Preview: Each year, particularly during the heating season, thousands of people are poisoned by carbon monoxide, with potentially devastating outcomes. Initial diagnosis can be difficult because symptoms closely resemble those of influenza and are often misinterpreted. Dr Tomaszewski discusses diagnosis and treatment, including the benefits and risks of hyperbaric oxygen therapy.

Also See: Carbon Monoxide

This winter a 22-year-old man presents to your emergency department following a syncopal episode. At home over the weekend, he has had a headache, chills, nausea, and dizziness. Your diagnosis is influenza. The patient is given intravenous hydration and is discharged neurologically intact with normal vital signs.

Two days later, the patient is readmitted semicomatose, and this time the diagnosis is carbon monoxide poisoning. He is treated with hyperbaric oxygen, but chronic headaches, memory problems, and parkinsonian-type tremor eventually develop. Sixteen months later, you receive a letter from the patient's attorney requesting compensation for allegedly failing to recognize carbon monoxide poisoning at the initial visit. The letter claims that your misdiagnosis resulted in reexposure of his client to a faulty furnace, which caused permanent neurologic sequelae.

Many substances can cause dramatic poisonings and even death, but carbon monoxide--an odorless, colorless, two-molecule gas--accounts for greater mortality and morbidity than all other poisonings combined. Carbon monoxide causes thousands of needless deaths each year in the United States . Patients who survive the initial poisoning still face the prospect of delayed neurologic dysfunction, which occurs in 14% to 40% of serious cases.

Sources of carbon monoxide

The body produces carbon monoxide as a by-product of hemoglobin degradation, but the gas does not reach toxic concentrations unless it is inhaled from exogenous sources, such as the incomplete combustion of any carbonaceous fossil fuel. According to a 10-year review of carbon monoxide-related deaths, more than half of unintentional deaths were caused by motor vehicle exhaust. Although natural gas is touted as a clean fuel, combustion in enclosed environments has resulted in poisonings, such as from forklifts and ice rink resurfacers. Burning of charcoal, wood, kerosene, or natural gas for heating and cooking also produces carbon monoxide.

Carbon monoxide can occur in the presence of other toxins, complicating both diagnosis and treatment. It is a major contributor in the thousands of smoke inhalation deaths that occur each year. People who work with methylene chloride, a paint stripper, can be poisoned because the fumes are readily absorbed and converted to carbon monoxide in the liver. In such cases, peak carboxyhemoglobin (COHb) levels may be delayed and prolonged because of ongoing production.

Toxicity

Carbon monoxide quickly binds with hemoglobin with an affinity 200 to 250 times greater than that of oxygen to form COHb. The resulting decrease in arterial oxygen content and shift of the oxyhemoglobin dissociation curve to the left explain the acute hypoxic symptoms (primarily neurologic and cardiac) seen in patients with carbon monoxide poisoning. But the toxic effects of carbon monoxide cannot be explained by this process alone. COHb levels do not correlate well with symptoms or outcome, and this process cannot account for the phenomenon of delayed neurologic sequelae.

Research suggests that the intracellular uptake of carbon monoxide is a mechanism for neurologic damage. When carbon monoxide binds to cytochrome oxidase, it causes mitochondrial dysfunction that results in oxidative stress. The release of nitric oxide from platelets and endothelial cells, which forms the free radical peroxynitrite, can further inactivate mitochondrial enzymes and damage the vascular endothelium of the brain. The end result is lipid peroxidation of the brain, which starts during recovery from carbon monoxide poisoning. With reperfusion of the brain, leukocyte adhesion and the subsequent release of destructive enzymes and excitatory amino acids all amplify the initial oxidative injury. The net result is cognitive defects, particularly in memory and learning, and movement disorders that may not appear for days following the initial poisoning.

Symptoms

The acute symptoms of carbon monoxide poisoning are reflected in the susceptibility of the brain and heart to hypoxia. Initially, patients may complain of headache, dizziness, or nausea, resulting in an incorrect diagnosis of influenza; vomiting may be the only presenting symptom in infants and may be misdiagnosed as gastroenteritis. Coma or seizures can occur in patients with prolonged carbon monoxide exposure. Elderly patients, especially those with coronary artery disease, may have accompanying myocardial ischemia, which may proceed to frank myocardial infarction.

The brain and heart are very sensitive to carbon monoxide poisoning; other organs are also affected. Prolonged exposures, especially those resulting in coma or altered mental status, may be accompanied by retinal hemorrhages and lactic acidosis. Myonecrosis can occur, reflected by elevated creatine kinase (CK) levels, but rarely leads to compartmental syndrome or renal failure. Cherry-red skin color is associated with severe carbon monoxide poisoning but is seen in only 2% to 3% of symptomatic cases.

Persistent and delayed effects

Patients can successfully recover from acute carbon monoxide poisoning, only to return days later with serious neurologic problems. Sequelae range from subtle cognitive deficits, apparent only on neuropsychological testing, to gross incapacitating movement disorders, resulting from carbon monoxide's predilection for basal ganglia. Within a day of exposures that result in coma, a computed tomographic (CT) scan can show decreased density in the central white matter and globus pallidus. Autopsies have shown involvement of other areas, including the cerebral cortex, hippocampus, cerebellum, and substantia nigra.

