Cyanide and Methemoglobinemia

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Cyanide and Methemoglobinemia

• Presented by Dr. Aric Storck
• Preceptor Dr. Ingrid Vicas
• Core Rounds
• February 20, 2003

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Cyanide
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Cyanide

• Anion (CN-)
• solid and gaseous forms
• Important component of many industrial reactions
• mining - recover silver and gold from ores
• photographic - recovery of silver
• plastic manufacturing
• Naturally occurs in many plant products
• Tobacco, apricot pits

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Cyanide pollution

• 1997 - 4,513,410 cyanide released by top 100
  polluters in USA
• Bhopal, 1984
• worst industrial poisoning in history
• 25,000 kg methyl isocyanate and combustion
  products released into atmosphere
• 1,800 - 5,000 deaths
• 200,000 injuries

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Man carries his wife past the Union Carbide
factory in Bhopal, India. Fumes from the factory
killed her the previous day
Source Greenpeace
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Skulls from victims of the Union Carbide disaster
in the Hamidia Hospital in Bhopal, India.
Source Greenpeace
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Cyanide a potential disaster

• 500,000 hazardous materials shipments / day in
  the USA
• Average 12,115 hazardous material accidents per
  year (1990-1996)
• Large potential for significant industrial
  accident involving cyanide

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Cyanide and terrorism

• 1984 - 7 Chicago area residents killed after
  ingesting cyanide-laced Tylenol
• Cyanide gas precursors (cyanide salt acid)
  found in Tokyo subway bathrooms following sarin
  gas attacks
• Cyanide believed to be involved in World Trade
  Center bombing (incinerated in attack)

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Cyanide and Fires

• Cyanide is a combustion product of
• plastic
• rugs
• silks
• furniture
• construction materials

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Cyanide and Fires

• Significant correlation between CO levels and CN-
  levels in fire victims
• estimated 35 of fire victims have toxic levels
  of cyanide

Source Sauer S, Keim M. Hydroxocobalamin
Improved public health readiness for cyanide
disasters. Ann Emerg Med. June 2001 37635-641.
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Cyanide - Pathophysiology

• CN- has high affinity for metals
• Complexes with metallic cations at catalytic
  sites of several enzymes
• Binds ferric (3) iron of mitochondrial
  cytochrome oxidase (cytochrome a-a3)
• cytochrome a-a3 mediates transfer of electrons
  to molecular oxygen (final step in oxidative
  phosphorylation)

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Oxidative Phosphorylation
Source Fords Clinical Toxicology
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Blockade of oxidative phosphorylation

• Tissue anoxia
• Anaerobic metabolism
• Lactic acidosis

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Cyanide - Pathophysiology

• Other metabolic effects
• Less relevant (...because you die of anoxia
  first)
• Interferes with lipid metabolism
• Interferes with glycogen metabolism

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Cyanide - Poisoning

• Rapid absorption
• Respiratory tract
• Mucous membranes
• Slow absorption
• Skin
• GI tract

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Cyanide Poisoning - Inhalation

• Hydrogen cyanide
• Combustion of nitrogen containing polymers
  (vinyl, polyurethane, silk)
• Immediate onset of symptoms
• 50 ppm
• Symptoms after several hours
• Anxiety, SOB, palpitations, headache
• 100 ppm
• Death after 30 minutes
• 270 ppm
• Immediate coma, asystole, death

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Cyanide Ingested Salts

• Symptoms within minutes
• Caustic oral burns
• Smell of bitter almonds
• 50 mg has been reported to cause death
• LD50 140-250 mg (untreated adult)

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Ingestion Cyanide producing compounds

• Compounds require metabolic activation to produce
  cyanide
• Organic nitriles
• Cyanogenic glycosides
• eg amygdalin found in bitter almonds, apricot
  pits
• Hydrolyzed to CN in small bowel
• Not toxic if taken intravenously
• Acetonitrile (solvent in artificial nail remover)
• Oxidized by hepatic enzymes
• Delayed onset of symptoms (up to 24 hours)

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Cyanide - Dermal Exposure

• LD50 100 mg/kg

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Cyanide Nitroprusside

• Deterioration in aqueous solutions releases
  cyanide
• Hydroxycobalamin and thiosulfate co-infusions
  used in critical care settings

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Chronic Cyanide Poisoning

• Clinical relevance controversial
• Cassava contains linamarin (cyanogenic)
• Common food in many countries
• Some evidence that B12 deficiency, goiter,
  demyelinating diseases may be related

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Cyanide - Detoxification

• Naturally occurs in small quantities
• tobacco
• cassava
• Small amounts routinely cleared from body

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Cyanide - Detoxification

• Cyanide thiosulfate thiocyanate
• Enzymatically
• Rhodanase
• Beta-mercaptopyruvate-cyanide sulfur transferase
• Nonenzymatically
• Sulfane-albumin complex combines with cyanide

