A 22-year-old previously healthy male was brought to the emergency department with nausea, vomiting, and a decline in mental status. Vital signs:
Physical examination revealed pain in the RUQ upon palpation with slight jaundice. While in the emergency department, his mental status continued to decline precipitously.
The patient was transferred to the ICU. What medication could be started empirically?
Correct Answer: B
Based on the initial presentation of this patient, high clinical concern for acute hepatic failure exists. History is limited to the mental status of this patient, but the differential for acute hepatic failure includes acetaminophen toxicity, ischemic liver, hepatic thrombosis/veno-occlusive disease, autoimmune hepatitis, infectious hepatitis, drug toxicity, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) if pregnant. Based on age and likelihood, N-acetylcysteine would be the most reasonable medication to start. Acetaminophen toxicity is the most common cause of acute hepatic failure in the United States. Acetaminophen ingestions greater than 10 g or 150 mg/kg are most commonly associated with acute hepatic failure. There are four stages of acute acetaminophen toxicity, which occur over 30 minutes to 4 weeks. The stages progress from nausea, vomiting, confusion to severe transaminitis with AST predominance, mild bilirubinemia, hypoglycemia, prolonged PT/INR with associated stupor. Patients are most vulnerable during stage III acute acetaminophen toxicity with associated stupor, coagulopathy, and metabolic derangement. If the patient can make it to stage IV/recovery phase, then full recovery without long-term sequelae is likely. Acute kidney injury can also be associated with acetaminophen toxicity, usually in the form of acute tubular necrosis. However, if the patient becomes oliguric, hepatorenal syndrome (HRS) must be considered and the patient should be transferred to a facility where liver transplantation is possible.
Acetaminophen level should be checked at 4 hours and plotted on the Rumack nomogram. If the acetaminophen level exists beyond the treatment line, treat with N-acetylcysteine. N-acetylcysteine replenishes reduced glutathione and detoxifying NAPQI products created by the CYP2E1 enzyme that lead to oxidative damage to the liver. IV NAC should be started at 150 mg/kg or PO NAC at 140 mg/kg based on a 72-hour protocol. When administering NAC, monitor for a non-IgE–mediated anaphylactoid reaction.
Methylprednisolone and azathioprine are used to treat autoimmune hepatitis, which is less likely in the patient’s gender and age group. Hepatitis B immunoglobulin treats acute hepatitis B exposure. Heparin treats veno-occlusive disease and Budd-Chiari syndrome seen in patients with hypercoagulable history.
An 84-year-old female with a history of hypertension and dementia presents to the emergency department with a fever, rigors, and chills. Vital signs:
After receiving 2.5 L of crystalloid solution in addition to broadspectrum antibiotic therapy (cefepime, metronidazole, and vancomycin), she remains hypotensive and is started on Levophed. After several days in the ICU, the patient is noticeably more confused. She had a brief generalized seizure that was treated with Ativan. MRI and LP were negative. EEG showed triphasic waves with diffuse slowing.
What medication may have caused the patient’s mental status changes in the context of a negative neurological workup?
Correct Answer: C
Cefepime, along with other cephalosporins, is a well-known neurotoxic antibiotic causing symptoms ranging from tardive dyskinesia, nonconvulsive status epilepticus, encephalopathy, confusion, and lethargy. Patients with impaired renal function are at increased risk for cefepime neurotoxicity. Cephalosporins have increased CNS penetration, leading to an imbalance of GABAergic and glutamatergic neurotransmission. Aminoglycosides may cause ototoxicity, peripheral neuropathy, and neuromuscular blockade. Carbapenems may cause seizures, myoclonus, and headache, whereas penicillins may cause tremors and tardive seizures. Fluoroquinolones are also known neurotoxic agents that may lead to encephalopathy and seizures. Antibiotic-related neurotoxicity is associated with increased mortality; therefore early diagnosis is key. Metronidazole may cause encephalopathy in patients, but patients usually have cerebellar signs and exhibit MRI abnormalities. The neurotoxic effects of metronidazole occur over weeks.
