Is Methylene Blue SafeIn Patients With Methemoglobinemia
And Glucose 6-phosphateDehydrogenase (G6PD) Deficiency?
Bob Hoffman
New York City Poison Center, NY, USA
Overview
• Review of G6PD deficiency
• Review of methemoglobinemia (very brief)
• Review of methylene blue (MB) (brief)
• Attempt to answer the question– Expert opinion– Case reports– In Vitro data
Introduction
• G6PD deficiency – one of the most common inherited disorders, 400 million people affected– Largely in tropical and subtropical countries
• Selection advantages– Against Plasmodium falciparum infection
• Most affected individuals asymptomatic, but the risk of acute hemolysis is well known
Frequency of G6PD deficiency
Genetics
• > 400 variants described• Different electrophoretic mobility, kinetic
properties. • 5 classes according to the residual enzyme
activity based (WHO). • Mediterranean and African (A-) variants
– The most clinically significant.
• Activity scarcely detectable in the Mediterranean type but close to normal in the African variant.
Inheritance of G6PD Deficiency
What Do We Need G6PD For?
• Phosphogluconate pathway
• Pentose phosphate pathway
• Hexose monophosphate pathway
• Hexose monosphosphate shunt
G6PD
Catalyzes the first step in the pentose phosphate pathway
Regulatory enzyme
The enzyme is highly specific for NADP+; the Km for NAD+ is 1000 greater than for NADP+.
Pentose Phosphate Yields
• Ribulose (ribose) 5-phosphate– Essential nucleotide in biosynthesis
leading to:• DNA• RNA• Various cofactors
–CoA, FAD, SAM, NAD+/NADP+
Glutathione reductase uses NADPH as a cofactor to reduce GSSG back to two moles of GSH.
G6PD Deficiency
• G6PD deficiency is not the absence of G6PD, it is a decreased activity– Many cells express G6PD– Red cells are the only important cell line
because they lack a nucleus – Activity of G6PD highest (normal) in young
erythrocytes and decreases with aging– Oxidants preferentially destroy senescent red
blood cells
Response to Oxidants
Oxidant Response
• If not reduced:
– Some produce hemolysis• Oxidation of the hemoglobin chain
– Some produce MetHb• Oxidation of iron
– Some produce both?
Physiology
• Direct reduction of the oxidant
Oxidant Reduced Oxidant
Glutathione
Sulfhydryls
Ascorbate
Catalase
RBCs with Heinz Bodies
• Precipitation of hemoglobin due to disulfide bond formation between Hb molecues
• Upper photo shows distorted RBCs with large Heinz bodies
• Bottom photo shows RBC stained with methylene blue
Methemoglobin Definition
• Oxidation of the iron molecule in hemoglobin from its normal Fe2+ to Fe3+
FeN
N
N
N
histidine O2- Oxyhemoglobin
C O COHb
OH
HMethemoglobin
Physiology
The oxidant is reduced by Hb (forming MetHb) • Then MetHb is reduced back to Hb
MetHb Reduced Hb
NADH MetHb reductase (67%)
Ascorbate (15%)
Glutathione (12%)
NADPH Met Hb reductase (5%)
Can You Use Methylene Blue In Patients with G6PD Deficiency?
Famous Textbook Quotes
• Methylene blue remains the first line therapy even in patients with known G6PD deficiency– Brent
• Should never be administered to someone with known G6PD deficiency– Shannon
• Should be used cautiously in patients with G6PD deficiency– Dart
• 28 year old man • Ingested 60-120mL of 18% aniline• MetHb 11 gm/dL (70-80%)• 75 mg methylene blue given• Didn’t get better• G6PD screening showed deficiency (A-)• Given ascorbate• Hemolyzed, Hb fell, recovered
– Rosen PJ: Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971;75:83-6
What happened between the 0 and 4 hour levels?
• 26 month, 9.8-kg boy with G6PD deficiency• Ingested 90 mL of nitroethane – MetHb 23.3%• MetHb rises to 37%, then over 40%• Cyanotic, in respiratory failure, intubated • Two doses of methylene blue (2mg/kg) given
“without response”• No hemolysis• Finally treated with exchange transfusion
– Golden PJ: Treatment of high-risk, refractory acquired methemoglobinemia with automated red blood cell exchange. J Clin Apher 1998;13:28-31.
