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 coinfusions 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
1)
2)
3)
4)
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
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
Coma, seizures, arrhythmias,
acidosis
7.5-10.5 g/dL 50-70
>10.5 g/dL
>70
death
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