Cyanide and methemoglobinemia
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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

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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

    • photographic - recovery of silver

    • plastic manufacturing

  • Naturally occurs in many plant products

    • Tobacco, apricot pits


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


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

Source: Greenpeace


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

Source: Greenpeace


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

  • 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 is a combustion product of

    • plastic

    • rugs

    • silks

    • furniture

    • construction materials


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

  • 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)


Oxidative Phosphorylation

Source: Ford’s Clinical Toxicology


Blockade of oxidative phosphorylation

  • Tissue anoxia

  • Anaerobic metabolism

  • Lactic acidosis


Cyanide - Pathophysiology

  • Other metabolic effects

    • Less relevant (...because you die of anoxia first)

    • Interferes with lipid metabolism

    • Interferes with glycogen metabolism


Cyanide - Poisoning

  • Rapid absorption

    • Respiratory tract

    • Mucous membranes

  • Slow absorption

    • Skin

    • GI tract


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

  • 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

  • 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 - Dermal Exposure

  • LD50 = 100 mg/kg


Cyanide & Nitroprusside

  • Deterioration in aqueous solutions releases cyanide

  • Hydroxycobalamin and thiosulfate co-infusions used in critical care settings


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

  • Naturally occurs in small quantities

    • tobacco

    • cassava

  • Small amounts routinely cleared from body


Cyanide - Detoxification

  • Cyanide + thiosulfate = thiocyanate

    • Enzymatically

      • Rhodanase

      • Beta-mercaptopyruvate-cyanide sulfur transferase

    • Nonenzymatically

      • Sulfane-albumin complex combines with cyanide


Cyanide - Elimination

  • Thiocyanate

    • Relatively non-toxic

    • Renal elimination (half life 2.5 days)


Cyanide – Clinical Presentation

  • Physiologic manifestations of hypoxia

    • Metabolic acidosis

    • Bradycardia

    • Dyspnea

    • CNS disturbances

  • Normal pulse oximetry


Cyanide – Clinical Presentation

  • CNS

    • Headaches

    • Drowsiness

    • Dizziness

    • Seizures

    • Coma


Cyanide – Clinical Presentation

  • Pulmonary

    • Dyspnea

    • Tachypnea

    • Apnea


Cyanide Poisoning - DDX

  • Ingestion with altered LOC and acidosis

    • sodium azide

    • salicylates

    • iron

    • Beta-adrenergic antagonists

    • cocaine

    • isoniazid

    • toxic alcohols


Cyanide Poisoning - DDX

  • Inhalational Exposures

    • hydrogen sulfide

    • carbon monoxide

    • simple asphyxiants


Cyanide – Clinical Presentation

  • Cardiovascular Effects

    • Hypertension

    • Tachycardia

    • Hypotension

    • Bradycardia

    • Asystole

    • Cardiac collapse


Laboratory Investigation

  • Electrolytes

    • Elevated anion gap (lactic acidosis)

  • ABG

    • Metabolic acidosis (lactic acidosis)

    • Normal PO2

  • SaO2

    • Normal


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 Investigation

  • Serum lactate – elevated

  • ECG

    • Sinus bradycardia

    • Sinus tachycardia


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

  • Monitors

  • IV access

  • Administer 100% O2

  • Gastric lavage

    • Indicated in very recent ingestion

  • Activated charcoal (1g/kg)


Cyanide Antidote Kit

Manufacturer: Taylor Pharmaceuticals

Cost: $317 USD


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 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

  • 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


  • 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

  • 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 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 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

  • 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)

  • 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 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


  • 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 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 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 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

  • 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


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

  • Hemoglobin tetrameric molecule

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


  • 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


  • Leftward shift of Hb-Oxygen dissociation curve

  • Impaired oxygen delivery to tissues


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

  • Spontaneous

  • Congenital

  • Transient (illness associated)

  • Toxic

  • Iatrogenic


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)


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

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

Source: Ford: Clinical Toxicology


Congenital Methemoglobinemia

  • Hemoglobin M

    • rare autosomal dominant disorder

    • stabilize heme iron in ferric (3+) state

    • death in homozygotes

    • lifelong cyanosis in heterozygotes


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 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


The Fugates of Troublesome Creek


Fugate pedigree with genotypes

  • Congenital NADH-diaphorase deficiency


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

  • side effect of therapeutic drugs

  • environmental

    • nitrates in well water

    • nitrates in spinach, carrots, beets, etc.

  • intentional OD


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


chloroquine

dapsone

local anaesthetics

methylene blue

metoclopramide

nitrates

nitrites

NTG

nitroprusside

phenacetin

pyridium

primaquine

rifampin

sulfonamides

vitamin K3

chlorhexidine

Toxins causing MHb


Therapeutic Methemoglobinemia

  • Iatrogenic induction of MHb in cyanide poisoning


Methemoglobinemia - Diagnosis

  • Physical Exam

    • cyanotic

“Chocolate brown” lips


Symptoms vs MHb concentration


  • 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


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


  • 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

  • Mild cases (no overt hypoxia)

    • Supportive care

    • Remove offending agent

    • (half-life of local anaesthetic induced MHb in normal individual = 55 minutes)


  • 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

  • Specific antidote for MHb

  • 1-2 mg/kg over 5 minutes

  • Repeat doses to maximum 7mg/kg


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

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

Source: Ford: Clinical Toxicology


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


  • Ascorbic Acid

    • 300-1000mg/day iv (divided tid-qid)

    • Nonenzymatic MHb reduction

  • N-acetylcysteine

    • Works in vitro, no in vivo studies yet


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%


Clinical decision making in methemoglobinemia


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