Carbon Monoxide, Cyanide, and Methemoglobinemia

Formed during incomplete combustion of carbon containing
compounds
Gas Characteristics:
• Odor: Odorless
• Color: Colorless
• Density: 0.98 (air 1.0)

”Dose”
• 9ppm- maximum indoor safe limit
• 200ppm- physical symptoms after 2-3 hours
• 800ppm- physical symptoms in 20 minutes, fatal within 1 hour
• 1600ppm- physical symptoms in 5-10 minutes, fatal within 25-30
minutes

Readily absorbed after inhalation
200-250x greater affinity for hemoglobin than oxygen

Coburn-Forster Kane model, approximates carboxyhemoglobin
(COHb) levels based on exposure history
COHb (%) = 100 / [1 + (643/ppm CO)]

Equilibrium takes >4 hours to be reached, early arterial COHb may overestimate COHb levels
t1/2h ~250 minutes

Early symptoms are nonspecific and can be easily confused with other illnesses
• Headache, nausea, dizziness

Exposures most common in winter when viral illnesses are also most common

With continued exposure:
• PVC’s, MI, dysrhythmias, ataxia, syncope, seizures, coma, lactic/metabolic acidosis, pulmonary edema
Acute mortality most often occurs due to dysrhythmias

CO toxicity may be associated with delayed neurologic sequelae
Neurologic sequelae are variable and include: dementia, amnestic
syndromes, psychosis, parkinsonism, paralysis, chorea, peripheral neuropathy, incontinence.
May be preceded by a lucid period of 2-40 days after exposure
Estimated to occur in ~14% of patients requiring ICU admission
Association with loss of consciousness in the acute phase of toxicity
Autopsies show necrosis of white matter, globus pallidus, cerebellum and
hippocampus

Most useful test for diagnosis is a carboxyhemoglobin (COHb) level
Normal COHb levels range from 0-5%, may be as high as 10% in
smokers

COHb must be measured using cooximetry
• May be performed using arterial or venous blood gases or pulse cooximeters
• Pulse oximeters cannot differentiate between O2 and CO bound hemoglobin!

While useful for diagnosis, COHb does not correlate exactly with clinical manifestations and does not predict symptoms or outcomes
Therapy decisions should not be based solely on degree of COHb elevation

Overview of Management
• ABC’s!
• Oxygen therapy (to compete with CO for binding)
• IV fluids +/- vasopressors for hypotension
• Monitoring & management of dysrhythmias
• Monitoring & management of myocardial ischemia

Administered at high concentration/flow rates to displace CO from
hemoglobin.
Greatly reduces t1/2h of CO (can decrease down to ~1 hour)

When discussing supplemental oxygen need to think about flow rate and fraction of inspired oxygen (FiO2)
• FiO2: fraction of oxygen breathed in by patient
• Function of method of delivery, respiratory rate
• FiO2 of “room air” = 0.21 (or 21%)
• Supplemental oxygen is 100% oxygen, but FiO2 depends on the type of device used to deliver and flow rate

For CO toxicity goal is 100% FiO2
Typically accomplished using high flow nasal cannula (HFNC) @ ≥ 40 L/min or
CPAP/BiPAP set to 100% FiO2

Uses pressure in addition to oxygen to
• Further reduce t1/2h of CO (can reduce to 20 minutes)
• Increase amount of dissolved oxygen by ~10x

Highly controversial
If any benefit, HBO may improve neurologic outcomes after severe CO poisoning

HBO may potentially cause harm by interfering with high quality supportive care and cause free radical production

7 RCT’s to date (HBO vs. standard of care)
• 2 studies suggesting improved neurologic function
• 3 studies showing no difference
• 2 studies showing harm (worse neurologic function)

”Emergency physicians should use HBO therapy or high-flow normobaric therapy for acute CO-poisoned patients. It remains unclear whether HBO therapy is superior to normobaric oxygen therapy for improving long-term neurocognitive outcomes” Level B recommendation

Cyanide (CN) is a chemical group containing one atom of carbon
triple bonded to one of nitrogen
CN salts (NaCN, KCN) are used in industry (metallurgy, photographic
development, plastic manufacturing, fumigation, mining)

NaCN reacts readily with water to form hydrogen cyanide gas

Manihot spp (Cassava) , Linum spp, Lotus spp, Prunus spp, Sorgumspp, Phaseolus spp contain cyanogenic glycosides.
• Apricots, bitter almond, cherry, peaches have amygdalin containing pits. CN is liberated during metabolism

Released from fire of paper, textiles, plastics
Gas Characteristics:
• Odor: Bitter almond smell, many cannot detect, does not provide adequate warning of hazardous conditions
• Color: Colorless
• Density: 0.94 (air 1.0)