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Cyanide - Elimination

• Thiocyanate
• Relatively non-toxic
• Renal elimination (half life 2.5 days)

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Cyanide Clinical Presentation

• Physiologic manifestations of hypoxia
• Metabolic acidosis
• Bradycardia
• Dyspnea
• CNS disturbances
• Normal pulse oximetry

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Cyanide Clinical Presentation

• CNS
• Headaches
• Drowsiness
• Dizziness
• Seizures
• Coma

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Cyanide Clinical Presentation

• Pulmonary
• Dyspnea
• Tachypnea
• Apnea

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Cyanide Poisoning - DDX

• Ingestion with altered LOC and acidosis
• sodium azide
• salicylates
• iron
• Beta-adrenergic antagonists
• cocaine
• isoniazid
• toxic alcohols

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Cyanide Poisoning - DDX

• Inhalational Exposures
• hydrogen sulfide
• carbon monoxide
• simple asphyxiants

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Cyanide Clinical Presentation

• Cardiovascular Effects
• Hypertension
• Tachycardia
• Hypotension
• Bradycardia
• Asystole
• Cardiac collapse

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Laboratory Investigation

• Electrolytes
• Elevated anion gap (lactic acidosis)
• ABG
• Metabolic acidosis (lactic acidosis)
• Normal PO2
• SaO2
• Normal

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Laboratory Investigation

• AVO2
• Decreased (decreased tissue oxygen utilization)
• Cyanide levels
• Not rapid enough for clinical utility
• Serum cyanide level
• Toxic gt0.5mg/L
• Fatal gt3.0 mg/L
• Erythrocyte cyanide level
• Normal lt1.9 uM/L (50ug/L)
• Fatal gt 40 uM/L (1mg/L)

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Laboratory Investigation

• Serum lactate elevated
• ECG
• Sinus bradycardia
• Sinus tachycardia

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Cyanide Poisoning - Sequellae

• Directly related to severity of exposure and
  delay in treatment
• long term sequellae are those of hypoxia
• cerebral hypoxia / encephalopathy (common)

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Cyanide - Treatment

• Monitors
• IV access
• Administer 100 O2
• Gastric lavage
• Indicated in very recent ingestion
• Activated charcoal (1g/kg)

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Cyanide Antidote Kit
Manufacturer Taylor Pharmaceuticals Cost 317
USD
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Cyanide Antidote Kit

• Contents
• Amyl nitrite 0.3 ml x 12
• Inhaled while IV access established
• Not necessary if immediate IV access
• Can be given in pre-hospital setting
• Sodium nitrite 300mg/10cc x 2
• Sodium thiosulfate 12.5g/50cc x2
• syringes, needles, tourniquet, stomach tube,
  instructions

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Cyanide Antidote Kit

• Instructions
• Crush and inhale one ampoule (0.3ml) of amyl
  nitrite q15-30 seconds until iv access achieved
• Rapid infusion sodium nitrite 300mg
• Infuse sodium thiosulfate 12.5g over 10 minutes
• Repeat sodium nitrite and thiosulfate infusion at
  half dose prn x 1
• Caution
• Sodium nitrite infusion limited by hypotension

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Cyanide Antidote Kit - Mechanism

• Nitrites
• Therapeutic induction of methemoglobinemia
• NO2 Hb MHb
• Methemoglobin binds strongly to CN- and removes
  it from tissues
• CN- MHB cyanomethemoglobin
• cyanomethemoglobin relatively non-toxic

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• Sodium Thiosulfate
• donates sulfur molecule to rhodanese (enzyme
  which catalyzes formation of thiocyanate)
• Na2S2O3 HCN O HSCN
• Synergistic effect
• Oxygen
• Synergy of 100 O2 with nitrites/thiosulfate

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CAK - Children

• 0.33 mL/kg of 3 NaNO2
• Adjust dose if anemic
• Hb 70 0.19mL/kg
• Hb 100 0.27mL/kg
• Hb 120 0.33mL/kg
• Hb 140 0.39mL/kg
• 1.65 mL/kg of 25 Na2S2O3

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Cyanide Antidote Kit

• Effectiveness
• able to detoxify 20 lethal ingested doses in dogs
• effective even after respiratory arrest as long
  as no cardiac arrest
• Complications
• Hypotension
• Related to vasodilatory effects of nitrites
• Methemoglobinemia
• Death reported in asymptomatic cyanide poisonings
  (NB only use CAK if symptomatic poisoning)

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Cyanide Antidote Kit

• Limitations
• MHb production prevents its use in unconfirmed
  cases
• not practical for smoke inhalation victims (bad
  idea to induce MHb when already high level of
  carboxyhemoglobin)
• many hospitals poorly supplied
• 81 of Tennessee hospitals unable to treat two 70
  kg patients

