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Carboxyhemoglobin Toxicity


Carboxyhemoglobin Toxicity

Article Author:
Renata Palmeri
Article Editor:
Vikas Gupta
Updated:
10/5/2020 10:03:10 AM
For CME on this topic:
Carboxyhemoglobin Toxicity CME
PubMed Link:
Carboxyhemoglobin Toxicity

Introduction

Carbon monoxide is a tasteless, odorless, colorless, and non-irritating gas formed with the combustion of hydrocarbons (fossil fuels). It binds to hemoglobin with a much greater affinity than oxygen to form carboxyhemoglobin, subsequently reducing oxygen-carrying capacity and oxygen utilization. Hypoxia ensues, and toxicity can lead to cerebrovascular ischemia and myocardial infarction. By acting as a direct toxin on the cellular level, carboxyhemoglobin disrupts cellular processes and inhibits aerobic metabolism, precipitating an inflammatory cascade that causes catastrophic damage to the central nervous system. Acute toxicity can be fatal, and carbon monoxide toxicity causes a large number of deaths due to both inadvertent exposure and suicidal poisonings.

Etiology

Carboxyhemoglobin is the complex formed within red blood cells when hemoglobin is exposed to carbon monoxide, subsequently binding to hemoglobin with an affinity 200 times that of oxygen. Carbon monoxide (CO) is an odorless, tasteless, and colorless gas. It is a by-product of the incomplete combustion of hydrocarbons (fossil fuels) and comprises less than 0.001 percent of the atmosphere. Common sources include motor vehicles, boats, faulty heaters, gas-powered generators, propane stoves, and charcoal grills, and toxicity becomes a concern when the aforementioned machines are operated in improperly ventilated or semi-enclosed spaces. Intentional carbon monoxide poisoning with motor vehicles is a common method of suicide, as lethal concentrations can be generated in just 10 minutes within a closed space. Other common sources include fires and tobacco smoke. Methylene chloride, an industrial solvent, and component of paint remover, also generates CO when metabolized. A small amount of carbon monoxide is generated endogenously with the breakdown of heme, and every person has a detectable amount of carboxyhemoglobin at baseline. This is typically 1 to 3 percent in non-smokers and 10 to 15 percent in smokers.[1]

Epidemiology

Carbon monoxide (CO) poisoning is a leading cause of morbidity by poisoning in the United States. It is responsible for 50,000 emergency department visits annually and 1,200 deaths. Exposure can be intentional or accidental. Inadvertent CO exposures account for approximately 1,000 to 2,000 deaths per year with an overall mortality of around 1% to 3%, though case-fatality rates vary.[1] Intentional poisoning is significantly more lethal, with rates of death 5 to 10 times higher. Intentional CO poisoning occurs more frequently in the northern United States and other cold climates, peaking during the winter months when there is increased utilization of gasoline-powered generators and kerosene heaters. Globally, the concentration of CO range between 0.06 and 0.14 mg/m3 (0.05 to 0.12 ppm) but is influenced by multiple factors, including weather, topography, and location, such as in urban areas where there is a much higher density of combustion. In the United States, the overall fatality rate of exposure is less than 5%, considerably less than in other countries. It is challenging to estimate the incidence and mortality of CO poisoning worldwide for several reasons. It is largely underreported and commonly not confirmed by testing. People with inadvertent exposure may not seek medical attention, and since CO poisoning can be an elusive diagnosis, it may be overlooked or attributed to another cause. Additionally, there are limitations in the ability to be evaluated in underdeveloped countries where CO exposure is common.

