A 49-year-old man comes to the emergency department with severe shortness of breath. The patient has a history of hypertension and medication nonadherence. Blood pressure is 260/144 mm Hg and pulse is 100/min. Chest examination demonstrates bibasilar crackles. There are no heart murmurs. Serum creatinine is 1.6 mg/dL. Intravenous furosemide and continuous nitroprusside infusion are started, along with noninvasive positive pressure ventilation, and he experiences improvement in his symptoms. The next morning, the patient is confused and lethargic, and he suffers a generalized tonic-clonic seizure. The skin appears flushed, and serum lactic acid level is elevated. The nitroprusside infusion rate is found to be higher than recommended. Which of the following mechanisms is most likely responsible for the drug toxicity seen in this patient?

Question

A 49-year-old man comes to the emergency department with severe shortness of breath.  The patient has a history of hypertension and medication nonadherence.  Blood pressure is 260/144 mm Hg and pulse is 100/min.  Chest examination demonstrates bibasilar crackles.  There are no heart murmurs.  Serum creatinine is 1.6 mg/dL.  Intravenous furosemide and continuous nitroprusside infusion are started, along with noninvasive positive pressure ventilation, and he experiences improvement in his symptoms.  The next morning, the patient is confused and lethargic, and he suffers a generalized tonic-clonic seizure.  The skin appears flushed, and serum lactic acid level is elevated.  The nitroprusside infusion rate is found to be higher than recommended.  Which of the following mechanisms is most likely responsible for the drug toxicity seen in this patient?

Quizplus · Accepted Answer

This patient's clinical presentation is consistent with cyanide toxicity from nitroprusside. Nitroprusside is a vasodilator with quick onset/offset kinetics commonly used for rapid blood pressure control in patients with hypertensive emergency. Nitroprusside [Na₂(CN)₅NO] rapidly decomposes to nitric oxide (NO: vasodilator) and cyanide ion (CN⁻: toxin). Key risk factors for nitroprusside-induced cyanide toxicity include high doses, prolonged infusions, and renal insufficiency (eg, acute kidney injury due to hypertensive emergency). Cyanide is a potent mitochondrial toxin that binds heme centers in cytochrome c oxidase (complex IV), blocking the electron transport chain. Because mitochondria are unable to reduce oxygen, venous blood returning from tissues remains saturated with oxygen and appears bright red. Loss of aerobic respiration also promotes lactic acidosis. As ATP is depleted, acute cyanide toxicity causes neurologic dysfunction (eg, altered mental status, seizures) and cardiovascular collapse. Cyanide is cleared by rhodanese, an enzyme that transfers sulfur to cyanide to form thiocyanate (SCN) for excretion in urine. Because cyanide overdose depletes available sulfur donors, one approach to treatment is to provide additional sulfur groups with sodium thiosulfate. Other treatments include hydroxocobalamin (directly sequesters CN⁻) and sodium nitrite (induces methemoglobinemia to scavenge CN⁻). (Choice A) Methemoglobinemia, caused by oxidizing agents (eg, nitrites, chloroquine), and carbon monoxide exposure increase hemoglobin's affinity for oxygen, which impairs oxygen unloading into the tissues. Both processes disrupt peripheral tissue oxygen delivery, leading to lactic acidosis. (Choice B) Arsenic inhibits pyruvate dehydrogenase, the rate-limiting enzyme governing conversion of pyruvate to acetyl-CoA for entry into the tricarboxylic acid cycle, causing depletion of ATP. Acute arsenic poisoning presents with severe enteritis (diarrhea) and neurologic dysfunction. (Choice C) Ethanol is converted to acetaldehyde by alcohol dehydrogenase, with concurrent reduction of NAD+ to NADH. High NADH levels subsequently cause feedback inhibition of lactate dehydrogenase (hepatic gluconeogenesis enzyme), leading to hypoglycemia and lactic acidosis. (Choice E) Electron transport uncouplers (eg, dinitrophenol [DNP]) cause protons to back-leak across the inner mitochondrial membrane, dissipating the gradient as wasted heat instead of generating ATP. Because they raise the metabolic rate, these agents are occasionally abused as catabolic weight loss agents. Accidental overdose results in fatal hyperthermia. Educational objective: Cyanide toxicity is an important adverse effect of nitroprusside. Blockage of mitochondrial electron transport leads to impaired oxygen utilization, causing lactic acidosis, neurologic dysfunction, and cardiovascular collapse.

A 49-Year-Old Man Comes to the Emergency Department with Severe