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Cyanide other antidotes

• Hyperbaric Oxygen
• No therapeutic effect
• Useful if concomitant CO inhalation
• Dicobalt edetate
• Widely used in UK
• Effective antidote with significant toxicity
  (esp. when cyanide not present)

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DMAP (4-dimethylaminophenol)

• Produces very rapid methemoglobinemia
• Used widely in Germany
• No more effective than sodium nitrite
• Less hypotension than sodium nitrite
• Linked with renal failure in animal models

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Hydroxycobalamin (vitamin B12a)

• Widely used in France
• Very effective and non-toxic
• precursor of B12 (cyanocobalamin)
• ideal choice for vegan victims of cyanide
  poisoning
• Recognized by FDA for cyanide poisoning
• Used in ICU settings to mitigate nitroprusside
  toxicity

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• Reduces cyanide to cyanocobalamin
• B12a CN- B12
• 5g B12a will treat patients with up to 40 umol/L
• Low concentrations available in US mean very
  large quantities required

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Hydroxycobalamin (vitamin B12a)

• When combined with sodium thiosulfate end product
  is thiocyanate
• Na2S2O3 B12 HSCN B12a
• Recycling of hydroxycobalamin
• Renally cleared
• Synergistic effect of thiosulfate and B12a

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Hydroxycobalamin (vitamin B12a)

• Advantages vs CAK
• less toxic
• does not produce MHb (thus appropriate for smoke
  inhalation victims)
• may be administered out of hospital
• cheaper

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Hydroxycobalamin (vitamin B12a)

• Available in Europe as Cyanokit
• 2.5 and 5.0 g doses
• very concentrated (5g/100 ml)
• in USA hydroxycobalamin available in 1mg/mL (5L
  infusion required for 5g dose)
• No pharmaceutical company willing to sponsor FDA
  approval and development in North America

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Cyanide Poisoning - Disposition

• Symptomatic
• ICU admision until complete resolution of
  metabolic acidosis
• Inhalation exposure
• Discharge if asymptomatic in ED
• Cyanide Salt Ingestion
• Discharge if asymptomatic at 4 hours
• Cyanogenic glycosides / organonitriles
• 24 hours of inpatient observation for symptoms
• Suicidal patients
• Psychiatric evaluation

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Methemoglobinemia
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What is methemoglobinemia?

• Oxidation of iron within heme from Fe2 to Fe 3

• Methemoglobinemia is due to an imbalance of MHb
  production and MHb reduction

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MHb - Biochemistry

• Hemoglobin tetrameric molecule
• 8 different dimers of MHb are produced when
  exposed to oxidative stress

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• Oxidized (Fe3) heme cannot carry oxygen
• Allosteric changes cause non-oxidized heme to
  bind oxygen more tightly
• Left shift of oxygen dissociation curve
• Thus 30 methemoglobinemia has lt70 of original
  oxygen carrying capacity

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• Leftward shift of Hb-Oxygen dissociation curve
• Impaired oxygen delivery to tissues

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Biochemistry, continued

• Positively charged MHb has high affinity for
  negative anions (cyanide, fluoride, chloride)
• Neutral Hb has high affinity for neutral ligands
  (CO, O2. CO2)
• .thus MHb is not particularly good at
  transporting oxygen (functional anemia)

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Methemoglobinemia - etiology

• Spontaneous
• Congenital
• Transient (illness associated)
• Toxic
• Iatrogenic

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Spontaneous Methemoglobinemia

• Autooxidation of Hb
• 0.5 - 3 Hb converted to MHb each day
• Autoreduction of MHb
• 99 occurs via NADH-dependent cytochrome b5
  reductase (b5r) pathway
• Ascorbic acid, glutathione minor role in
  reduction
• Conversion of MHb to Hb is 15 per hour (assuming
  no ongoing production)

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A. The NADH-dependent cytochrome b5 methemoglobin
reductase system (endogenous). B, The
NADPH-dependent methemoglobin reductase system
(therapeutic).
Source Ford Clinical Toxicology
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Congenital Methemoglobinemia

• Hemoglobin M
• rare autosomal dominant disorder
• stabilize heme iron in ferric (3) state
• death in homozygotes
• lifelong cyanosis in heterozygotes

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Congenital Methemoglobinemia

• cytochrome b5 reductase deficiency
• autosomal recessive
• lifelong cyanosis in homozygotes
• but very few symptoms due to other adaptations
• very sensitive to xenobiotic oxidizing agents
• cytochrome b5 deficiency
• very rare
• autosomal recessive

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Congenital Methemoglobinemia

• NADPH-MHb reductase deficiency
• exceedingly rare
• Does not cause MHb
• Enzyme only reduces MHb in presence of exogenous
  catalyzing agent (ie methylene blue)
• Patient would not respond to therapeutic
  methylene blue

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The Fugates of Troublesome Creek
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Fugate pedigree with genotypes

• Congenital NADH-diaphorase deficiency

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Transient (illness-associated) Methemoglobinemia

• MHb common in septic infants with gastroenteritis
  and acidosis
• Infants lt6 months
• NADH-dependent reductase deficiency
• Presence of fetal Hb
• Thus infant Hb more prone to oxidative stress
• Exact mechanism poorly understood
• altered flora, RTA, low Cl, UTI, protein
  intolerance .