Pathophysiology

Carbon monoxide gas diffuses rapidly across the pulmonary capillary membrane, binding to hemoglobin with an affinity 200 times that of oxygen to form carboxyhemoglobin. By displacing oxygen, CO decreases oxygen-carrying capacity and delivery of oxygen to tissues, causing marked cellular hypoxia and acidosis. In addition, CO directly disrupts multiple metabolic processes. It binds to mitochondrial cytochrome oxidase, directly inhibiting aerobic metabolism. In the brain, CO binds to cytochrome c oxidase, resulting in impaired mitochondrial function and ATP synthesis, platelet to neutrophil aggregation and neutrophil degranulation. Myeloperoxidase, proteases, and reactive oxygen species are subsequently released, causing cellular damage. In endothelial cells, proteases (via xanthine dehydrogenase) form xanthine oxidase, which blocks inherent protective mechanisms against oxidative stress.[1] Lipid peroxidation via myeloperoxidase causes degradation of unsaturated fatty acids and alters the structure of myelin, triggering an immunologic response and demyelination of CNS lipids ensues.[2] Toxicity is multifactorial, resulting from a combination of tissue hypoxia, direct carbon monoxide mediated damage at the cellular level, and subsequent harm due to oxidative stress, activation of inflammatory cascades, and lipid peroxidation. To add insult to injury, re-oxygenation, and reperfusion following periods of hypoxia generates partially reduced oxygen species, which can oxidize proteins, nucleic acids, and cause further inflammation and apoptosis, analogous to reperfusion injury described in other acute ischemic processes.[1]

Organs with the highest oxygen demand, the brain, and heart, are the most susceptible to the ischemic injuries described above. The deleterious effects to the heart, in particular, can vary widely as the cardiovascular health of the exposed person heavily influences compensatory mechanisms. In the event of hypoxemia, cardiac output increases to maintain oxygen delivery to the brain, as with anemia or at altitude. With sustained and progressive hypoxemia, cardiac output will maximize and yet cannot compensate for the reduced oxygen-carrying capacity in carboxyhemoglobinemia. Demand ischemia and subsequent reduction of cardiac output ensue, exacerbating cardiac ischemia. This is a vicious cycle, propagating cerebral and peripheral ischemia as well. Hence, loss of consciousness, presumably due to decreased cardiac output and/or cerebral ischemia, has been identified as a strong predictor of severe toxicity.[3] The ability of the individual to compensate for decreased oxygen-carrying capacity determines the degree of insult; therefore, those with underlying respiratory, cardiac, or vascular disease may develop severe manifestations of toxicity (pulmonary edema, acute coronary syndrome, syncope) at lower concentrations of exposure.

Carbon monoxide exposure has a particularly deleterious effect in utero. The fetus is much more sensitive to hypoxia and direct toxic effects on a cellular level. Fetal hemoglobin has a higher affinity for oxygen, to begin with, demonstrated by the left-shift of the hemoglobin dissociation curve. Carboxyhemoglobin further exaggerates the left-shift, decreasing the release of oxygen into tissues causing profound hypoxia. Additionally, data in animal studies suggests a delay in fetal steady-state levels of carboxyhemoglobin up to 40 hours after maternal steady-state is reached, and levels in the fetus may exceed that of the mother.[1] Due to the heightened sensitivity of the fetus to hypoxia and lag time in fetal steady-state, most clinical guidelines warrant more aggressive treatment of pregnant women with hyperbaric therapy.

Histopathology

Postmortem histopathology has demonstrated various CNS abnormalities, including foci of ischemic or hemorrhagic necrosis in the globus pallidus and perivascular foci of demyelination in deep white matter.[4][5]

Toxicokinetics

Carbon monoxide binds to hemoglobin, with an affinity 200 times that of oxygen, to form carboxyhemoglobin. This is a reversible process; however, due to tight binding and high affinity, the elimination half-life in room air can be 2 hours or more. This is hastened by supplemental oxygen and hyperbaric oxygen. In the fetus, the elimination half-life is much longer than the mother. One well-known model to describe the toxicokinetics of carboxyhemoglobin is the Coburn-Foster-Kane equation. Carboxyhemoglobin demonstrates an exponential growth curve; the concentration increases rapidly upon exposure, continues to increase but levels off after approximately 3 hours, and then reaches steady-state after 6 to 8 hours. The most crucial variables in determining total body carboxyhemoglobin levels are the ambient concentration of carbon monoxide in the air, duration of exposure, and alveolar ventilation. Since children have higher minute ventilation, they typically recover faster.[6] The unborn fetus, on the other hand, is highly susceptible to CO toxicity due to preexisting left shift of the hemoglobin-dissociation curve secondary to fetal hemoglobin. Elimination half-life is longer since the fetus has even less propensity to release oxygen to tissues and is also affected by maternal hypoxemia.

