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Cyanide and Methemoglobinemia. Presented by: Dr. Aric Storck Preceptor: Dr. Ingrid Vicas Core Rounds February 20, 2003. Cyanide. Cyanide. Anion (CN - ) solid and gaseous forms Important component of many industrial reactions mining - recover silver and gold from ores

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cyanide and methemoglobinemia

Cyanide and Methemoglobinemia

Presented by: Dr. Aric Storck

Preceptor: Dr. Ingrid Vicas

Core Rounds

February 20, 2003

cyanide1
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
cyanide pollution
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
slide5

Man carries his wife past the Union Carbide factory in Bhopal, India. Fumes from the factory killed her the previous day

Source: Greenpeace

slide6

Skulls from victims of the Union Carbide disaster in the Hamidia Hospital in Bhopal, India.

Source: Greenpeace

cyanide a potential disaster
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
cyanide and terrorism
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)
cyanide and fires
Cyanide and Fires
  • Cyanide is a combustion product of
    • plastic
    • rugs
    • silks
    • furniture
    • construction materials
cyanide and fires1
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; 37:635-641.

cyanide pathophysiology
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)
slide12

Oxidative Phosphorylation

Source: Ford’s Clinical Toxicology

blockade of oxidative phosphorylation
Blockade of oxidative phosphorylation
  • Tissue anoxia
  • Anaerobic metabolism
  • Lactic acidosis
cyanide pathophysiology1
Cyanide - Pathophysiology
  • Other metabolic effects
    • Less relevant (...because you die of anoxia first)
    • Interferes with lipid metabolism
    • Interferes with glycogen metabolism
cyanide poisoning
Cyanide - Poisoning
  • Rapid absorption
    • Respiratory tract
    • Mucous membranes
  • Slow absorption
    • Skin
    • GI tract
cyanide poisoning inhalation
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
cyanide ingested salts
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)
ingestion cyanide producing compounds
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)
cyanide nitroprusside
Cyanide & Nitroprusside
  • Deterioration in aqueous solutions releases cyanide
  • Hydroxycobalamin and thiosulfate co-infusions used in critical care settings
chronic cyanide poisoning
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
cyanide detoxification
Cyanide - Detoxification
  • Naturally occurs in small quantities
    • tobacco
    • cassava
  • Small amounts routinely cleared from body
cyanide detoxification1
Cyanide - Detoxification
  • Cyanide + thiosulfate = thiocyanate
    • Enzymatically
      • Rhodanase
      • Beta-mercaptopyruvate-cyanide sulfur transferase
    • Nonenzymatically
      • Sulfane-albumin complex combines with cyanide
cyanide elimination
Cyanide - Elimination
  • Thiocyanate
    • Relatively non-toxic
    • Renal elimination (half life 2.5 days)
cyanide clinical presentation
Cyanide – Clinical Presentation
  • Physiologic manifestations of hypoxia
    • Metabolic acidosis
    • Bradycardia
    • Dyspnea
    • CNS disturbances
  • Normal pulse oximetry
cyanide clinical presentation1
Cyanide – Clinical Presentation
  • CNS
    • Headaches
    • Drowsiness
    • Dizziness
    • Seizures
    • Coma
cyanide clinical presentation2
Cyanide – Clinical Presentation
  • Pulmonary
    • Dyspnea
    • Tachypnea
    • Apnea
cyanide poisoning ddx
Cyanide Poisoning - DDX
  • Ingestion with altered LOC and acidosis
    • sodium azide
    • salicylates
    • iron
    • Beta-adrenergic antagonists
    • cocaine
    • isoniazid
    • toxic alcohols
cyanide poisoning ddx1
Cyanide Poisoning - DDX
  • Inhalational Exposures
    • hydrogen sulfide
    • carbon monoxide
    • simple asphyxiants
cyanide clinical presentation3
Cyanide – Clinical Presentation
  • Cardiovascular Effects
    • Hypertension
    • Tachycardia
    • Hypotension
    • Bradycardia
    • Asystole
    • Cardiac collapse
laboratory investigation
Laboratory Investigation
  • Electrolytes
    • Elevated anion gap (lactic acidosis)
  • ABG
    • Metabolic acidosis (lactic acidosis)
    • Normal PO2
  • SaO2
    • Normal
laboratory investigation1
Laboratory Investigation
  • AVO2
    • Decreased (decreased tissue oxygen utilization)
  • Cyanide levels
    • Not rapid enough for clinical utility
    • Serum cyanide level
      • Toxic = >0.5mg/L
      • Fatal = >3.0 mg/L
    • Erythrocyte cyanide level
      • Normal = <1.9 uM/L (50ug/L)
      • Fatal = > 40 uM/L (1mg/L)
laboratory investigation2
Laboratory Investigation
  • Serum lactate – elevated
  • ECG
    • Sinus bradycardia
    • Sinus tachycardia
cyanide poisoning sequellae
Cyanide Poisoning - Sequellae
  • Directly related to severity of exposure and delay in treatment
  • long term sequellae are those of hypoxia
    • cerebral hypoxia / encephalopathy (common)
cyanide treatment
Cyanide - Treatment
  • Monitors
  • IV access
  • Administer 100% O2
  • Gastric lavage
    • Indicated in very recent ingestion
  • Activated charcoal (1g/kg)
cyanide antidote kit
Cyanide Antidote Kit

