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What is the on Carbon Monoxide?

Carbon monoxide is produced from incomplete complete combustion instead of CO2, CO is produced.

It is commonly associated with fires, car exhaust, natural disasters, broken furnaces. Or the, “I’m symptomatic but my pet died!”

Symptoms include nausea, vomiting, headache, syncope, dyspnea, altered mental status, and can precipitate shock, seizures, coma, and death.


CO has multiple mechanisms of effect: Displace O2 from Hgb, Left shift of Bohr effect, and inhibition of the electron transport chain @Complex IV.


Symptoms can start at a HbCO level of 10-15, but 25 is the level to consider hyperbaric oxygen.

Initial intervention (in the field through ED course): OXYGEN. Get a non-rebreather!

Goal is to reduce the half-life of CO-Hgb using supplemental oxygen! Get your CO level <5%!

Indications for hyperbaric oxygen: COHgb level >25%, AMS, Coma, Seizure, cerebellar dysfunction, >35 years old, end-organ ischemia/significant acidosis/myocardia infarction, loss of consciousness, pregnant with COHgb>20%.

Greatest concern is neurologic sequelae; CO damages the basal ganglia! Consider a CT/MRI if the patient looks bad!

When to suspect?

Carbon monoxide (CO) poisoning can occur in a variety of circumstances. Given that it is most commonly due to incomplete combustion, fires are a common cause of CO poisoning. Additionally, incomplete combustion from cars, or broken furnaces cause be a cause as well. There are instances where intentional poisoning occurs with the car running in the garage, but also unintentional from wanting to ‘warm the car up’ before going to work. Natural disasters, surprisingly, account for a significant amount of carbon monoxide poisoning as makeshift charcoal stoves or grills, or gas stoves when people are displaced from their homes. It is also very important to ask who else was around the patient as, “my dog died!” or, “other people in the house have been sick too!” may be the only tip-offs that this is CO poisoning.

Mechanism of Action?

Cooperativity
Bear in mind that carbon monoxide’s affinity to hemoglobin is 250X greater than oxygen! This plays an important role in the mechanism of action. Oxygen binds to hemoglobin through an effect called cooperativity. Each oxygen bound increases hemoglobin’s affinity for an additional oxygen, from allosteric protein conformation changes. That is why the oxygen saturation curse has an exponential slope near the beginning, however tapers off at an inevitable ceiling since hemoglobin can only bind up to 4 oxygen molecules. With carbon monoxide, it does not induce the allosteric protein changes and does not cause cooperativity to occur. Therefore, the carrying capacity of each hemoglobin molecule is diminished.

Changes to the Oxygen saturation curve (the opposite Bohr Effect)
Remember the days of biochemistry in medical school? For some of you, this was a dreadful experience. However, the Bohr effect and understanding carbon monoxide’s effect on the saturation curve makes a significant difference in the delivery of oxygen. To review, the oxygen saturation curve is shown below.
As this graph shows, some things can cause the saturation curve to shift to the left, and to the right. The Bohr effect, describes a rightward shift as blood carrying oxygen moves to end organs and delivers oxygen. Why does the shift occur? Because metabolism occurs at the muscle, converting ATP to ADP + PO4 + H+. Such acidosis (or presence of H+) induces oxygen to unload, and therefore will unload more at a given partial pressure of oxygen. Same is seen with the presence of carbon dioxide as well, which is a product of cellular respiration. Therefore at the top-right area of the curve, oxygen saturation is at 100%. This is where you sit on the curve when blood is at the lungs, where maximum oxygenation is occurring (at highest partial pressure of oxygen). And on this next curve, changes in pH cause more oxygen to fall off (as saturation decreases) which occurs where there is low partial pressure of oxygen (muscle/end organs).

You may ask, what does carbon monoxide do then? Well, it is similar to myoglobin (above), in that it binds much more tightly to oxygen, and has a curve that is shifted to the left. Therefore, instead of unloading more oxygen at a given partial pressure of oxygen, it in fact unloads LESS. You will sit higher on the oxygen saturation curve for a given partial pressure of oxygen, which means your organs are not receiving enough oxygen.

Electron transport chain
No classic toxidrome would not have an effect on the electron transport chain! Carbon monoxide binds to complex IV (cytochrome c oxidase). A quick reminder: protons are being pumped out of the matrix into the intermembrane space in mitochondria from each complex in the ETC to induce a proton gradient, harnessed by the ATP synthetase to power production of ATP. Carbon monoxide binds to complex IV tightly as a competitive inhibitor as oxygen normally binds to complex IV to receive electrons to reduce it to water (H2O). Cytochromes all have heme molecules, and this is no exception: CO’s affinity to heme over oxygen again causes oxygen to be competitively inhibited by CO’s presence. Since carbon monoxide unlike O2 cannot be reduced, electrons do not flow from cytochrome C and the ETC is put to a halt. Given that it is affecting complex IV (which is further downstream) versus complex I, a greater metabolic effect is appreciated since the pathway converges to this point. As ATP production stops, the paucity in energy causes injury in organs, akin to ischemia. Damage to the brain, especially in the basal ganglia occurs as this is an area of the brain that is similar to a watershed zone in that organ perfusion is limited at baseline. Additionally, once CO poisoning is treated with supplemental oxygen, there is increased risk for reperfusion injury, which is proposed to be the real mechanism for damage to the basal ganglia, with lipid peroxidation producing free radicals causing neuronal damage.

