Carbon Monoxide, Cyanide, and Methemoglobinemia

Kelly

What should you consider when talking about gas ingestions?

•Gas characteristics (density, limit of detection, toxic “dose”)

•Patient respiratory characteristics (underlying respiratory disease, alterations of consciousness)

•Patient exposure/”dose” (gas concentration, duration, respiratory intake)

Parts per million def

+nl: CO2

•Number of molecules of a gas in a mixture of 1 million gas particles

•For reference: normal CO₂ level = 400-1000 ppm

Carbon Monoxide

+formation, characteristics: color, ordor, density, dose+symptoms

Formed during incomplete combustion of carbon containing compounds

Gas Characteristics: - reason for monitors

•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

Sources of Carbon Monoxide

formed during incomplete combustion of carbon contains compounds

Camp stoves and lanterns

gas powered equipment (ex: generators)

methylene bromide and methylene chloride

charcoal grills

propane powered equipment (resurfacing machines, forklifts)

fires

• internal combustion engines (cars, trucks, boats)

• hookah smoking

CO can diffuse through dry wall

Respiratory pathophysiology

Hemoglobin - 4 heme → place O2 binds and interacts

rely on Fe +2 to bind O2

Fe+3 (oxidized form) - cannot bind O2

body relies on binding and release of O2 (either interruption can cause problems)

• want to bind under conditions where O2 is rich → lungs

• when at places that are less O2 rich (tissues, vasculature) → want O2 to be released

CO binds very tightly (high affinity) to Heme (O2 cannot easily displace)

• readily absorbed

• even when a lot of O2 is around

• Hypoxic presentation

carboxyhemoglobin - hemoglobin thats bound to CO

• early estimations may appear high - takes time to equilibrate

CO toxicokinetics

+absorption , model, equilibrium, t1/2

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

Clinical manifestations of MO tox

+acute + chronic exposures, when are common exposures

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

Neurocognitive Sequelae

+mechanism, examples

CO toxicity may be associated with delayed neurologic sequelae

Neurologic sequelae (condition developing from previous injury) 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

Association with loss of consciousness in the acute phase of toxicity

Autopsies show necrosis of white matter, globus pallidus, cerebellum and hippocampus

Diagnostic Testing in MO tox

+use, nl: COHb, how to measure + limitations, tests

• 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!

Tests

• Arterial/venous blood gas

• lactate (correlated with severity)

• continuous cardiac monitoring and 12-lead EKG (ID schema or dysrhythmias)

• troponin/BNP

CO tox overview of management

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!

• primary treatment: Oxygen therapy (to compete with CO for binding)

• V fluids +/- vasopressors for hypotension

• Monitoring & management of dysrhythmias

• Monitoring & management of myocardial ischemia

Supplemental Oxygen in CO management

+administration, efficacy, two things to consider, goal+markers,

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)

•Supplemental oxygen is 100% oxygen, but FiO2 depends on the type of device used to deliver and flow rate

Goals+markers

• 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

Oxygen delivery Systems

Non-Invasive Delivery Devices

• nasal cannula

• face mask

• Venturi face mask

• face mask reservoir nag

Advanced non-invasive O2 delivery devices

• high flow nasal oxygen

• BiPAP/CPAP

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%)

Hyperbaric Oxygen

+use, efficacy, indication

use: MO tox

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

indication: Indications for consideration of hyperbaric oxygen (i.e. patients with risk factors for neurologic sequelae)

• Syncope

  • altered mental status or confusion

  • pregnancy with COHb >15%

• Coma

  • COHb >25%

  • fetal distress in pregnancy

• Seizures

  • abnormal cerebellar function

  • age >35 years with prolonged CO exposure (>24 h)

Hyperbaric Oxygen controversy

Resource intensive: need team and knowledgeable nurse (incase math happens in the chamber)

• must emerge slowly out the chamber because of changes in pressure

may interfere with care by causing free radical production

evidence not strong

American College of Emergency physicians CO policy 2017

emergency physicians should use HBO therapy or high flow normobaric therapy for acute CO-poisoned patients

• superiority not confirmed (over normobaric therapy)

Cyanide

+def, use, reactions, what contains cyanides

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

not common: takes a lot to cause tox

• Manihot spp (Cassava root) , Linum spp, Lotus spp, Prunus spp, Sorgum spp, Phaseolus spp contain cyanogenic glycosides.

  •   Apricots, bitter almond, cherry, peaches have amygdalin   containing pits. CN is liberated during metabolism

Hydrogen Cyanide Gas

+formation, characteristics: color, odor, density, dose+symptoms

Released from fire of paper, textiles, plastics

Gas Characteristics:

•Odor: Bitter almond smell, many cannot detect, does not provide adequate warning of hazardous conditions

• by the time you smell it, too late…

• unable to detect early enough

•Color: Colorless

•Density: 0.94 (air 1.0)

”Dose”

•110 ppm: life threatening after 30 minutes (half conc of CO in air?compare #s)

•270 ppm: immediately fatal

Aerobic Metabolism normal

Processes like Glycoclysis and Cirtic acid (Krebs cycle) all exist to fed into the ETC

majority of ATP production - happens in electron transport chain

glycolysis produces NADH

critic acid cycle produces FADH and H2O (important byproducts for ETC)

electrons for ETC reducing species throughout

Hydrogen ions pumped across the membrane

heat and O2 produced drive production of ATP

rely on O2 presence and electrons and produce H20 to make ATP

Aerobic Metabolism in HCN tox

O2 present but there is inhibition of multiple proteins in ETC

prevent O2 to be incorportated with H ions - cannot make water and energy

• ATP not produced → shift into anaerobic metabolism (like in exercising)

• not completely bad unless the ability to do aerobic respiration is completely lost

Electron Transport Chain (ETC) normal function

Final step in aerobic metabolism, generates ATP from products of glycolysis and Krebs cycle using series of redox reactions

Electrons travel through chain of proteins increasing reduction potential.