”Dose”
• 110 ppm: life threatening after 3o minutes
• 270 ppm: immediately fatal

No reliable pathognomonic symptoms or toxic symptoms
Significant exposure to cyanide is rapidly fatal (occurs within
seconds)
Ingestion of cyanogenic compounds may result in delayed symptoms (3-24 hours)
• CNS: headache, anxiety, confusion, lethargy, seizures, coma
• CV: bradycardia, hypotension
• Pulmonary edema
• GI: abdominal pain, nausea, vomiting

Toxicity is rapid, cyanide levels are not typically performed in house
and take days to result
Diagnosis relies on circumstance and clinical findings
Laboratory findings:
• Significant lactic acidosis (elevated anion gap metabolic
acidosis)
• Lactate >8 is 94% sensitive for cyanide toxicity
• Elevated venous oxygen saturation (from decreased tissue
oxygenation)

1. Airway, breathing, circulation
a. Airway: assess patency (inhalation injury)
b. Breathing: 100% oxygen
2. Rapid Identification
a. Arterial blood gas & serum lactate
3. Prompt antidotal therapy
a. Hydroxocobolamin (Cyanokit)
b. Sodium thiosulfate & sodium nitrite (Nithiodote)

Contained
• Amyl nitrite pearls: crushed and inhaled
• Mechanism: induction of methemoglobinemia (CN higher affinity for MetHb than cytochrome oxidase)
• Sodium nitrite (IV)
• Mechanism: induction of methemoglobinemia
• Sodium thiosulfate (IV)
• Mechanism: provides substrate for rhodanese mediated conversion of CN to thiocyanate
No longer available, amyl nitrite associated with hypotension, syncope, excessive methemoglobinemia.

Mechanism: complexes CN to form cyanocobalamin (B12) which is eliminated in the urine
Dosing: 5g IV infusion over 15 minutes
• Second dose of 5g may be considered if response
Well tolerated, few adverse effects
Rash, reddish discoloration of skin, mucous membranes, urine
Relatively high cost, short supply

Mechanism:
• Sodium nitrite: induction of methemoglobinemia
• Sodium thiosulfate: substrate for rhodanese conversion of CN to thiocyanate
Dosing/Administration:
• Sodium nitrite: administered first 300mg IV slow push (~5 minutes)
• Sodium thiosulfate: 12.5g IV administered over 10-30 minutes

Methemoglobin (MetHb) exists when the iron atom in hemoglobin loses one electron to an oxidant to into the Ferric (Fe+3) state, which cannot bind oxygen
~1% of hemoglobin exists as methemoglobin in most individuals
Erythrocytes can reduce (donate electron to) MetHb back to Hb
(t1/2h ~1-3 h)

Methemoglobinemia exists when methemoglobin levels exceed normal values (> 1%).
Occurs when rates of Hb oxidation to MetHb exceeds reduction capabilities
May be acquired or hereditary
• Hereditary: very rare, abnormal hemoglobin synthesis or
imbalance in reduction/oxidation of hemoglobin
• Acquired: environment & xenobiotics
Methemoglobin elevated above baseline is relatively common and
generally is not associated with symptoms (~19% of patients have a
MetHb >1.5%)

Nitrates & Nitrites
• Water contamination with nitrogen-based fertilizers
• Nitroglycerin
Topical anesthetics
• Cetacaine spray (14% benzocaine, 2% tetracaine, 2% butylaminobenzoate)
• Benzocaine spray (20%)

Nitric oxide
Dapsone
Phenazopyridine
Some inhalants (amyl nitrite, nitrous oxide)

Clinical manifestations are related to impaired oxygen-carrying
• Decreased available oxygen-carrying capacity
• Increased affinity of unaltered hemoglobin for oxygen (decreased delivery to tissues)
Clinical presentation correlates relatively well with methemoglobin percentage
Concurrent anemia, CHF, COPD, and respiratory disease increase the clinical effects of methemoglobinemia
• A patient with Hb of 14 g/dL with 28% MetHb has more oxygen carrying capacity than a patient with a Hb of 9 g/dL with 5% MetHb

Arterial blood gas
• Color may be altered (brown) if significant methemoglobinemia
• ABG or VBG can be used to measure methemoglobin level (takes time to result)
Pulse oximetry is unreliable when dyshemoglobinemias are present.
Measured oxygen saturation will likely decline but not by a defined
proportion
Cooximetry may be used to determine relative concentrations of
oxyhemoglobin, methemoglobin, and carboxyhemoglobin.

Methemoglobin can be reduced using NADPH produced in the hexose
monophosphate shunt, methylene blue and NADPH MetHb reductase

Common Adverse Effects: extremity pain, GI upset, dizziness, flushing, diaphoresis, nausea, headache
Doses >7 mg/kg may cause paradoxical induction of methemoglobinemia through oxidation of hemoglobin
Given methylene blue is a dye, color changes interfere with skin coloration (cyanosis) and pulse oximetry.
G6PD deficiency:
• G6PD is necessary for generation of NADPH which is requiredfor reduction of methylene blue to leuko-methylene blue
• Individuals with G6PD deficiency have varying degrees of deficiency, methylene blue may be less effective in some