History and Physical

Clinical symptoms of CO toxicity are largely non-specific and involve multiple organ systems; thus, physicians need to maintain a high clinical suspicion to make this challenging diagnosis. The most common complaint of patients presenting with CO toxicity is a headache. Dizziness, weakness, and nausea are also common, followed by confusion, difficulty concentrating, and shortness of breath. Loss of consciousness and chest pain are infrequent but suggest severe toxicity. The triad of cherry-red lips, cyanosis, and retinal hemorrhages are rare. Symptoms of CO toxicity range from mild, constitutional symptoms that may mimic a viral illness to severe to extreme presentations (comatose, hemodynamically unstable, respiratory depression, even cardiac arrest). Increased cardiac output in an attempt to compensate for hypoxia can cause tachycardia and tachypnea, as well as arrhythmias and pulmonary edema. Decreased oxygen release due to the left-shift of the hemoglobin dissociation curve plus compensatory tachycardia can lead to myocardial ischemia. Keep in mind, those with underlying pulmonary or cardiac disease can experience worsening of their chronic symptoms with CO exposure.

As always, a comprehensive history and physical exam is key to the diagnosis. Inquire about the use of gas appliances in the home, use of propane stoves, exposure to fires, and source of heat if applicable. Ask about occupation and consider exposures in the workplace as with construction workers or painters, who may use gas-powered paint sprayers. Determine if other close contacts, coworkers, or family members are experiencing symptoms and have a heightened suspicion for CO toxicity when multiple people from the same household or setting present with similar complaints.

As above, carbon monoxide toxicity causes hypoxia as well as significant inflammatory changes and oxidative stress, including free radical production, inhibition of aerobic metabolism, damage to myelin, and apoptosis upon reperfusion. Organs with high oxygen demand (heart and brain) are the most prone to damage; thus, clinically apparent neurological and cardiac complaints should be of concern. Those exposed should have a comprehensive neurological exam, and neuropsychiatric testing should be considered to assess for subtle deficits, such as difficulty with concentration, short-term memory loss, motor or gait problems, or changes in mood. In the acute setting, symptoms may not be perceptible; however, risk factors for long-term neurological damage include early and apparent neurologic abnormalities and sustained loss of consciousness, thus anyone presenting as such needs referral for follow-up.

Evaluation

The initial evaluation should include carboxyhemoglobin levels, ideally obtained via blood gases. Studies have determined that venous COHb levels are equivalent to arterial levels; thus, an arterial sample is not required. The FDA has approved the use of a pulse CO-oximeter device; however, clinical studies demonstrate a poor correlation with blood gases, and thus, a CO-oximeter should not be used unless blood gases are unavailable.[7] A level greater than 3% in nonsmokers and 10% in smokers confirms exposure to carbon monoxide; however, initial carboxyhemoglobin levels are not a measure of severity, nor do they predict long-term outcomes.[1] Additionally, initial measurements may not be representative of the degree of exposure since there is typically a delay in presentation, and the elimination half-life is highly variable and reliant on cardiorespiratory function. Again, levels do not correlate well clinically since damage from CO poisoning is not due to hypoxia alone but also due to disruption of metabolism and activation of inflammatory cascades. 

ECG and cardiac monitoring are needed to assess for cardiac ischemia and dysrhythmias. Those with an abnormal ECG, complaints of angina, known CAD, and arguably anyone over 65 years of age should also have cardiac biomarkers (troponin, CK-MB). In females, a pregnancy test is imperative, as this may change management. Elevated lactate is seen but does not correlate with severity. Blood gases are helpful for both a carboxyhemoglobin level as well as assessing the degree of metabolic acidosis. In cases of intentional CO poisoning, additional toxicology screens are indicated (acetaminophen and salicylate levels, urine drug screen). Of note is that CO poisoning can have overlapping features with cyanide poisoning, which would be of concern in the setting of a house fire; however, administration of hydroxocobalamin can affect carboxyhemoglobin levels, and blood gases would ideally be obtained prior to administration.