Manufacturer: Taylor Pharmaceuticals

Cost: $317 USD

cyanide antidote kit1
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
cyanide antidote kit2
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
cyanide antidote kit mechanism
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
slide40
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
cak children
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
cyanide antidote kit3
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)
cyanide antidote kit4
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
cyanide other antidotes
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)
dmap 4 dimethylaminophenol
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
hydroxycobalamin vitamin b12 a
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
slide47
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
hydroxycobalamin vitamin b12 a1
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
hydroxycobalamin vitamin b12 a2
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
hydroxycobalamin vitamin b12 a3
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
cyanide poisoning disposition
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
what is methemoglobinemia
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
mhb biochemistry
MHb - Biochemistry
  • Hemoglobin tetrameric molecule
  • 8 different dimers of MHb are produced when exposed to oxidative stress
slide55
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 <70% of original oxygen carrying capacity
slide56

Leftward shift of Hb-Oxygen dissociation curve

  • Impaired oxygen delivery to tissues
biochemistry continued
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)
methemoglobinemia etiology
Methemoglobinemia - etiology
  • Spontaneous
  • Congenital
  • Transient (illness associated)
  • Toxic
  • Iatrogenic
spontaneous methemoglobinemia
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)
slide60

A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous).

B, The NADPH-dependent methemoglobin reductase system (therapeutic).

Source: Ford: Clinical Toxicology

congenital methemoglobinemia
Congenital Methemoglobinemia
  • Hemoglobin M
    • rare autosomal dominant disorder
    • stabilize heme iron in ferric (3+) state
    • death in homozygotes
    • lifelong cyanosis in heterozygotes
congenital methemoglobinemia1
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
congenital methemoglobinemia2
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
fugate pedigree with genotypes
Fugate pedigree with genotypes
  • Congenital NADH-diaphorase deficiency
transient illness associated methemoglobinemia
Transient (illness-associated) Methemoglobinemia
  • MHb common in septic infants with gastroenteritis and acidosis
  • Infants <6 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 ….
toxic methemoglobinemia
Toxic Methemoglobinemia
  • side effect of therapeutic drugs
  • environmental
    • nitrates in well water
    • nitrates in spinach, carrots, beets, etc.
  • intentional OD
toxic methemoglobinemia1
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
toxins causing mhb
chloroquine

dapsone

local anaesthetics

methylene blue

metoclopramide

nitrates

nitrites

NTG

nitroprusside

phenacetin

pyridium

primaquine

rifampin

sulfonamides

vitamin K3

chlorhexidine

Toxins causing MHb
therapeutic methemoglobinemia
Therapeutic Methemoglobinemia
  • Iatrogenic induction of MHb in cyanide poisoning
methemoglobinemia diagnosis
Methemoglobinemia - Diagnosis
  • Physical Exam
    • cyanotic

“Chocolate brown” lips

slide73
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
slide74
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
        • >5% discrepancy suggests MHb, carboxyhemoglobin, or sulfhemoglobin
    • HCO3 – from Henderson-Hasselbach equation
slide75
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)
mhb treatment
MHb - Treatment
  • Mild cases (no overt hypoxia)
    • Supportive care
    • Remove offending agent
    • (half-life of local anaesthetic induced MHb in normal individual = 55 minutes)
slide77
Severe Cases
    • overt hypoxia, CNS depression, CVS instability
    • manage more aggressively in patients with coexisting medical problems (CAD, etc.)
    • Recommend antidote for MHb > 30% (or 20% in symptomatic patients)
    • 100% oxygen
    • GI/skin decontamination (charcoal, etc.)
methylene blue
Methylene Blue
  • Specific antidote for MHb
  • 1-2 mg/kg over 5 minutes
  • Repeat doses to maximum 7mg/kg
slide79

A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous).

B, The NADPH-dependent methemoglobin reductase system (therapeutic).

Source: Ford: Clinical Toxicology

methylene blue1
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
slide81
Ascorbic Acid
    • 300-1000mg/day iv (divided tid-qid)
    • Nonenzymatic MHb reduction
  • N-acetylcysteine
    • Works in vitro, no in vivo studies yet
treatment
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 >30%
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