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794 Part VI: The Erythrocyte Chapter 50: Methemoglobinemia and Other Dyshemoglobinemias 795

are normal in cytochrome b5 reductase deficiency; they are abnormal rate-limiting heme oxygenase–cytochrome P450 complex, which pro-
in hemoglobin M disease. In the case of toxic methemoglobinemia, cya- duces CO and biliverdin. Caloric restriction, dehydration, infancy,
nosis is generally of relatively recent origin, and a history of exposure and the genetic variations reported in Japanese and Native Americans
to drug or toxin may usually be obtained; in hereditary methemoglob- generate higher endogenous levels of CO. Hemolytic anemia (Chap.
inemia, a history of lifelong cyanosis may usually be elicited. 33), hematomas, and infection tend to increase CO production up to
threefold. Fetuses and newborns have double the normal adult levels
OTHER DYSHEMOGLOBINS of COHb. Drugs such as diphenylhydantoin and phenobarbital, by
inducing the cytochrome P450 complex, increase CO production. Nor-
CARBON MONOXIDE AND mal adult level of COHb is less than 2 percent. Hemolysis can produce
COHb levels of more than 2 percent. Levels more than 3 percent must
CARBOXYHEMOGLOBIN have an exogenous origin, except for rare conditions as occur in carriers
Carbon monoxide (CO) is a toxic, odorless, colorless, and tasteless gas. of abnormal hemoglobins such as Hb Zurich . The affinity of Hb Zurich for CO
It can be unknowingly inhaled to dangerous levels with serious clinical is approximately 65 times that of normal hemoglobin. 121
122
implications when present in high concentration in the atmosphere. 107 Pregnant women and fetuses are particularly at risk because they
already have higher levels of COHb. CO readily crosses the placenta,
Epidemiology and the half-life of CO in the fetus is as much as five times longer than it
123
Acute CO intoxication is one of the most common causes of morbidity is in the mother. The O affinity of fetal hemoglobin (HbF) is shifted to
2
from poisoning in the United States. In the United States, CO poison- the left 124,125 owing to its lack of 2,3-BPG binding, making the Darling–
ing results in approximately 50,000 emergency department visits per Roughton effect particularly pernicious. This is one of the reasons why
year, 108,109 and approximately 500 accidental deaths as a result of CO cigarette smoking during pregnancy is hazardous to the fetus.
poisoning occur annually, with the number of intentional CO-related
deaths being five to 10 times higher. 110,111 Primary sources of CO are Clinical and Laboratory Features
home appliances, and the majority of exposures occur during the fall CO poisoning is a clinical diagnosis that is confirmed by laboratory
and winter months and during weather-related disasters. 112,113 During testing. Signs and symptoms consistent with CO poisoning in certain
warmer months, boating activities are another source of exposure. The circumstances should raise the suspicion of CO intoxication. A higher
114
death rate is highest among the elderly and can be attributed to delayed index of suspicion should attend the simultaneous presentation of mul-
diagnosis because symptoms often resemble those of associated comor- tiple patients from the same family or housing complex. The eight-wave-
bidities. 115,116 The exhaust produced by the typical home-use 5.5-kW length pulse oximeter, Masimo Rad-57 (see paragraphs on “Laboratory
generator contains as much CO as that of six idling automobiles. 117 features” of methemoglobinemia.) has been reported to be accurate in
69
Chronic CO intoxication is commonly caused by cigarette smok- measuring COHb concentration in normal healthy volunteers, as well
ing, which can increase the COHb level up to 15 percent. Houses with as in emergency room patients. 126
defective heating exhaust systems and vehicles that leak CO into the Acute intoxication with CO rapidly affects the central and periph-
passenger compartment, either because of mechanical failure or driv- eral nervous systems and cardiopulmonary functions. Cerebral edema
ing with the rear hatch-door open, are the second most common cause is common, as is impairment of the peripheral nervous system. CO
of chronic CO exposure. Occupations that involve a high risk for induces increased capillary permeability in the lungs, resulting in acute
CO intoxication include garage work with improper ventilation, toll pulmonary edema. Cardiac arrhythmias, generalized hypoxemia, and
booth attendants, tunnel workers, fire fighters, and workers exposed respiratory failure are the common causes of CO-related death. In
to paint remover, aerosol propellant, or organic solvents containing survivors, considerable neuropsychological deficits might remain. In
dichloromethane. 118 a prospective longitudinal study, approximately 45 percent of patients
with CO poisoning had cognitive sequelae 6 weeks after poisoning. 127,128
Etiology and Pathogenesis Acute CO intoxication in children sometimes has unique symptoma-
129
CO binds with high affinity to heme and with lesser affinities to myoglo- tology resembling gastroenteritis. Surviving children are more likely to
bin and cytochromes at the iron core, a site it shares with O 2. 119 have severe sequelae such as leukoencephalopathy and severe myocar-
At equilibrium in physiologic conditions, CO affinity for hemo- dial ischemia. 130
globin is approximately 240 times greater than that of O . This very Chronic intoxication in adults might result in irritability, nausea,
2
high equilibrium constant is the result of reaction kinetics. Contrary to lethargy, headaches, and sometimes a flu-like condition. Higher COHb
popular belief, CO reacts more slowly than O with the heme of hemo- levels produce somnolence, palpitations, cardiomegaly, and hyperten-
2
globin. Once CO is bound to heme, its “off” rate is only 0.015 mol/L sion, and could contribute to atherosclerosis. Chronic CO poisoning can
per second in contrast to 35 mol/L per second for O 2. 119 This extraor- produce erythrocytosis, the magnitude of which varies with the level of
dinarily slow-release process produces a very high affinity constant of COHb. By increasing red cell production, chronic CO poisoning can
CO for heme and a life-threatening danger for individuals exposed to mask the mild anemia of acquired or congenital hemolytic disorders.
high levels of CO. Once two molecules of CO are bound to hemoglobin,
the hemoglobin switches to the relaxed (R) state, which increases the Therapy, Course, and Prognosis
affinity of hemoglobin for oxygen. As a consequence of this phenom- The most important step in the treatment for CO poisoning is prompt
80
enon, called the Darling–Roughton effect, the hemoglobin O affinity removal of patients from the source of CO, followed by administering
2
increases in parallel with increasing CO levels, making tissue delivery of 100 percent supplemental O via a tight-fitting mask. The serum elimi-
2
oxygen more difficult. nation half-life of CO is 5 hours when breathing room air and 30 min-
In the absence of environmental CO, the blood of adults contains utes with O therapy (100 percent O at 3 atmospheres). 123
2
2
approximately 1 to 2 percent COHb. This represents approximately For mild to moderate cases of CO poisoning, which more often
80 percent of the total body CO, the remainder probably sequestered happen with chronic intoxication, removing the patient from the source
in myoglobin and other heme binding proteins. This CO is endoge- of environmental CO is usually curative. If the COHb level is high,
120
nously produced, originating from the degradation of heme by the breathing 100 percent O will increase the rate of CO removal.
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