Vancomycin may cause red-man syndrome, acute renal failure, ototoxicity, and neutropenia. Vancomycin is not classically associated with neurotoxicity. Levophed is known to cause tachyarrhythmias. Ativan may cause sedation and delirium; however, a single dose should not cause persistent symptoms.
A 23-year-old male with hypermobile joints and vision loss was admitted to the ICU after a CT scan was concerning for an aortic dissection. He was placed on IV medications to control his HR and blood pressure. Over the next 24 hours he became lethargic, tachypneic, and short of breath. Vital signs:
VBG: 7.10/28/90. Lactate: 6.
What medication is causing this patient’s metabolic derangement?
Correct Answer: D
This patient has an anion gap metabolic acidosis with a high lactate and normal renal function and glucose; tachypnea and shortness of breath is the respiratory compensation component. Nitroprusside is an antihypertensive that is known to cause cyanide toxicity when metabolized. Cyanide inhibits the function of cytochrome c leading to increased lactic acid production secondary to a decrease in aerobic metabolism. The degree of lactic acidosis correlates with the degree of toxicity. During nitroprusside administration, cyanide is converted to thiocyanate and exerted in the urine. The metabolism to thiocyanate occurs in the mitochondria. Renal insufficiency is an independent risk factor for developing cyanide toxicity during nitroprusside use.
Early cyanide toxicity presents with tachydysrhythmias, respiratory distress but can progress to flash pulmonary edema, seizures, and cardiopulmonary arrest. The skin may be bright red and the patient’s breath may have a bitter almond scent. Nitroprusside can also prevent hypoxia-mediated vasoconstriction, leading to sustained V/Q mismatch, especially in those with congestive heart failure. Thrombocytopenia may occur as well.
Treatment includes thiosulfate, amyl-nitrite, and hydroxocobalamin. Thiosulfate produces a more renally excretable thiocyanate, which prevents cyanide and thiocyante buildup. Amyl-nitrite produces methemoglobin, to which cyanide will have a higher affinity for. Hydroxocobalamin can be used in the treatment and prophylaxis of cyanide toxicity by creating cyanocobalamin, which is excreted in the urine.
Nicardipine, esmolol, and labetalol toxicity is associated with hypotension and bradycardia. Nitroglycerin can be associated with severe hypotension when used in patients with recent myocardial infarctions who have taken sildenafil.
A 47-year-old apple farmer presented to the emergency department after she was found down. In the trauma bay, her vital signs were:
Physical examination was remarkable for wet and clammy skin with diminished pulses, bilateral wheezing, and copious secretions. She was intubated with rocuronium and etomidate. EMT and nursing began to feel ill with diaphoresis.
Which pharmacological agent(s) will improve this patient’s symptoms based on her underlying clinical syndrome?
Correct Answer: E
Based on the constellation of signs of symptoms, this patient has suspected organophosphate poisoning from farming her land. Organophosphate poisoning presents with a cholinergic toxidrome of diarrhea, urination, miosis, bradycardia, bronchorrhea, bronchoconstriction, emesis, lacrimation, salivation (DUMBBBELSS) from action at muscarinic receptors via phosphorylation of serine side group, leading to inactivation of acetylcholinesterase enzyme. The inhibition has varying degrees of reversibility depending on the type of organophosphate that leads to a cholinergic syndrome. Patients can become quite hypotensive secondary to the extreme bradycardia and the degree of bronchoconstriction can lead to severe hypoxia. Bronchoconstriction, bronchorrhea, and bradycardia are important contributors to the mortality from organophosphate poisoning. However, if the nicotinic receptors are overstimulated in the sympathetic pathway, then patients may present with tachycardia, diaphoresis, and hypertension. If nicotinic receptors at the neuromuscular junction are affected, then patient may present with muscle paralysis and fasciculations.
