Methylene Blue Rescue Therapy for Vasoplegic Shock After Antihypertensive Drug Overdose

Introduction

The prevalence of polysubstance abuse and multidrug toxicity is increasing, creating substantial therapeutic challenges for clinicians [1]. β-blocker and calcium channel blocker overdose typically manifests with bradycardia and hypotension, which can progress to refractory shock in cases of severe toxicity [2].

Methylene blue is a potent inhibitor of nitric oxide (NO) synthase within the vascular endothelium, leading to increased systemic vascular resistance. Therefore, it can be used in cases of vasoplegic shock refractory to vasopressor therapy [3]. Methylene blue is considered a rescue therapy in such cases when conventional agents (eg, norepinephrine and vasopressin) fail to restore adequate mean arterial pressure. Its use is supported by studies demonstrating rapid and sustained increases in systemic vascular resistance and arterial pressure [3,4]. The hemodynamic effects of methylene blue include increased mean arterial pressure, reduced vasopressor requirements, and improved tissue perfusion [3]. Some authors have reported use of methylene blue as rescue therapy in vasoplegic shock due to toxicity from antihypertensive agents [5,6].

Here, we describe successful use of methylene blue in a woman who developed profound vasoplegic shock induced by an overdose of multiple antihypertensive agents, including a calcium channel blocker (amlodipine), a β-blocker (bisoprolol), and an angiotensin receptor blocker (valsartan).

Case Report

A 47-year-old woman with a history of hypertension presented to the emergency department after a suicide attempt. She had ingested 10 tablets of bisoprolol 5 mg and 10 tablets of a combined amlodipine 10 mg/valsartan 160 mg formulation, approximately 1 h before arrival. On initial assessment, she was somnolent and reported abdominal discomfort but remained hemodynamically stable.

Five hours later, the patient developed hypotension (80/46 mmHg), bradycardia (54 bpm), rapid oxygen desaturation, and increased work of breathing; thus, she required endotracheal intubation. Initial resuscitative measures, including intravenous fluids, atropine, glucagon, and calcium gluconate, failed to restore blood pressure despite improvement in heart rate. Continuous infusions of epinephrine (0.3 μg/kg/min) and norepinephrine (0.05 μg/kg/min) resulted in modest hemodynamic improvement. Epinephrine was later discontinued; the patient was maintained on norepinephrine (3 μg/kg/min), phenylephrine (7 μg/kg/min), and dopamine (20 μg/kg/min), with only minimal improvement in blood pressure. High-dose hydroxocobalamin (5 g) and a high-dose dextrose–insulin infusion were administered. However, she remained hypotensive, with a mean arterial pressure (mmHg) declining further into the low 50s. This decline was accompanied by progressive multiorgan dysfunction, including ischemic liver injury and acute kidney injury requiring continuous renal replacement therapy.

Given the patient’s worsening clinical status despite maximal vasopressor and metabolic support, methylene blue (1 mg/kg) was administered over a 5-min period within 48 h of intensive care unit admission. Thirty minutes after the methylene blue bolus, blood pressure considerably improved to 113/50 mmHg, and lactate levels (normal <2 mmol/L) gradually began to decrease, as shown in Figure 1. Due to limited methylene blue availability, a continuous infusion was not initiated. Over the subsequent 2 h, dopamine was discontinued, norepinephrine was gradually reduced to 1.8 μg/kg/min, and phenylephrine was tapered to 2 μg/kg/min before a switch to vasopressin (0.04 U/min). Vasopressin was subsequently discontinued, and norepinephrine was gradually weaned over the following 72 h.

The patient was successfully extubated on day 12 of hospitalization, with substantial improvement in liver function. Renal function continued to improve over the subsequent 3 weeks without any requirement for hemodialysis. She returned to baseline blood pressure status, and her antihypertensive medications were carefully reintroduced before discharge.

Discussion

This report describes the successful use of methylene blue in the management of refractory vasoplegic shock resulting from an overdose of multiple antihypertensive agents. Overdoses of antihypertensive medications such as amlodipine, valsartan, and bisoprolol can lead to profound vasoplegia through complementary mechanisms that severely impair vascular tone [2]. Amlodipine, a dihydropyridine calcium channel blocker, inhibits calcium influx into vascular smooth muscle and enhances endothelial NO production, thereby activating the NO–cyclic guanosine monophosphate (cGMP) pathway and promoting arteriolar vasodilation [2,7]. Through angiotensin II receptor blockade, valsartan inhibits the renin–angiotensin–aldosterone system, resulting in reduced vasoconstrictive tone and diminished responsiveness to catecholamines [8]. In parallel, bisoprolol overdose may cause loss of β1 selectivity, leading to β2 blockade, suppression of renin release, and reduction of intracellular cyclic adenosine monophosphate, all of which further attenuate vasoconstrictive mechanisms [9,10]. The combined effects of these agents in overdose produce synergistic suppression of sympathetic, hormonal, and intracellular pathways that maintain vascular tone, resulting in refractory vasoplegia that is often unresponsive to standard vasopressors and may require nonadrenergic interventions such as methylene blue [3,4].

Previous reports have described the use of methylene blue in refractory shock associated with antihypertensive drug overdose [5,6]. Aggarwal et al reported successful administration of methylene blue in a 69-year-old woman with a history of hypertension, hypothyroidism, and depression who was admitted after a suicide attempt involving overdose of a calcium channel blocker (amlodipine) and a β-blocker (atenolol). The patient developed profound shock despite treatment with multiple vasopressors, including norepinephrine 1 μg/kg/min, dopamine 20 μg/kg/min, and vasopressin 0.8 U/min. Methylene blue (1 mg/kg bolus) was administered as salvage therapy, resulting in blood pressure improvement within 20 min; this was followed by a continuous infusion of 1 mg/kg/h for 10 h, which allowed vasopressor weaning within 72 h [5]. Similarly, Ahmed et al reported successful use of a methylene blue infusion in a 50-year-old man with hypertension, type 2 diabetes mellitus, and bipolar disorder who developed progressive shock after ingesting 80 mg of amlodipine [6]. Although these reports highlight the potential utility of methylene blue as a rescue agent for refractory vasoplegia after antihypertensive drug overdose, the present case demonstrates effective hemodynamic stabilization after administration of a single dose of methylene blue in the setting of combined antihypertensive toxicity.

Methylene blue exerts its hemodynamic effects in refractory shock primarily through inhibition of the NO–cGMP pathway, a key mediator of vasodilation in vasoplegic conditions such as septic shock and toxicologic etiologies [3,4]. By directly inhibiting soluble guanylyl cyclase, methylene blue prevents NO-induced increases in cGMP levels [11,12]. Additionally, methylene blue nonselectively inhibits nitric oxide synthase, further reducing NO production and reinforcing its vasoconstrictive effects [11,12]. This dual inhibition of NO synthesis and downstream cGMP signaling renders methylene blue particularly effective in counteracting vasoplegic shock refractory to catecholamines and vasopressin [11–13].

Conclusions

This case contributes to the growing body of evidence supporting the use of methylene blue in refractory vasoplegia and highlights its application in antihypertensive-induced vasoplegia. It reinforces the potential utility of methylene blue as a therapeutic option for managing vasoplegic shock induced by overdose of multiple antihypertensive agents, including calcium channel blockers, β-blockers, and angiotensin receptor blockers.