Download Methylene Blue - Developing Anaesthesia

METHYLENE BLUE
Left: a beautiful volumetric flask of pure methylene blue, (Amanda Slater). Right: a
medical ampoule of methylene blue.
Introduction
Methylene blue is tetramethylthionine.
It is the specific treatment for symptomatic drug induced methemaglobinemia.
It may also have a role in the treatment of refractory states of Distributive Shock,
(though more work needs to be done in this area). 3
History
Methylene blue was once used as a treatment for malaria and for cyanide poisoning, until
more effective treatments became available.
Chemistry
Methylene blue is a phenothiazine-related heterocyclic aromatic molecule.
It is a solid, odorless, dark green powder at room temperature that yields a striking blue
solution when it is dissolved in water.
Preparation
Methylene blue trihydrate as:
Ampoules:
●
50 mg in 5 mls (i.e. a 1% solution)
Mechanism of action
In methemaglobin metabolism:
Methylene blue acts to greatly promote the minor metabolic pathway of met Hb
metabolism.
Fe+++ Hb
NADPH dependent
Met Hb reductase
(5%)
NADH dependent
Met Hb reductase
(95%)
Fe++ Hb
Methylene Blue (acts as a co-factor for the minor pathway and therefore greatly
enhances the activity of this pathway)
For the role of methylene blue in the treatment of Distributive Shock - see Appendix
1 below.
Pharmacokinetics
Absorption:
●
Methylene Blue is given intravenously.
Metabolism and excretion:
●
Methylene blue is rapidly reduced to leucomethylene blue, which is then
predominantly excreted in the urine as a salt complex.
Indications
For methemaglobinemia:
1.
Consider in all cases above 20% met Hb 1
2.
All symptomatic patients with elevated met Hb levels.
Symptoms usually will occur at around 15-30% met Hb.
For Distributive Shock:
Consider for cases of refractory distributive shock, in particular: 3
1.
Septic shock.
2.
Anaphylactic shock.
3.
Some CVS drug overdoses, such as dihydropyridine calcium channel blockers.
Contraindications/ Precautions
1.
G6PD deficiency:
●
The lack of NADPH in this condition means that methylene blue will be
ineffective as it cannot be reduced to leucomethylene blue. Hemolysis
may also be induced.
2.
Known hypersensitivity.
3.
Renal impairment, (relative: requires dosage reduction).
Adverse reactions
1.
Excessive doses (> 7 mg/Kg) have oxidizing properties of its own and can
therefore paradoxically induce metHb in its own right!
Doses in this range may also induce an acute hemolytic anemia, and have
detrimental effects on pulmonary function.
2.
May induce mild hemolysis in normal individuals.
3.
In those with G-6-P deficiency massive hemolysis can be induced. It is therefore
contra-indicated in these patients.
4.
Rarely patients may have a congenital deficiency of NADPH met Hb reductase.
5.
May be irritating to the vein (follow doses with saline flushes)
6.
Blue staining of mucous membranes (which may further mimic cyanosis) and
urine.
Failure of Methylene Blue Treatment for Methemaglobinemia
The following will need to be considered.
1.
Wrong diagnosis:
●
e.g. In sulfhemoglobinemia or CO poisoning methylene blue is not
effective.
2.
The patient has NADPH met Hb reductase deficiency (very rare)
3.
The dose of methylene blue given has been excessive.
4.
The dose of methylene blue given has not been adequate.
5.
There is ongoing formation of methemaglobinemia, such as continual GIT
absorption of a toxic agent.
Dosing
For methemaglobinemia:
1 mg / Kg (= 0.1 ml / kg of the 1% solution) IV slowly over 5 minutes.
Up to 2 mg/kg (= 0.2 ml/ Kg of the 1% solution) IV slowly over 5 minutes may be
given.1
Improvement is usually seen with a single dose, however the dose can be repeated in 30
minutes to one hour if necessary.
Follow each dose with a saline flush to reduce venous irritation.
Improvement should be seen within 30-60 minutes.
Therapeutic end points:
1.
Resolution of symptoms
2.
Falling methemoglobin levels.
●
Levels should be measured hourly until a consistent fall is recorded.
If methylene blue fails to control methemaglobinemia consider exchange transfusion or
hyperbaric oxygen therapy.
For Distributive shock:
The dosing regimen for methylene blue based on experimental and clinical data is not
entirely clear but does seem to be similar to what is used for the treatment of
methemoglobinemia, i.e. 1- 2 mg/kg. 3
The dosing used for refractory septic shock has included:
●
A single bolus
●
Repeated bolus based on response
●
Low-dose infusions.
Appendix 1: Vasodilation as regulated by Nitric Oxide
Endothelial Nitric oxide synthase, (primarily within endothelial cells)
L- arginine
Nitric Oxide (NO)
Activates
+
L-citrulline
Inhibits
Guanylate cyclase
METHYLENE BLUE
GTP (in vascular smooth muscle)
cGMP
Activates
cGMP -dependant protein kinase
Decreased myosin sensitivity
And
Inhibition of stored calcium release from sarcoplasmic reticulum
And
Blockade of L -type Calcium channels (hence reducing available intracellular calcium)
VASODILATION
Excessive production of NO is implicated in the pathogeneses of vasodilation in cases of
distributive shock. Methylene blue blocks guanylate cyclase, thus inhibiting this
biochemical pathway.
References:
1.
Methylene blue in L Murray et al. Toxicology Handbook 3rd ed 2015.
2.
Zalstein S Methaemoglobinaemia case report in Emergency Medicine: 1993:5 p
71.
3.
Jang D.H et al. Methylene Blue for Distributive Shock: A Potential New Use of
an Old Antidote. J. Med. Toxicol. (2013) 9:242-249.