Treatment of organophosphate poisoning includes atropine (a cholinergic antagonist), pralidoxime (2-PAM), prompt airway management, which may include intubation for securing the airway, and diazepam to treat seizures. Gastric lavage may be considered if the patient ingested an organophosphate within 1 hour of presentation to the emergency department. Pralidoxime (2-PAM) aids in the regeneration of acetylcholinerase by breaking the covalent bond that leads to the inactivity of acetylcholinerase. Atropine is titrated to heart rate and respiratory secretions. An infusion of pralidoxime should be continued until the patient is extubated or at least 12 hours have elapsed without the need for administration of atropine. Diazepam is the preferred agent in the management of seizures in patients with organophosphate poisoning. Patients should be monitored for a delayed cholinergic syndrome, which may have a delayed presentation up to weeks after the original exposure secondary to fat solubility of organophosphates.
It can be appropriate to repeat 0.5 mg of atropine, initate transcutaneous pacing, or consider an epinephrine infusion in the context of hypotension and bradycardia; however, high-dose atropine and 2-PAM would be the most appropriate next step in treatment. Physostigmine would worsen this patient’s condition because acetylcholinerase would be further inhibited. This would lead to further elevated levels of acetylcholine at the synapse.
A 24-year-old previously healthy female graduate student has suffered from multiple witnessed seizures in the ED and is intubated for airway protection. Per report, EMS said they found multiple unidentified pill bottles next to her bed. Upon transfer to the ICU she is noted to have another seizure that occurred after she went into a pulseless wide complex tachycardia. ECG was obtained and revealed: PR 150, QRS 175, QTc 500 with right axis deviation, wide S in leads I and aVL, and deep terminal R in lead aVR. On examination, the patient has dilated pupils and a palpable mass in the suprapubic region.
What is the most appropriate next step in treating this patient?
Based on the clinical scenario, symptoms, and ECG findings, this patient likely overdosed on tricyclic antidepressants (TCAs). Examples of TCAs are nortriptyline, amitriptyline, doxepin, clomipramine, and imipramine. TCAs are weakly basic compounds that inhibit sodium channels, alpha-1- receptors, cholinergic receptors, histamine receptors, and serotonin and/or norepinephrine reuptake. Patients who overdose usually present with sinus tachycardia, hypotension, delirium, seizures, respiratory depression, dry mouth, urinary retention, and hyperthermia. Ventricular arrhythmias and bradycardia are also possible. Gastric lavage can be trialed if the ingestion occurred within 1 hour of arrival to a treating facility. First-line treatment of hypotension caused by TCA overdose is IV fluids; however, secondary to the cardiac effects of TCAs, sodium bicarbonate would be an appropriate next choice for this patient. Sodium bicarbonate is indicated when the pH <7.1, QRS >100, R/S ratio in aVR >0.7 hypotension, and/or arrhythmia events occur. Other ECG findings include QTc >415 to 430, wide/deep S in leads I and aVL, and acute right axis deviation. QRS >100 is predictive of seizure, whereas QRS >160 is predictive of ventricular arrhythmias. Although there are classic ECG findings as described above, sinus tachycardia is the most common ECG finding. If sodium bicarbonate is given, one must target a sodium concentration of 150 to 155 and pH of 7.5 to 7.55 and closely monitor for hypokalemia. Additionally, hyperventilation can aid in alkalizing the serum pH. Sodium bicarbonate displaces the TCA molecule from the cardiac myocytes as well as leading to decreased free TCA molecules in serum by increasing protein binding capacity. Large volumes of sodium bicarbonate or continuous infusions are necessary at times to reverse the cardiotoxicity. Magnesium sulfate can be helpful in refractory arrhythmias with associated long QTc. Benzodiazepines are used to treat seizures in TCA overdose as compared with phenytoin, which should be avoided secondary to its proarrhythmic effects in setting of TCA overdose.
Ammonium chloride acidifies the serum leading to more deleterious effects from TCAs owing to proarrhythmic nature in an acidic environment. Lidocaine is considered an adjunctive treatment of arrhythmias if the patient remains hemodynamically unstable despite initial treatment with bicarbonate. In theory, physostigmine would be appropriate for anticholinergic syndrome, but multiple studies have recommended to exclude its use in TCA overdose. In patients with suspected local anesthetic toxicity and continued circulatory collapse despite fluids, intralipid infusion should be considered, as the infusion will scavenge fat-soluble agents and slow the vasodilation.
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