Neurologic sequelae may be immediately evident in the hospital upon initial recovery or may occur after a lucid interval of up to 3 weeks. The incidence of such sequelae can be as high as 40% (for memory impairment), and sequelae can persist for more than a year. Children may present with behavioral or school problems, while the elderly appear to be more susceptible to devastating consequences. The development of neurologic sequelae cannot be reliably predicted; however, most cases are associated with loss of consciousness in the acute phase of intoxication.

Diagnosis

Physicians need to be alert for the symptoms of carbon monoxide poisoning, especially during the winter, when risk of continued, prolonged exposures may be greater. Patients who present with flu like symptoms (i.e., headache, nausea, dizziness) should be questioned about the use of gas- or oil-fueled heat and appliances in the home or at work. The same symptoms occurring in housemates are also a warning sign of environmental exposure and thus present an opportunity for intervention to prevent continued exposure.

If the history and physical examination findings suggest carbon monoxide exposure, COHb levels can be measured with a co-oximeter, which spectrophotometrically determines the percentage of carbon monoxide-saturated hemoglobin. Arterial puncture is unnecessary in mildly poisoned patients, because venous COHb levels closely predict arterial levels and samples contained in a heparinized tube are accurate and stable for hours. A handheld breath analyzer can be used at the bedside to quickly rule out carbon monoxide poisoning; however, the incidental presence of ethanol can result in a false-positive reading.

Carbon monoxide poisoning is difficult to diagnose without use of the previously mentioned devices. Pulse oximetry is unreliable because it grossly overestimates oxygen saturation in the presence of COHb. Arterial blood gas analysis measures dissolved oxygen and thus overestimates the true oxygen saturation of hemoglobin; however, it may still be useful to confirm lactic acidosis, which is a marker of prolonged, serious exposure to carbon monoxide. Patients who have been comatose can be monitored for rhabdomyolysis by measuring CK levels.

Initial treatment

The initial treatment of patients with symptomatic carbon monoxide poisoning is relatively straightforward. A nonrebreather mask supplies 100% oxygen to quickly clear COHb from the blood; this therapy reduces the half-life of COHb from about 4 to 5 hours to 1 hour. The presence of hypotension implies myocardial dysfunction or peripheral vasodilation, which can be treated with fluids and vasopressors as needed. In confused patients, a fingerstick glucose test is essential to rule out hypoglycemia. Hyperglycemia may exacerbate central nervous system damage and thus should be treated with insulin.

Complications of carbon monoxide poisoning can be treated with supportive measures. Occasionally seizures result, requiring routine administration of benzodiazepines. Patients with suspected coronary artery disease may benefit from an electrocardiogram, CK testing, and therapy for angina. Rhabdomyolysis may elevate CK levels; in such cases, the kidneys can be protected with aggressive hydration to increase urination.

Neuroimaging is useful in some patients with carbon monoxide poisoning, but it is not necessary in most cases. Although neurologic changes are usually delayed, a CT scan of the brain can reveal some changes as soon as 24 hours after severe poisoning. Lucencies of the basal ganglia, especially the globus pallidus and cerebral white matter, are most commonly noted. Patients with these early changes have a poor prognosis. Magnetic resonance imaging and single photon emission CT scans for perfusion are more sensitive imaging methods; the latter is used for research purposes.

It is tempting to base treatment decisions on specific COHb levels. Unfortunately, COHb levels do not correlate well with symptoms and definitely do not predict sequelae. A single measurement is not representative of peak level or total tissue exposure. However, COHb levels are important in diagnosis of carbon monoxide exposure. In nonsmoking patients, a COHb level greater than 5% confirms exposure if 100% oxygen therapy has been administered for no more than 1 hour. Patients who smoke more than two packs per day can have COHb levels approaching 10%. A venous sample collected earlier in a heparinized tube may provide important clues to the presence of COHb in patients who have been treated with oxygen for some time. Any patient with a high COHb level (>25%) or serious symptoms (e.g., syncope) may need more intensive treatment beyond routine oxygen therapy.

Hyperbaric oxygen

Once a patient with acute carbon monoxide poisoning has received initial treatment and is in stable condition, the physician must decide whether to initiate hyperbaric oxygen therapy. Early use of neuropsychiatric testing has been advocated as an appropriate assessment tool. Unfortunately, such testing cannot reliably distinguish carbon monoxide poisoning from other intoxications (e.g., ethanol), and deficiencies in test performance are not necessarily predictive of delayed neurologic sequelae. Therefore, emergent neuropsychiatric testing, especially in patients with acute poisoning, is not recommended.