• 74 G6PD deficient men
• 3 day regimen– Chloroquine 1500 mg
– Methylene blue 780 mg (mg/kg PO BID)
• No hemolysis occurred – Mandi G: Safety of the combination of chloroquine and
methylene blue in healthy adult men with G6PD deficiency from
rural Burkina Faso. Trop Med Int Health. 2005;10:32-8.
• 3 case reports
• Intraamniotic methylene blue given for PROM (2); IV for maternal MetHb (1)– Dose varied
• All developed elevated bilirubin
• Only 2 G6PD deficient– Gauthier TW: Methylene blue-induced hyperbilirubinemia in
neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency. J Matern Fetal Med. 2000;9:252-4.
• Neonate, known G6PD deficiency• Multiple cardiac abnormalities• Undergoes surgical repair on day 28 of life• Requires nitroglycerin IV• Develops MetHb: 75%• Given low dose (0.1 mg/kg) methylene blue• Has mild hemolysis requiring no therapy
– Middali MM: Postoperative methemoglobinemia with associated G-6-P-D deficiency in infant cardiac surgery--enigmas in diagnosis and management. Paediatr Anaesth 2005;15:334-7.
• 59-year-old man with metastatic renal cell CA• Trial of 3-aminopyridine-2-carboxaldehyde
thiosemicarbazone (3-AP; Triapine)• Developed MetHb 35%• Given 3 doses (1 mg/kg) methylene blue• MetHb fell to 10%, then 6.5 %• Masive hemolysis • Severe G6PD deficiency confirmed later
– Foltz LM: Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 2006;81:210-1.
• Metoclopramide 10 mg administered twice• Cyanosis and dyspnea; 28 hours later• MetHb was 43% • Ascorbic acid 150 mg and methylene blue 60 mg
given • Consciousness deteriorated• Methylene blue 40 mg was repeated at 2 hours • Deteriorated rapidly and he died 12 hours • Blood taken a before death was hemolysed • Postmortem: b5R and severely G6PD deficient
– Karadsheh NS: Metoclopramide-induced methemoglobinemia in a patient with co-existing deficiency of glucose-6-phosphate dehydrogenase and NADH-cytochrome b5 reductase: failure of methylene blue treatment Haematologica 2001;86:659
• 25 year old man; large dermal exposure to aniline
• 5 hours later – MetHb 51%• Methylene blue 40mg IV improved symptoms• MetHb fell to 2.1%• Developed significant hemolysis• G6PD deficient• Recovered (transfused)
– Liao YP: Hemolytic anemia after methylene blue therapy for aniline-induced methemoglobinemia. Vet Hum Toxicol. 2002;44:19-21.
In Vivo Summary
• Does Methylene blue fail?– Often works– Usually slowly
• Does methylene blue cause hemolysis– It can, and it can be severe– Especially when hemolysis is present prior to
therapy
Beutler E: Methemoglobin Reduction: Studies of the interaction between cell popluations and of the
role of methylene blue. Blood 1963;22:323-333
• Incubated human RBCs with nitrite to induce MetHb
• Treated with methylene blue and glucose
• Observed rates of fall– Normal cells– G6PD cells (A-)– Mixture of cells
Implications
• G6PD deficient cells clear MetHb slowly in response to methylene blue
• Either NADPH or leukomethylene blue can move from healthy cells to deficient cells
• This effect is more pronounced at lower levels of MetHb– Young cells and reticulocytes are G6PD
present– Role of transfusion (fresh blood)?
Summary (1)
• Data on the use of methylene blue in patients with G6PD deficiency are limited – Most support some degree of efficacy– Significant risk of hemolysis
• Would administer methylene blue in:– Patients with no history of G6PD deficiency– Patients with known G6PD deficiency and life-
threatening MetHb• Ascorbate, Exchange transfusion, HBO, NAC
Summary (2)
• Withhold methylene blue in:– Patients with known severe variant G6PD
deficiency (Mediterranean) not significantly ill – Patients with known or suspected G6PD
deficiency and marginal indications for treatment
– Patients with significant active hemolysis in addition to MetHb
Summary (3)
• If giving methylene blue to patients with a known or suspected history of G6PD deficiency– Keep the first dose small (1 mg/kg)– Recheck the MetHb often– Do not repeat if unsuccessful– Observe closely for hemoylsis
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