Cyanide and Methemoglobinemia Presented by: Dr. Aric Storck Preceptor: Dr. Ingrid Vicas Core Rounds February 20, 2003.

Cyanide and Methemoglobinemia

Presented by: Dr. Aric Storck

Preceptor: Dr. Ingrid Vicas

Core Rounds

February 20, 2003

Cyanide

Cyanide

Anion (CN-)solid and gaseous formsImportant 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

Significant correlation between CO levels and CN- levels in fire victims

estimated 35% of fire victims have toxic levels of cyanide

Cyanide and Fires

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)

Source: Ford’s Clinical Toxicology

Oxidative Phosphorylation

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 + thiosulfate = thiocyanate

Enzymatically Rhodanase Beta-mercaptopyruvate-cyanide sulfur transferase

Nonenzymatically Sulfane-albumin complex combines with cyanide

Cyanide - Detoxification

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


CNS Headaches Drowsiness Dizziness Seizures Coma


Pulmonary Dyspnea Tachypnea Apnea

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

Cyanide Poisoning - DDX

Cyanide Poisoning - DDX

Inhalational Exposures hydrogen sulfide carbon monoxide simple asphyxiants


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


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)


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


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


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 KitEffectiveness 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)


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


When combined with sodium thiosulfate end product is thiocyanate

Na2S2O3 + B12 = HSCN + B12a

Recycling of hydroxycobalamin Renally cleared Synergistic effect of thiosulfate and B12a

Advantages vs CAK less toxic does not produce MHb (thus appropriate for

smoke inhalation victims) may be administered out of hospital cheaper


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 - DispositionSymptomatic 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

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


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

Factors influencing degree of MHb1) rate of entry of oxidant into circulation and

RBCs

2) rate of metabolism of toxin in body

3) rate of excretion of toxin

4) effectiveness of cellular MHb reduction systems

Toxic Methemoglobinemia

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

MHb conc. %MHb Symptoms

<1.5 g/dL <10 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

>10.5 g/dL >70 death

Chocolate-brown arterial blooddoes not become red with exposure to oxygenfilter 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

Cyanide and Methemoglobinemia Presented by: Dr. Aric Storck Preceptor: Dr. Ingrid Vicas Core Rounds February 20, 2003.

Documents

cyanide slide

fires cyanide

ingestion cyanide

cyanide disasters

cyanide pollution

death slide

greenpeace slide

cyanide pathophysiology