Carbon Monoxide Toxicity

Etiology

Carbon monoxide toxicity occurs due to hypoxic-ischemic cellular injury caused by carboxyhemoglobin (COHb) formation. Exposure to high ambient levels of carbon monoxide is necessary for toxicity to develop. Common sources include cooking appliances, vehicles, generators, and heaters. Exposure in poorly ventilated enclosed spaces increases the risk of toxicity. Additionally, colder weather correlates with higher rates of carbon monoxide poisoning, likely due to the use of faulty or alternative heating sources in confined spaces.[4]

Epidemiology

Annually, over 40,000 cases of carbon monoxide toxicity in the U.S. result in emergency department visits. Of these instances, 14,000 lead to hospitalization. Among hospitalized individuals, approximately 2% ultimately die. Around 10% of admitted patients experience partial recovery, and 23% to 47% suffer delayed neurologic sequelae.[5] Over 400 to 500 deaths annually are attributed to carbon monoxide toxicity. Overall, as many as 30% to 40% of carbon monoxide poisoning victims die before reaching the hospital. Significant toxicity and death from unintentional exposures have recently overtaken that of intentional exposures in the U.S.

Globally, male patients have a higher hospitalization rate, and the male mortality rate exceeds that of female patients. Children aged 0 to 9 years experience the highest rates of poison center calls and emergency department visits, while patients older than 80 years are most likely to require hospitalization. Approximately 30% to 40% of carbon monoxide poisoning victims die before reaching the hospital.[6]

The majority of carbon monoxide exposures are reported in residential settings (>76%). In the U.S., workplace exposures are the next most common, followed by schools, healthcare facilities, and other public areas. Carbon monoxide is also a leading cause of death among fire victims.

Pathophysiology

Carbon monoxide binds to hemoglobin to form COHb, which has 200 to 250 times greater affinity for hemoglobin than oxygen. COHb formation reduces the oxygen-carrying capacity of hemoglobin and leads to cellular hypoxia. This moiety also increases the affinity of unbound hemoglobin for oxygen, causing a leftward shift in the oxyhemoglobin dissociation curve and reducing oxygen delivery to tissues. This shift results in lower intracellular partial pressure of oxygen (PO2) than expected for a given blood oxygen concentration.

While the hemoglobin concentration and measured PO2 in the blood may appear normal on laboratory tests, the oxygen content of the blood is significantly reduced.[7][8] Carbon monoxide also binds to the heme moiety of cytochrome c oxidase in the electron transport chain, inhibiting mitochondrial respiration. The resulting buildup of reactive oxygen species contributes to cellular damage or death.[9]

Carbon monoxide enters the body via the lungs and may damage the lung parenchyma through local biochemical interactions. The gas crosses alveoli to bind with hemoglobin in the bloodstream, forming COHb and disseminating throughout the body. Carbon monoxide causes capillary leakage of macromolecules from the lungs and systemic vasculature, which can occur even with prolonged exposure to relatively low ambient concentrations. As COHb levels rise, cerebral blood vessels dilate, and coronary blood flow and capillary density increase. Continued exposure may result in central respiratory depression due to cerebral hypoxia. Cardiac ventricular arrhythmias may develop and often contribute to death in cases of carbon monoxide toxicity. Myocardial impairment has been observed at COHb concentrations as low as 20%.[10]

Toxicokinetics

Hemoglobin combines with carbon monoxide 220 times more avidly than it does with oxygen. On room air under 1 atm of pressure (1 atm, oxygen concentration 21%), the half-life of carbon monoxide is 320 minutes. At 1 atm pressure with 100% oxygen, the half-life is reduced to less than 90 minutes. With hyperbaric oxygen at a pressure of 3 atm, the half-life decreases to approximately 23 minutes. Hyperbaric oxygen therapy (HBOT) reduces the potential toxicity of carbon monoxide by accelerating its elimination from the body.

History and Physical

The presentation of carbon monoxide toxicity varies and depends on the level of exposure. The most common symptoms reported in symptomatic unintentional carbon monoxide toxicity include headache (25%), nausea (14%), dizziness or vertigo (12%), drowsiness or fatigue (6%), and vomiting (6%). Less than 3% of patients report cough, confusion, shortness of breath, syncope, chest pain, weakness, or throat irritation.

Vital signs and physical examinations may be unremarkable in patients with mild or moderate poisoning. However, individuals with severe toxicity may present with tachycardia, tachypnea, or hypotension. Only 1% to 2% of patients evaluated for carbon monoxide exposure are tachycardic.[11] Mental status changes such as confusion, altered level of consciousness, disorientation, and memory loss may occur. Intraocular findings can include retinal hemorrhages and congestion with papilledema. Additional neurologic findings may include ataxia, apraxia, incontinence, and cortical blindness. The classically described signs of "cherry red nail beds and mucous membranes" are typically postmortem findings and should not be relied upon for diagnosis.