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Toxic Methemoglobinemia

• side effect of therapeutic drugs
• environmental
• nitrates in well water
• nitrates in spinach, carrots, beets, etc.
• intentional OD

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Toxic Methemoglobinemia

• Factors influencing degree of MHb
• rate of entry of oxidant into circulation and
  RBCs
• rate of metabolism of toxin in body
• rate of excretion of toxin
• effectiveness of cellular MHb reduction systems

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Toxins causing MHb

• chloroquine
• dapsone
• local anaesthetics
• methylene blue
• metoclopramide
• nitrates
• nitrites
• NTG

• nitroprusside
• phenacetin
• pyridium
• primaquine
• rifampin
• sulfonamides
• vitamin K3
• chlorhexidine

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Therapeutic Methemoglobinemia

• Iatrogenic induction of MHb in cyanide poisoning

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Methemoglobinemia - Diagnosis

• Physical Exam
• cyanotic

Chocolate brown lips
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Symptoms vs MHb concentration
MHb conc. MHb Symptoms
lt1.5 g/dL lt10 None
1.5-3.0 g/dL 10-20 Cyanotic skin
3.0-4.5 g/dL 20-30 Anxiety, lightheadedness, headache, tachycardia
4.5-7.5 g/dL 30-50 Fatigue, confusion, dizziness, tachypnea, tachycardia
7.5-10.5 g/dL 50-70 Coma, seizures, arrhythmias, acidosis
gt10.5 g/dL gt70 death
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• Chocolate-brown arterial blood
• does not become red with exposure to oxygen
• filter paper test
• place drop of blood on filter paper - MHb will
  not turn red
• Potassium cyanide test
• MHb turns red when CN added, sulfhemoglobin does
  not

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ABG

• Measured - pH, pCO2, PO2
• Remember PO2 refers to dissolved oxygen and has
  nothing to do with Hb
• Calculated
• SaO2 from normal Hb-oxy dissociation curve
• Assumes all Hb is normal
• Abnormal Hb (MHb) which do not interfere with
  pulmonary diffusion with falsely elevate SaO2
• Saturation gap measured calculated sats
• gt5 discrepancy suggests MHb, carboxyhemoglobin,
  or sulfhemoglobin
• HCO3 from Henderson-Hasselbach equation

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• Pulse oximetry
• Not accurate in MHb!!
• Only measures 2 wavelengths 660 940nm
• 100 MHb will read 85 saturation
• Co-oximetry
• Measures four wavelengths
• Maximal absorption peak at 630-631 nm (little
  interference from oxyhemoglobin)

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MHb - Treatment

• Mild cases (no overt hypoxia)
• Supportive care
• Remove offending agent
• (half-life of local anaesthetic induced MHb in
  normal individual 55 minutes)

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• Severe Cases
• overt hypoxia, CNS depression, CVS instability
• manage more aggressively in patients with
  coexisting medical problems (CAD, etc.)
• Recommend antidote for MHb gt 30 (or 20 in
  symptomatic patients)
• 100 oxygen
• GI/skin decontamination (charcoal, etc.)

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Methylene Blue

• Specific antidote for MHb
• 1-2 mg/kg over 5 minutes
• Repeat doses to maximum 7mg/kg

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A. The NADH-dependent cytochrome b5 methemoglobin
reductase system (endogenous). B, The
NADPH-dependent methemoglobin reductase system
(therapeutic).
Source Ford Clinical Toxicology
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Methylene Blue

• G6PD deficiency Contraindication
• Enzyme used in formation of NADPH
• Insufficient NADPH produced to reduce methylene
  blue (oxidizing agent) to leukomethylene blue
  (reducing agent)
• Relative buildup of methylene blue (oxidizing
  agent)
• Can get paradoxical methemoglobinemia and
  methylene blue induced hemolysis

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• Ascorbic Acid
• 300-1000mg/day iv (divided tid-qid)
• Nonenzymatic MHb reduction
• N-acetylcysteine
• Works in vitro, no in vivo studies yet

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Treatment

• Congenital MHb
• Generally asymtomatic due to compensatory
  mechanisms
• Methylene blue 100-300mg/day
• Ascorbic acid 200-500mg/day
• Illness associated MHb in infants
• Supportive care (hydration, etc.)
• Treat MHb gt30

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Clinical decision making in methemoglobinemia