methylene blue for eapcct

8/12/2019 Methylene Blue for EAPCCT

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Is Methylene Blue SafeIn Patients With Methemoglobinemia

And Glucose 6-phosphate

Dehydrogenase (G6PD) Deficiency?

Bob Hoffman

New York City Poison Center,

NY, USA


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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


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Introduction

G6PD deficiencyone of the mostcommon inherited disorders, 400 millionpeople affected

Largely in tropical and subtropical countries Selection advantages

Against Plasmodium falciparum infection

Most affected individuals asymptomatic,but the risk of acute hemolysis is wellknown


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Frequency of G6PD deficiency


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Genetics

> 400 variants described

Different electrophoretic mobility, kinetic

properties.

5 classes according to the residual enzymeactivity 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.


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Inheritance of G6PD Deficiency


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What Do We Need G6PD For?

Phosphogluconate pathway

Pentose phosphate pathway

Hexose monophosphate pathway

Hexose monosphosphate shunt


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G6PD

Catalyzes the first step in the

pentose phosphate pathway


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Regulatory enzyme

The enzyme is highly specific for NADP+; theKmfor NAD

+is 1000 greater than for NADP+.


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Pentose Phosphate Yields

Ribulose (ribose) 5-phosphate

Essential nucleotide in biosynthesis

leading to:

DNA

RNA

Various cofactors

CoA, FAD, SAM, NAD+/NADP+


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Glutathione

reductase usesNADPH as a

cofactor to

reduce GSSG

back to twomoles of GSH.


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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


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Response to Oxidants


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Oxidant Response

If not reduced:

Some produce hemolysis

Oxidation of the hemoglobin chain

Some produce MetHb

Oxidation of iron

Some produce both?


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Physiology

Direct reduction of the oxidant

Oxidant Reduced Oxidant

Glutathione

Sulfhydryls

Ascorbate

Catalase


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RBCs with Heinz Bodies

Precipitation ofhemoglobin due todisulfide bond formation

between Hb molecues Upper photo shows

distorted RBCs withlarge Heinz bodies

Bottom photo showsRBC stained withmethylene blue


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Methemoglobin Definition

Oxidation of the iron molecule in

hemoglobin from its normal Fe2+to Fe3+

Fe

N

N

N

Nhistidine O

2-

Oxyhemoglobin

C O COHb

OH

HMethemoglobin


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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%)


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Can You Use Methylene Blue In

Patients with G6PD Deficiency?


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Famous Textbook Quotes

Methylene blue remains the first line therapy

even in patients with known G6PD deficiency

Brent

Should never be administered to someone withknown G6PD deficiency

Shannon

Should be used cautiously in patients with G6PD

deficiency

Dart


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28 year old man

Ingested 60-120mL of 18% aniline MetHb 11 gm/dL (70-80%)

75 mg methylene blue given

Didnt get better G6PD screening showed deficiency (A-)

Given ascorbate

Hemolyzed, Hb fell, recovered Rosen PJ: Failure of methylene blue treatment in toxicmethemoglobinemia. Association with glucose-6-phosphate

dehydrogenase deficiency. Ann Intern Med 1971;75:83-6


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What

happened

between the

0 and 4 hourlevels?


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26 month, 9.8-kg boy with G6PD deficiency

Ingested 90 mL of nitroethaneMetHb 23.3%

MetHb rises to 37%, then over 40%

Cyanotic, in respiratory failure, intubated

Two doses of methylene blue (2mg/kg) givenwithout 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.


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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.


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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 inneonatal glucose-6-phosphate dehydrogenase (G6PD)

deficiency. J Matern Fetal Med. 2000;9:252-4.


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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 cardiacsurgery--enigmas in diagnosis and management.Paediatr Anaesth 2005;15:334-7.


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59-year-old man with metastatic renal cell CA

Trial of 3-aminopyridine-2-carboxaldehydethiosemicarbazone (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 drugTriapine. Am J Hematol 2006;81:210-1.


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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-phosphatedehydrogenase and NADH-cytochrome b5 reductase: failure ofmethylene blue treatment Haematologica 2001;86:659


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25 year old man; large dermal exposure toaniline

5 hours laterMetHb 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.


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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

B tl E M th l bi R d ti St di f


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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


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Implications

G6PD deficient cells clear MetHb slowly inresponse 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 G6PDpresent

Role of transfusion (fresh blood)?


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Summary (1)

Data on the use of methylene blue inpatients 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


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Summary (2)

Withhold methylene blue in:

Patients with known severe variant G6PD

deficiency (Mediterranean) not significantly ill

Patients with known or suspected G6PDdeficiency and marginal indications for

treatment

Patients with significant active hemolysis inaddition to MetHb


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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

methylene blue for eapcct

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