Evaluation

Resuscitation of severely poisoned patients begins with stabilization of the airway, breathing, and circulation, as with any critically ill patient. Supplemental oxygen remains the cornerstone of treatment. However, standard peripheral pulse oximetry devices cannot distinguish COHb from oxyhemoglobin. Consequently, bedside assessments of oxygen saturation cannot be relied upon.[12]

An arterial blood gas sample with co-oximetry analysis is necessary to determine COHb saturation. Since COHb levels correlate poorly with clinical symptoms, they should not be used in isolation to guide treatment decisions. COHb levels greater than 3% to 4% in nonsmokers and greater than 10% in smokers are considered abnormal in otherwise healthy individuals. Levels exceeding 20% in adults and 15% in children suggest significant poisoning.

Additional laboratory tests may include a complete blood count, electrolytes, blood urea nitrogen, creatinine, and baseline troponin. An electrocardiogram should be obtained to evaluate for signs of ischemia. New ischemic changes are indicative of severe carbon monoxide poisoning. Chest radiographs are also recommended. If cerebral imaging is performed, findings may include globus pallidus hemorrhage.

Treatment / Management

The first step in treatment is immediate removal from the carbon monoxide source. Supplemental oxygen should be initiated without delay. Oxygen delivery may involve normobaric oxygen therapy (NBOT), using a nasal cannula or facemask, or HBOT in severe cases. Supplemental oxygen enhances carbon monoxide clearance by increasing the PO2 in the lungs. The half-life of COHb is approximately 4 to 6 hours on room air. With normobaric oxygen therapy, this interval is reduced to 40 to 80 minutes. With HBOT, the COHb half-life decreases to 15 to 30 minutes.

Indications for HBOT vary. Commonly accepted criteria include neurologic deficits, transient loss of consciousness, cardiac ischemia, altered mental status, persistent metabolic acidosis (pH less than 7.1-7.25), end-organ ischemia, or hypotension. Patients with COHb concentrations greater than 25% in adults or greater than 15% to 20% in pregnant individuals are also considered candidates. Although hyperbaric oxygen facilities are available in every state, only several hundred centers operate across the U.S. The best outcomes are observed when treatment is initiated within 6 hours of exposure.

Most hyperbaric physicians administer 3 sessions within the first 24 hours, followed by reassessment of the patient’s symptoms and response before continuing with daily sessions. Notably, some individuals with significant neurologic injury have experienced remarkable recovery following HBOT.[13] However, up to 40% of patients develop chronic neurocognitive impairment despite treatment, and these individuals should undergo neuropsychological evaluation approximately 1 to 2 months after recovery.[14][15][16](A1)

Case reports describe the successful resuscitation of critically ill patients with carbon monoxide toxicity using extracorporeal membrane oxygenation (ECMO), which facilitates carbon monoxide removal and provides circulatory and respiratory support.[17] Specific criteria for ECMO initiation in this context remain undefined.

Few alternative treatments currently exist. Ongoing research explores the use of reactive oxygen species scavengers and agents that directly bind carbon monoxide. Pulmonary phototherapy, both alone and combined with ECMO, is under investigation. Although therapies such as methylene blue, corticosteroids, and hydroxycobalamin with ascorbic acid have shown promise in animal studies, human trials remain limited.

Differential Diagnosis

Given its nonspecific symptoms, carbon monoxide toxicity can resemble a wide range of medical conditions, making the differential diagnosis broad and challenging. However, clinicians should consider the following potential mimics in more severe presentations:

• Alcohol toxicity
• Opioid toxicity
• Other sedative-hypnotic toxicity
• Methemoglobinemia
• Depression
• Diabetic ketoacidosis
• Hypothyroidism
• Hypoglycemia
• Labyrinthitis
• Meningitis
• Encephalitis
• Migraine headache

Careful clinical assessment, history-taking, and targeted investigations are essential to avoid misdiagnosis. Prompt identification of carbon monoxide exposure can prevent unnecessary delays in initiating life-saving treatment.

Prognosis

Fortunately, patient morbidity and mortality from carbon monoxide toxicity have declined over time, likely due to increased community awareness and public health efforts. The prognosis for patients with significant carbon monoxide exposure varies based on the intensity of exposure, initial clinical presentation, and comorbidities. Severe exposures may result in long-term neurologic and psychiatric sequelae.

Certain baseline laboratory tests and imaging studies can help predict recovery in the most severely affected patients. For example, individuals with abnormal findings on brain magnetic resonance imaging or head computed tomography attributable to carbon monoxide exposure generally have a poor long-term prognosis. Patients with low Glasgow Coma Scores on presentation develop persistent neuropsychiatric sequelae at higher rates, particularly when the initial score is below 9.[18] Persistent focal neurologic deficits also indicate a poorer overall prognosis. HBOT reduces the incidence of cognitive sequelae in some patients.[19]

Complications

Acute complications of carbon monoxide toxicity stem from end-organ dysfunction due to ischemic injury and may improve with supplemental oxygen and supportive care. In contrast, long-term sequelae are predominantly neurologic and psychiatric, often irreversible. These conditions include the following:

• Amnesia
• Dementia
• Irritability
• Psychosis
• Memory loss
• Loss of executive function
• Speech deficits
• Parkinson disease
• Depression
• Cortical blindness

Persistent symptoms can significantly impair a patient's quality of life and daily functioning. Early recognition and appropriate treatment are critical to reducing the risk of these long-term sequelae.