deficiency, 2) oculomotor abnormalities, 3) cerebellar dysfunction and 4) altered mental status or memory impairment. Oculomotor findings include nystagmus and ophthalmoplegia. Cerebellar signs typically manifest as ataxia. Patients with chronic malnourishment including alcoholics, patients with eating disorders and patients with advanced cancer are at risk for Wernicke’s. Emergent treatment consists of thiamine administration. Ophthalmoplegia and nystagmus may resolve in hours and confirms diagnosis.

.Flumazenil remains a controversial antidote, but it can be used safely both diagnostically and therapeutically in a very select group of patients. Contraindications to the use of flumazenil include the coingestion of a proconvulsant drug (such as bupropion) and a history of convulsions. Bupropion, both therapeutically and in overdose, can cause convulsions. In the setting of an ingestion of both a benzodiazepine and a proconvulsant drug, flumazenil can reverse the protective effect of the benzodiazepine on seizure prevention and is thus contraindicated. In the setting of an overdose of unknown medications, the presence of findings inconsistent with a pure benzodiazepine overdose or suggestive of a proconvulsant coingestant (such as convulsions, mydriasis, tachycardia, and QRS width prolongation) contraindicates flumazenil administration.

.Alcoholic ketoacidosis typically occurs in undernourished alcoholics who have recently binged on alcohol and have had limited food intake. Abdominal pain and vomiting are common. These symptoms might be related to the condition, but a thorough evaluation for other etiologies such as pancreatitis is necessary. These patients characteristically have a normal mental status despite the presence of potentially severe acidosis, and this helps distinguish alcoholic ketoacidosis from poisoning with a toxic alcohol. The acidosis in alcoholic ketoacidosis predominantly results from the presence of beta-hydroxybutyrate (a ketoacid that is not typically detected as a ketone on urinalysis). As with most acidosis, tachypnea is expected. Treatment of alcoholic ketoacidosis involves hydration with glucose-containing solutions, thiamine, food intake, and treatment of any other underlying medical conditions.

.Opioid withdrawal is characterized by a constellation of clinical manifestations that can include abdominal pain, anxiety, diaphoresis, diarrhea, irritability, myalgias, mydriasis, piloerection (involuntary erection of the skin hairs “gooseflesh’), rhinorrhea, vomiting, and yawning. Although very uncomfortable, opioid withdrawal is not life-threatening nor is it characterized by altered level of consciousness.