Also, given predominance of ADP from ATP hydrolysis, an abundance of protons is produced, causing acidosis. Remember, a lactate level is a surrogate marker for poor organ perfusion and is inevitably produced in anaerobic metabolism, but it is NOT the cause of the acidosis. Acidosis is due to the fact that all remaining ATP is depleted into ADP which results in a proton (ACID!). This is a reason why rigor mortis occurs rapdily, because all of the ATP is all used up! (Remember, ATP is used for the relaxation phase, and after ATP is hydrolyzed to ADP, it contracts!)

Signs and Symptoms

Any situation where something is burning, is good enough to raise suspicion for carbon monoxide poisoning. Symptoms at a lower level of CO poisoning include headache, nausea, vomiting, and fatigue. As the HbCO level rises, patients develop dyspnea, syncope, altered level of consciousness, chest pain, and confusion. At levels of 50 or higher, it is concerning for shock, cardiac dysrhythmias, seizures, coma, and/or death.

Something to keep in mind: Carboxyhemoglobin and oxyhemoglobin absorb light at the same frequency, therefore the color is similar. Thus, when measured on a pulse oximeter, the O2 saturation is falsely normal!

Occasionally you may have heard that those with carbon monoxide poisoning are oddly ‘reddish’ in color (also known as cherry red lividity), however this is a sign that is often appreciated in those who have expired, and should never be used as a true prognostic indicator as prognosis is well determine by the time this is observed.

CO poisoning can also cause myocardial infarction as the mitochondria within the heart are most sensitive to the effects of ETC inhibition from carbon monoxide. They can present with both STEMIs and NSTEMIs. Retinal hemorrhage and acute kidney injury have also been described in setting of carbon monoxide poisoning.

Management:

When CO poisoning is suspected, EMS providers should be aggressive in providing early supplemental oxygen, in particular, oxygen through a non-rebreather (NRB) at 100% O2. It should be continued throughout the course in the ED. The half life of CO is 4-6 hours at room air, 1-2 hours with an NRB, and 22 minutes under hyperbaric oxygen. Putting the patient on supplemental oxygen reduces their half life and improves CO clearance. Treat the patient until the level is <5% with resolution of symptoms.

Obtaining a carbon monoxide level, lactate, and metabolic panel (evaluate for an anion gap) should be of paramount importance once the patient arrives to the ED, and the emergency physician should not forget that carbon monoxide gives a falsely reassuring pulse oximetry oxygen saturation. Severe poisoning can cause shock, and thus fluids and pressors are indicated in this circumstance. Considering most carbon monoxide poisonings are associated with combustion, treatment for cyanide toxicity should be considered given cyanide is produced in combustion and its exposure affects the ETC the same way carbon monoxide does–therefore, consider giving hydroxycobalamin as necessary. The patient may have a mild acidosis (7.2-7.3) that may be permissible, which causes two beneficial outcomes: 1) CO clearance is a function of minute ventilation, and mild acidosis may cause tachypnea that will help breathe out the CO, and 2) mild acidosis will shift the oxygen saturation curve to the right at the area of tissues, which is essentially a Bohr effect, that is protective. Just be sure to continually monitor the patient to ensure he/she doesn’t decompensate.

If severe, with neurological compromise, consider obtaining a CT of the head (or MRI), however it’s more for prognostic purposes generally.

Hyperbaric oxygen (HBO, also known as “diving”) is a point of contention within circles of toxicologists as it has been demonstrated to reduce the half-life of carbon monoxide. Generally, the indications for HBO have been: older than 35 years old, a CO level greater than 25, pregnancy with a level >15, loss of consciousness, altered mental status, or evidence of end organ injury. However, the literature is not convincing that this is always the case. Randomized control trials have both demonstrated superior and inferior outcomes with HBO, with inferior outcomes being secondary to barotrauma or worse neurological sequelae. HBO appears to have an effect early within exposure, however in circumstances it is indicated, it is often long after exposure that anticipated gains from diving are limited. Instead, HBO is timely to set up, expensive, and without medical risk of barotrauma.

References

Nelson L., et al. Goldfranks Toxicologic Emergencies

Text written by: Alex Huh, MD
Podcast by: Anthony Scoccimarro, MD
Reviewed by: Anthony Scoccimarro, MD
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