Update on Methylene Blue: It's Not Just for Methemoglobinemia Anymore

Treating methemoglobinemia used to be a relatively simple affair. Most often, the condition resulted from a therapeutic dose of a drug such as dapsone or benzocaine oxidizing the iron in hemoglobin from the ferrous (+2) to the ferric (+3) state, producing methemoglobin. Methemoglobin cannot carry or deliver oxygen to vital organs and tissues. Until recently, cases of methemoglobinemia were usually relatively mild, presenting with cyanosis that did not respond to supplemental oxygen, chocolate-colored blood, and a pulse oximeter reading that was typically stuck at around 85%. Even symptomatic patients tended not to be seriously ill, and the clinical protocol was straightforward: give supplemental oxygen and supportive care, send a methemoglobin level to confirm the diagnosis, and then administer the antidote, methylene blue (MB), if indicated. On the still-unvalidated sphincter-tightening scale of clinical acuity, the vast majority of these cases were 2 out of 10 at best. All that changed around the time of COVID, when sodium nitrite started being recommended in online forums and manuals as an agent for self-harm and suicide. Since sodium nitrite has legitimate uses for purposes, such as curing meat, massive amounts could be easily purchased online. Patients who ingested massive amounts of sodium nitrite rapidly became critically ill and often suffered cardiac arrest before they could reach the emergency department (ED) or receive an initial dose of MB. Sodium nitrite is an especially dangerous threat because it has two deadly effects. First, it is a potent oxidizing agent, capable of producing critically high methemoglobin levels. Second, it increases levels of nitric oxide—a potent vasodilator—causing severe hypotension and vasoplegic shock. Fortunately, MB is the perfect antidote for sodium nitrite overdose, since it counteracts both of these deadly mechanisms. It facilitates the reduction of methemoglobin back to oxygen-carrying ferrous hemoglobin. (In a previous column, I explained the fascinating mechanism by which MB—a strong oxidizing agent—can donate an electron and convert Fe3+ to Fe2+.)1 And MB is also a vasoconstrictor, inhibiting nitric oxide synthase activity and reversing hypotension. When it comes to administering MB in cases of massive sodium nitrite overdose, time is of the essence. These patients can deteriorate quickly, and once they arrest, it is virtually impossible to achieve return of spontaneous circulation. Because of this, some centers have considered the possibility of having MB available for prehospital administration. In a recent paper, Garcia-Galindo et al described a 31-year-old woman who called 9-1-1 shortly after ingesting a “massive amount” of sodium nitrite in a suicide attempt.2 When first responders arrived 15-20 minutes after the ingestion, they found the patient coherent and regretful. However, she quickly developed cyanosis and tachypnea, with a pulse oximetry reading of 84% that did not respond to supplemental oxygen. She suffered an asystolic cardiac arrest en route to hospital and could not be resuscitated. The authors note that although most hospitals in their area (Hennepin County, MN) stock MB, most keep it in their central pharmacy but not in the ED, potentially creating delays in administration. They emphasize that the keys to maximizing successful outcomes in these cases are early notification by EMS to the hospital that a possible sodium nitrite overdose case is on the way, and immediate access to MB. They also discuss the possibility of having the antidote available for administration in the prehospital setting. Since MB inhibits synthesis of nitric oxide and is thus a vasoconstrictor, there is increasing interest in its use for treating vasoplegic shock, especially in overdose from dihydropyridine calcium channel blockers such as amlodipine and nifedipine. These agents act selectively on peripheral blood vessels, causing vasodilatation rather than depressing myocardial function, although in significant overdose that selectivity can be lost. Clinical signs of vasoplegic shock include hypotension, tachycardia, and normal or supernormal cardiac function with increased ejection fraction on formal or point-of-care bedside echocardiography.The 2025 American Heart Association updated guidelines on cardiopulmonary resuscitation in special circumstances note that typical vasopressors, such as norepinephrine, constitute primary treatment for hypotension in life-threatening CCB toxicity in adults and children.3 Unfortunately, their take on use of MB in these cases is frustratingly ambivalent: “Methylene blue, a nitric oxide synthase inhibitor, is described in adult case series and case reports as an effective adjunct to treat refractory vasodilatory shock after CCB overdose (involving primarily amlodipine). However, responses are mixed, and the effects may be transient.” As I've noted before, “recommendations” such as this are not at all helpful to the clinician trying to treat the patient in front of her and could just as easily be replaced with a shrug emoji. It seems to me that the comment “responses are mixed, and the effects may be transient” could be said about almost any intervention used in medical toxicology cases. In my view, a more helpful approach has been laid out in a recent article on CCB poisoning by Simpson and Cole: “Based on current evidence, we recommend methylene blue for vasoplegia refractory to multiple vasopressors, dosed as an intravenous bolus of 1-2 mg/kg and an infusion of 1 mg/kg/h, not to exceed a maximum cumulative dose of 7 mg/kg.”4 That is actually a real recommendation, not a .