Imaging of the brain is frequently obtained to rule out other disorders that may be causing mental status changes. CT of the head is typically normal, though hemorrhage of the globus pallidus and deep white matter have been reported. MRI can show increased T2-weighted hyperdensities, basal-ganglia lesions, and atrophy of the hippocampus, though these findings are largely non-specific.[6]

There are 2 biological markers showing substantial promise in identifying patients at high-risk for neurologic damage: neuron-specific enolase (NSE), a glycolytic enzyme in the neuronal cytoplasm, and S100B, a calcium-binding protein in astroglial cells. Both are released from the cell following hypoxia and subsequent cell death. One study demonstrated 15-fold higher S100B levels in patients who developed delayed neurologic sequelae (DNS) and found this to be an independent risk factor with levels greater than 0.165 mcg/L predicting DNS with high sensitivity and specificity.

Treatment / Management

First and foremost, remove the patient from the source of exposure and administer oxygen, preferably 100% oxygen by non-rebreather mask. Intubation may be required in those with severely depressed consciousness. Oxygen shortens the half-life of carboxyhemoglobin by competing at the binding site and should be administered for at least 6 hours or until levels normalize. The half-life of CO in room air is 4 or more hours but is decreased to 40 to 80 minutes, with 100% oxygen and just 23 minutes with hyperbaric oxygen (HBO). Despite hastening carboxyhemoglobin elimination, HBO therapy has not been shown to decrease the devastating long-term neuropsychiatric sequelae, and studies thus far have not demonstrated improved outcomes or reduced mortality. Hence, the role of HBO remains controversial. Some propose that HBO can actually increase oxidative stress, free radical production, and apoptosis seen with a re-oxygenation injury. Additionally, treatment with HBO is not inherently benign and may cause barotrauma, pulmonary edema, and seizures. It is unclear whether hyperbaric treatment is beneficial in the setting of severe CO poisoning (coma, seizures, cardiac ischemia) as trials have generally excluded such patients. Clinical guidelines for the use of HBO vary among professional groups; however, the consensus is that it should be considered in consultation with poison control, a toxicologist, or a hyperbaric medicine center in cases of serious CO poisoning manifested by abnormal neurologic signs, cardiovascular dysfunction, severe acidosis, transient or prolonged loss of consciousness, in pregnancy, and those with carboxyhemoglobin levels greater than 25%.[6]

Erythropoietin (EPO) is an emerging novel therapy for the treatment of carbon monoxide toxicity. Erythropoietin is of interest since it has been shown in animal models to have neuronal protective effects in global and local ischemia. One study on CO toxicity showed decreased delayed neurologic sequelae versus placebo; however, studies regarding the use of EPO in ischemic strokes have shown higher death rates, and additional research is necessary before this can be considered.

Differential Diagnosis

Due to non-specific symptoms and highly variable presentations, the diagnosis of CO toxicity can be delayed and misdiagnosed. The differential diagnosis is broad and can vary based on the presence or absence of headache, nausea/vomiting, altered mental status, chest pain, dyspnea, and syncope, but considerations are as follows: viral syndrome/influenza, viral or bacterial meningitis, intracranial hemorrhage, idiopathic intracranial hypertension, temporal arteritis, altitude sickness, tick-borne illness, cyanide poisoning, alcohol intoxication, ethylene glycol or methanol toxicity, gastroenteritis, colitis, acute coronary syndrome, pneumonia, congestive heart failure, pulmonary embolism, peri/myocarditis, aortic dissection, and hyperglycemia.