Energy generated is dissipated as heat or used to pump H+ ions across membrane

H+ gradient  is used by ATP synthase to generate large amount (32) of ATP

Electron Transport Chain (ETC) in HCN tox

Cyanide inhibits a number of enzymes including succinate dehydrogenase (II), superoxide dismutase, carbonic anhydrase and cytochrome oxidase (IV)

Without cytochrome oxidase oxygen cannot be incorporated into the ETC and consequently ATP cannot be produced

Cyanide Metbaolism

+pathways and mech

Rhodanase - MAJOR

• HCN + thiosulfate (donates sulfur atom) → thiocyanate

Cysteine

Hydroxocarbalamin

• converts HCN→ cyanocobalamin (vitb12)

Clincal Manifestations of HCN tox

No reliable pathognomonic symptoms or toxic symptoms

• either “dead (cardiac arrest) or alive”

• no in between

• fatal within seconds

Significant exposure to cyanide is rapidly fatal (occurs within seconds)

Ingestion of cyanogenic compounds may result in delayed symptoms (3-24 hours) → in cases of digestion

•CNS: headache, anxiety, confusion, lethargy, seizures, coma

•CV: bradycardia, hypotension

•Pulmonary edema

•GI: abdominal pain, nausea, vomiting

Diagnostic Testing in CN tox

+lab findings and interpretations

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)

Management of CN tox

1.Airway, breathing, circulation

• Airway: assess patency (inhalation injury)

• Breathing: 100% oxygen

2.Rapid Identification

• Arterial blood gas & serum lactate

3.Prompt antidotal therapy

• Hydroxocobolamin (Cyanokit)

• Sodium thiosulfate & sodium nitrite (Nithiodote)

“Cyanide Antidote Kit"

+components,

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.

Currently available antidotes for HCN poisoning

Thiosulfide + Nitrite

Hydroxocobalamin

Hydroxocobalamin

+use, mech, administration, ADEs

use:

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

Sodium Nitrite

+use, moa, admin, ADEs

use: HCN toxicity

Mechanism: induction of methemoglobinemia

Administration: administered with Sodium thiosulfate?

Sodium nitrite: administered first via IV slow push (~5 minutes)

ADEs:

•May result in production of excessive methemoglobinemia (potentially lethal)

•Hypotension, tachycardia, arrhythmias, nausea, vomiting

•Contraindicated in concomitant carbon monoxide toxicity

Sodium Thiosulfate

+use, moa, admin, ADEs

use: HCN toxicity

Mechanism:

•substrate for rhodanese conversion of CN to thiocyanate

Administration: administered with Sodium nitrite?

• IV administered over 10-30 minutes

ADEs:

•Generally well tolerated

•Hyperosmolar (osmotic diuretic), delivers significant sodium load

•May cause hypotension, prolonged bleeding, nausea/vomiting

Methemoglobinemia pathophysiology

+cause, mechanism, what level is associated with symptoms

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%).

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

Methemoglobinemia Reduction

reducing MetHb back to Hb

Methemoglobin is reduced primarily using NADH produced in glycolysis, cytochrome b5 and cytochrome b5 reductase

NADH (reduced NAD+) reduces oxidized cytochrome b5 to reduced cytochromee b5 via cytochrome b5 reductase

• Reduced cytovchrome b5 reduces MetHb to Hb

Hemoglobin Physiology

Fe2+ can bind O2

when Hb→ oxidized → F3+ → cannot bind O2

Xenobiotic-Induced Methemoglobinemia (agents)

Nitrates and Nitrites

• Water contamination with nitrogen-based fertilizers

• Nitroglycerin

Topical Ansethetics

• •Cetacaine spray (14% benzocaine, 2% tetracaine, 2% butylaminobenzoate)

  •Benzocaine spray (20%)

Nitric oxide

Daspone

Phenazopyridine

Some inhalants (amyl nitrite, nitrous oxide)

Nx3, PADS

Clinical Presentation of Methemoglobinemia

+effects concurrent conditions (give examples)

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

• levels used to predict toxicity

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

S/S Methemoglobinemia

+level and s/s associated

0-3% → none

3-15% → low O2 saturation, gray skin discoloration

15-20% → chocolate brown blood, cyanosis

20-50% → dizziness, syncope, dyspnea, fatigue, headache, weakness

50-70% → CNS depression, coma, dysrhythmias, metabolic acidosis, seizures, tahcypnea

>70% → death, grave hypoxic symptoms

Methemoglobinemia Management Overview

Airway, Breathing, Circulation

Supportive care, ABG, consider decontamination (oral ingestions)

High flow O₂

Clinical symptoms, laboratory findings and methemoglobin levels should guide treatment

levels < 30%

• asymptomatic symtoms = observation

• symptomatic observation = methylene blue

levels > 30%

• methylene blue

Methylene Blue

+formation, pathway?

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

• NADPH reduces Methylene blue in the presence of NAPDH MetHB reeductase → Leuko-methylene blue → reduces MEtHb (Fe3+) → Hb (Fe 2+)

Methylene Blue

+administration, onset, MDD, clinical pearls

administration: 1% solution administered IV over 5 minutes → should be followed by a 15-30 mL flush to reduce pain

Onset is rapid, occurs within 30 minutes. Dose may be repeated in 30-60 minutes if needed.

Continuous infusions of 0.1 mg/kg/h may be considered

MDD: Maximum total daily dose of 7mg/kg

ADEs:

• 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

Clinical Pearls

G6PD deficiency:

• G6PD is necessary for generation of NADPH which is required for 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