ACMT Toxicology Visual Pearl: Is the Silver Bullet for Refractory Vasoplegia Really Blue?

Answer

3 – Inhibition along the nitric oxide (NO)/cyclic GMP pathway

Background

Vasoplegic shock is a maldistribution of blood flow and inadequate oxygen delivery secondary to an abnormally low systemic vascular resistance [1]. Catecholamine- resistant vasoplegic shock can occur, refractory to norepinephrine, epinephrine, and dopamine. Methylene blue increases systemic vascular resistance through inhibition along the NO/cyclic GMP pathway. Although evidence is limited, methylene blue may serve as a salvage vasopressor in catecholamine-resistant vasoplegic shock – particularly in shock secondary to sepsis, anaphylaxis, or post cardiopulmonary bypass [2].

How does methylene blue work as a vasopressor?

• Methylene blue is FDA approved for the treatment of methemoglobinemia but has increasingly been used off-label in vasoplegic shock as a potent vasoconstrictor.
• Mechanisms of Action
  • Vasopressor: Methylene blue inhibits NO-induced guanylyl cyclase conversion of GTP to cyclic GMP, an intracellular signaling molecule for vasodilation [2]. It also downregulates endothelial NO synthase [3].
  • Methemoglobinemia: Methylene blue is an electron shuttle from NADPH in order to reduce Fe3+ in methemoglobin to Fe2+ in hemoglobin.

What is the evidence for methylene blue as a vasopressor?

The evidence is limited. The majority of studies are in catecholamine-resistant vasoplegic shock secondary to sepsis, anaphylaxis, and following cardiopulmonary bypass although there has been increasing use in the setting of poisoning with agents such as calcium channel blockers.

• Sepsis: Two randomized control trials (n=20 and n=30) demonstrated administration of methylene blue resulted in increased SVR, increased MAP, and decrease in catecholamine vasopressor requirements. No mortality benefit was observed [4, 5].
• Anaphylaxis: Review of case reports demonstrate successful treatment of 11 patients with methylene blue in refractory anaphylactic shock [6]. Systemic vasodilation in anaphylactic shock is partially attributed to NO activity induced by histamine release [7]. In rat models with anaphylactic shock, epinephrine and methylene blue produce a synergistic effect in reversing histamine-induced vasodilation [8].
• Post-cardiopulmonary bypass: Two large retrospective analyses have demonstrated a mortality benefit, increase in SVR, and increase in MAP with early administration of methylene blue when compared to late administration [9,10].

The exact role for methylene blue in vasoplegia has yet to be fully elucidated but currently should be considered for use in catecholamine-resistant vasoplegic shock secondary to post cardiopulmonary bypass, sepsis, and anaphylaxis. Further research is needed to determine efficacy and additional indications.

What are the proposed dosing, contraindications, and common adverse effects?

Note that methylene blue dosing is DIFFERENT for vasoplegia as compared to methemoglobinemia treatment. The proposed dosing for vasoplegia is the following [11, 12]:

• Initial bolus: 1-2 mg/kg in 50 mL of 5% dextrose IV over 5 minutes
• Additional dosing:
  • Repeat boluses every 4-6 hours, OR
  • Continuous infusion at 0.25-2 mg/kg/hour immediately following the initial bolus
• Doses over 7 mg/kg are associated with a higher incidence of adverse effects.
• There is variation in the literature concerning the dosing; the authors use the bolus followed by an infusion

Adverse Effects [12]:

• Nausea
• Diaphoresis
• Pain with infusion at the IV site
• Blue-green urine
• Hemolytic anemia
• Hypersensitivity reaction
• Increased risk of serotonin toxicity at higher doses in patients concurrently taking other serotoninergic medications

Contraindications/Cautions:

• History of hypersensitivity reaction
• Pregnancy category X
• Concomitant use of serotoninergic agents
  • Relative contraindication as risk of serotonin toxicity is increased, especially with higher doses of methylene blue >7 mg/kg
• Glucose-6-phosphate dehydrogenase deficiency
  • Relative contraindication as risk of hemolysis is increased
• Severe right ventricular dysfunction and pulmonary hypertension
  • Relative contraindication as methylene blue increases pulmonary vascular resistance which could exacerbate these conditions [13]

Bedside Pearls on Methylene Blue

• It serves as a vasopressor through inhibition along the nitric oxide/cyclic GMP pathway
• It can be considered in vasoplegic shock refractory to catecholamine pressors (the authors suggest refractory to 2 pressors) – particularly in post cardiopulmonary bypass induced hypotension, sepsis, or anaphylaxis.