Prognosis

In the United States, the overall mortality of carbon monoxide exposure is less than 5%. Unfortunately, neurologic and neuropsychiatric disturbances are common; the incidence varies, but prospective studies estimate about 34% of patients experienced headaches or memory problems at 4 weeks and 45% with neuropsychiatric symptoms at 6 weeks.[6] The level at initial presentation does not predict later outcomes. One study that followed adult patients over the age of 36 with significant exposure (defined as exposure for at least 24 hours or those with cerebellar abnormalities on presentation) and treated with normobaric oxygen were found to have increased risk of sequelae at 6 weeks versus those without these features. Information regarding sequelae 1-year post-exposure is limited.[6] One study followed an adult cohort 6 years following exposure and report 19% of subjects with cognitive issues and 37% with an abnormal neurologic evaluation.[8] There has been substantial research on hyperbaric therapy with some mixed results; however, some studies report a decreased incidence of neurocognitive deficits with hyperbaric treatment, yet its use remains controversial. There is limited data on children, though overall, they tend to recover faster due to higher minute ventilation.[6] In the fetus, mortality exceeds 50% in severe poisoning.[6] Although carboxyhemoglobin levels have not correlated with the severity of toxicity, there is some data suggesting no visual impairment or behavior or effect changes in otherwise healthy young subjects with levels below 18%. Generally, levels greater than 50% are lethal, and in patients with underlying ischemic cardiomyopathy, toxicity can be lethal at levels of 10% to 30%.

Complications

The most feared complication following carboxyhemoglobin toxicity is brain damage, divided into persistent neurologic sequelae (PNS) or delayed neurologic sequelae (DNS). Vision loss, loss of coordination, cognitive impairment, personality/mood changes, short-term memory loss, dementia, psychosis, incontinence, and parkinsonism have been reported, and luckily for some, these symptoms may be transient. With the persistent subgroup, some degree of neurological damage is present acutely and does not resolve. Delayed onset includes those who develop sequelae days to weeks after exposure. The estimated incidence of delayed-onset complications is estimated to be 10% to 30%; however, it is difficult to estimate since neuropsychiatric and cognitive testing is highly variable, depends on age and intelligent quotient (IQ), and is difficult to assess change due to unknown pre-exposure baseline. The best-identified risk factors for developing neurologic complications include early and obvious deficits and loss of consciousness. Carboxyhemoglobin levels do not correlate with the degree of damage and are a poor predictor; however, more recent studies are investigating the utility of neuron-specific enolase and S100B as biological markers.

Cardiac ischemia is also a feared complication. Due to hypoxia and inflammatory changes, carbon monoxide exposure can exacerbate angina and cause cardiac injury, especially so in those with underlying cardiovascular disease but potentially in patients with non-diseased coronary arteries as well. A rise in troponin after carbon monoxide toxicity inferred a higher mortality rate; however, this data did not distinguish those with pre-existing cardiovascular disease.[3] Thankfully, insults related to cardiac ischemia have demonstrated some reversibility following management, and a prospective study utilizing transthoracic echocardiogram (TTE) showed that 80% of subjects with impaired left ventricular systolic function normalized 3 days following exposure.

Consultations

In the setting of unstable angina, elevated troponin, EKG abnormalities, new-onset pulmonary edema, and/or heart failure, consultation to cardiology is warranted. With supportive therapy, abnormal cardiac function due to ischemic insults may be reversible. Of note is that those with underlying cardiovascular disease are particularly susceptible, and the risk of mortality increases over 10 years in those suffering cardiac injury. For neurologic complaints such as dysmetria, memory loss, cognitive impairment, dementia, or other signs and symptoms of persistent or delayed neurologic sequelae, neurology consultation is appropriate. Symptoms may be reversible or transient; however, it is not uncommon to suffer long-lasting neuropsychiatric deficits, some of which may benefit from rehabilitation. With acute toxicity, some indications to consider a consultation with a hyperbaric treatment center are pregnancy, loss of consciousness, early-onset and apparent neurologic deficits, carboxyhemoglobin level greater than 25%, acute coronary syndrome, or age greater than 65. Also, consider contacting the American Association of Poison Control Centers, (800) 222-1222, for further recommendations.