The clinical utility of hyperbaric oxygen has been best studied in the context of carbon monoxide poisoning. The most obvious effect is enhanced clearance of COHb (half-life, <30 minutes), but this is usually clinically unimportant. In fact, because of the long delay between a patient's initial presentation and actual entry into the chamber, it is unlikely that much COHb remains. Patients may still benefit from other, more important physiologic effects of hyperbaric oxygen. A rather elegant set of studies demonstrated that hyperbaric oxygen therapy in animals attenuates carbon monoxide-induced ischemic reperfusion injury to the brain by blocking adhesion of leukocytes to the microvasculature. The ability of hyperbaric oxygen to regenerate inactivated cytochrome oxidase, and thereby restore mitochondrial function, may contribute to this effect.

Although results of studies involving animals appear convincing, few clinical studies document the efficacy of hyperbaric oxygen therapy in preventing delayed neurologic sequelae. A 1989 randomized, controlled study involving over 600 patients failed to show any benefit of hyperbaric oxygen therapy for carbon monoxide poisoning. Flaws in the study included an average delay of 6 hours to therapy and a chamber pressure of only 2.0 atmospheres absolute (ATA), which is well below the 2.5 to 3.0 ATA used currently. A more recent study of patients with moderate carbon monoxide poisoning (i.e., symptomatic without loss of consciousness) showed that delayed neurologic sequelae developed in 7 (23%) of 30 patients who were treated with ambient-pressure oxygen, whereas no sequelae developed in 30 patients who received hyperbaric oxygen therapy. Although definitive studies of the efficacy of hyperbaric oxygen therapy are incomplete, it should be considered in patients with acute poisoning. The risks of hyperbaric oxygen therapy (primarily ear barotrauma) are trivial compared with the potential neurologic disabilities resulting from carbon monoxide poisoning. Many centers use hyperbaric oxygen in patients with less severe poisoning if the COHb level is 25% or greater.

Clinicians should be aware of symptoms that are associated with delayed neurologic sequelae. Syncope is an important factor that patients may fail to relate in the history. Studies have confirmed that transient hypotension is an important factor in carbon monoxide-induced brain damage in animals. Hypotension results from a combination of events, including cardiac dysfunction caused by carbon monoxide binding to myoglobin and vascular relaxation caused by increased nitric oxide levels and stimulation of endothelial cyclic guanosine monophosphate. Prolonged exposures, or "soaking," especially in the presence of elevated lactic acid levels, are particularly worrisome.

As previously mentioned, COHb levels should not be used as the basis for treatment of carbon monoxide poisoning. Hyperbaric oxygen therapy should be considered for patients who do not initially meet the criteria for such therapy but have persistent neurologic symptoms despite several hours of 100% oxygen therapy. This is especially true in patients who have a severe headache or ataxia or who fail a bedside mental status examination. However, the decision to use hyperbaric oxygen therapy should be made early, because efficacy may decrease with delay, especially beyond 6 hours. The final considerations regarding use of hyperbaric oxygen should be the stability of the patient's condition and the distance to the nearest chamber.

Pregnancy

Fetal hemoglobin has a high affinity for carbon monoxide; thus a fetus may be more susceptible to toxic effects than the mother. This may explain why pregnant patients with only moderate symptoms and no syncope have had devastating fetal outcomes. Carbon monoxide is also an abortifacient and a teratogen, resulting in physical deformities and psychomotor disabilities.

The primary concern in pregnant patients is that COHb clearance may take 4 to 5 times longer in the fetus than in the mother. To date, there are no controlled studies showing that the indications for hyperbaric oxygen therapy are different in pregnant patients than in others. However, pregnant patients with carbon monoxide poisoning do need aggressive treatment, and hyperbaric oxygen therapy should be offered if neurologic symptoms or signs of fetal distress are present. Several studies of animals and successful clinical outcomes confirm the safety of hyperbaric oxygen therapy during pregnancy. Therefore, many centers use hyperbaric oxygen in any pregnant patient with a COHb level of at least 15%, regardless of symptoms.

Prevention

An awareness of the symptoms of carbon monoxide poisoning can lead to early intervention and prevent needless deaths. Burn victims, especially those with evidence of smoke inhalation from an enclosed fire, should undergo testing for COHb levels and receive appropriate treatment. During the winter, carbon monoxide poisoning should be suspected in patients presenting with flu like symptoms (e.g., headache, dizziness, nausea), which they may not attribute to a faulty furnace or other source. Symptoms coinciding with the use of a combustion engine (i.e., motor vehicle, boat, forklift) in an enclosed area should also raise suspicion. Physicians can help facilitate evaluation of an offending environment by local utilities or fire department personnel and raise patient awareness of symptoms and potential sources of carbon monoxide. In addition, carbon monoxide detectors can have a profound impact on home safety and are recommended by many safety organizations.

Conclusion

Carbon monoxide is a colorless, odorless, poisonous gas that causes vague flu like symptoms which are often misinterpreted by both patients and physicians. Fortunately, its slow action allows time for diagnosis and appropriate intervention. Patients who present with flu like symptoms, especially during the winter, should be questioned regarding risk factors (i.e., gas furnace) that may warrant testing for carbon monoxide poisoning. The mainstays of treatment are the liberal use of 100% oxygen therapy and attention to potential poisoning of housemates. The use of hyperbaric oxygen is encouraged in serious poisonings (e.g., patients with syncope), but definitive indications for this therapy await further controlled clinical trials.