Deterrence and Patient Education

The primary prevention of carbon monoxide toxicity relies on awareness and education through public health resources, broadcasts, and media, especially in anticipation of national disasters and emergencies such as hurricanes, floods, power outages, and winter storms as people will be utilizing alternative sources of fuel or electricity for heating, cooling, or cooking. Additionally, generators, camp stoves, space heaters, and other devices should be accompanied by specific instructions stating they are not be used in enclosed spaces. Nationally, the United States government has established air-quality standards to keep the level of carboxyhemoglobin and other pollutants low and also reports an air-quality index to alert the public. Insurance companies may offer incentives for those who implement carbon monoxide alarms in their home.

Pearls and Other Issues

Maintain a high clinical suspicion for carbon monoxide toxicity as symptoms are very non-specific, variable, and overlap with many different etiologies. CO-oximetry is unreliable and may underestimate carboxyhemoglobin levels – always obtain via blood gases when possible. Start 100% oxygen immediately. In fire-exposed patients, consider cyanide poisoning as well but obtain a carboxyhemoglobin level before administering hydroxocobalamin. Risk factors for severe toxicity causing neurological sequelae include loss of consciousness and early, apparent neurologic deficits. Carbon monoxide toxicity can present with cardiac ischemia, both in those with an underlying history and those without it. Hyperbaric oxygen treatment is not the standard of care, but it should be given high consideration in those with an altered level of consciousness, neuropsychiatric complaints, acute coronary syndrome, pregnant women, anyone over the age of 65, and those with initial carboxyhemoglobin levels greater than 25%. Use all available resources and contact Poison Control and/or the local hyperbaric center for further recommendations.

Enhancing Healthcare Team Outcomes

Carbon monoxide toxicity is a leading cause of fatal toxic exposures in the United States as well as a significant concern worldwide. 

Evaluating for carbon monoxide toxicity and instituting prompt management requires an interprofessional team of healthcare professionals, beginning with pre-hospital personnel such as first responders, as well as nurses and a number of physicians in different specialties. Additionally, it is the responsibility of public health professionals to maintain awareness of this issue and educate the public on potential sources of toxicity, especially in times of natural disasters and emergencies where people will be using alternative sources of fuel or electricity. Carboxyhemoglobinemia can manifest with myriad presentations, severe toxicity characterized by respiratory depression, hemodynamic instability, cardiac arrest, and loss of consciousness. However, mild to moderate exposures can present as headache, flu-like illness, confusion, difficulty concentrating, dizziness, and nausea, which are very non-specific, and hence carboxyhemoglobinemia is often misdiagnosed. It is paramount for the triage team (mid-level provider or nurse) to inquire about the context of these symptoms and recognize carbon monoxide toxicity as a possible cause, especially if multiple family members or close contacts complain of similar symptomatology. Without recognition, the diagnosis can be easily missed; therefore, it is the responsibility of all providers to entertain the possibility of toxicity if plausible. With suspicion, providers need to begin prompt treatment with 100% oxygen and order blood gases for carboxyhemoglobin levels as indicated. Do not assess with CO-oximetry/noninvasive monitoring. [Level B] The emergency medicine clinician is responsible for performing a thorough neurologic evaluation as well as assessing for hypoxia and cardiac ischemia, as this may change management. Providers, as well as non-clinicians, should be aware of the resources at your institution. Consider hyperbaric treatment in those with abnormal neurologic signs, cardiovascular dysfunction, severe acidosis, transient or prolonged loss of consciousness, in pregnancy, and those with carboxyhemoglobin levels greater than 25%, and consult with your toxicologist and/or poison control. Presently, we have level II evidence (small randomized control trials) demonstrating the role of hyperbaric treatment with possible reduced frequency of cognitive sequelae. It remains unclear as to whether physicians should use hyperbaric therapy or high-flow normobaric therapy for acute CO-poisoned patients. [Level B]


References

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