Carbon Monoxide Poisoning

A 39-year-old female executive has a several-month history of fatigue, headache, and memory lapse. Multiple specialists have performed evaluations, but no diagnosis has been established. During a period of feeling worse than usual, she called a friend, who arrived at the residence to find the woman semicomatose and called 911. The patient was given supplemental oxygen and transported to the emergency department, where she is alert and has nonfocal findings on examination. Her carboxyhemoglobin level is 18%. How should she be treated? What is the expected outcome?

The Clinical Problem

Carbon monoxide poisoning is common, resulting in more than 50,000 emergency department visits per year in the United States.¹ Sources of carbon monoxide include faulty furnaces, inadequate ventilation of heating sources, and exposure to engine exhaust.

The symptoms of carbon monoxide poisoning are nonspecific.² Mild exposures result in headache, myalgia, dizziness, or neuropsychological impairment.³ Severe exposures to carbon monoxide result in confusion, loss of consciousness, or death (Figure 1). Patients with subclinical exposures may recognize poisoning only after an acute event or on coincidental discovery of a carbon monoxide leak.

View larger version (18K): [in this window] [in a new window] Figure 1. Spectrum of Symptoms and Effects of Exposure to Carbon Monoxide, According to the Level and Duration of Exposure. In all humans, small amounts of carbon monoxide are present and are important for multiple physiologic functions, including neurotransmission. Exogenous exposure to amounts of carbon monoxide above physiologic levels can result in a protective or adaptive response, but exposure to even higher levels results in toxic effects. Toxic exposures can cause inflammation, followed by hypoxia, although there is uncertainty regarding the range of carbon monoxide exposures above which inflammation occurs (as indicated by the dashed line). The signs and symptoms of poisoning are highly variable, depending on the acuity and duration of the exposure.

In physiologic amounts, endogenous carbon monoxide functions as a neurotransmitter.⁴ At low levels, carbon monoxide may favorably modulate inflammation,⁵ apoptosis,⁶ and cell proliferation,⁷ and it up-regulates mitochondrial biogenesis.⁸ As the carbon monoxide exposure increases, poisoning results (Figure 1).⁵

Carbon monoxide causes hypoxia by forming carboxyhemoglobin and shifting the oxyhemoglobin dissociation curve to the left (Figure 2).² Carbon monoxide's affinity for hemoglobin is more than 200 times that of oxygen,¹⁴ resulting in the formation of carboxyhemoglobin with even relatively low amounts of inhaled carbon monoxide. Carbon monoxide increases cytosolic heme levels, leading to oxidative stress,¹² and binds to platelet heme protein and cytochrome c oxidase,¹⁴ interrupting cellular respiration⁹ and causing production of reactive oxygen species,¹³ which in turn leads to neuronal necrosis¹³ and apoptosis.¹¹ Impaired cellular respiration provokes a stress response, including the activation of hypoxia-inducible factor 1,¹⁵ resulting in neurologic and cardiac protection⁵ or injury, dependent on the dose of carbon monoxide, by means of gene regulation. Carbon monoxide exposure also causes inflammation through multiple pathways that are independent of the pathways to hypoxia, resulting in neurologic and cardiac injury.

View larger version (60K): [in this window] [in a new window] Figure 2. Pathophysiological Mechanisms of Carbon Monoxide Poisoning. Carbon monoxide (CO) diffuses quickly into the blood by way of the lungs and causes injury and an adaptive response that continue after carboxyhemoglobin levels have returned to normal. CO causes hypoxemia through the formation of carboxyhemoglobin and a leftward shift of the oxyhemoglobin dissociation curve.2 CO binds to heme proteins such as cytochrome c oxidase (CCO), impairing mitochondrial function9 and thereby contributing to hypoxia. Brain hypoxia elevates levels of excitatory amino acids, increasing brain nitrite levels and causing subsequent injury.10 Brain hypoxia causes oxidative stress, necrosis, and apoptosis,11 contributing to inflammation and injury. CO also causes inflammation by increasing levels of cytosolic heme and the heme oxygenase-1 (HO-1) protein, resulting in intracellular oxidative stress.12 CO binds to platelet heme proteins, causing the release of nitric oxide (•NO).13 Excess •NO produces peroxynitrite (ONOO–),13 impairing mitochondrial function,14 which contributes to hypoxia. CO causes platelet-to-neutrophil aggregation and neutrophil degranulation,13 involving the release or production of myeloperoxidase (MPO), proteases, and reactive oxygen species13 — which cause oxidative stress, lipid peroxidation,13 and apoptosis.11 Proteases interact with xanthine dehydrogenase (XD) in endothelial cells, forming xanthine oxidase (XO), which inhibits endogenous mechanisms against oxidative stress.13 Lipid-peroxidation products form adducts with myelin basic protein, altering its structure, triggering a lymphocytic immunologic response, increasing microglia activation and activity, and causing neuropathologic effects.14 Finally, CO induces cellular stress responses such as the activation of hypoxia-inducible factor 1 (HIF-1),15 which can induce gene regulation. This gene regulation can be protective5 or can result in injury, depending on the CO dose and on host factors, which remain largely unknown. NMDA denotes N-methyl-D-aspartate, and nNOS neuronal nitric oxide synthase.

Long-term, subacute exposures to carbon monoxide lasting more than 24 hours generally occur intermittently and may span weeks or even years. The incidence of long-term exposure is unknown. Symptoms of chronic poisoning may differ from those of acute poisoning and can include chronic fatigue, affective conditions and emotional distress, memory deficits, difficulty working, sleep disturbances, vertigo, neuropathy, paresthesias, recurrent infections, polycythemia, abdominal pain, and diarrhea.¹⁶

Patients commonly have neuropsychological sequelae after carbon monoxide poisoning.^2,17,18 In one randomized trial, 46% of poisoned patients treated with normobaric oxygen had cognitive sequelae 6 weeks after poisoning,¹⁷ and 45% had affective sequelae.¹⁹ Other sequelae include gait and motor disturbances, peripheral neuropathy, hearing loss and vestibular abnormalities, and dementia and psychosis,²⁰ which can be permanent.

Magnetic resonance imaging (MRI) of the brain (performed for research purposes or, in some cases, for clinical indications, such as to rule out disorders unrelated to carbon monoxide exposure) may reveal abnormal findings after carbon monoxide poisoning (Figure 3). In one prospective study of patients with carbon monoxide poisoning, brain MRI revealed increased numbers of T₂-weighted hyperintensities as compared with the numbers in a normative database.²¹ Although the prevalence of imaging abnormalities is unknown, other studies of carbon monoxide–poisoned patients have reported basal-ganglia lesions²² and atrophy of the hippocampi²³ and other structures²⁴ years after poisoning, as well as abnormal results of diffusion tensor imaging²⁵ 1 month after poisoning. However, none of these abnormalities are specific to carbon monoxide poisoning.

View larger version (53K): [in this window] [in a new window] Figure 3. Findings on Brain MRI after Carbon Monoxide Poisoning. Carbon monoxide–related brain damage, which may be seen in poisoned patients presenting with sequelae, is shown here. The images were obtained with the use of highly sensitive 3-T MRI, which is not universally available, according to specific protocols; typical clinical 1.5-T scans would generally depict less damage. White-matter fiber tracks are revealed on diffusion tensor imaging in a 21-year-old normal volunteer (Panels A and B) and in an age-matched patient with a history of carbon monoxide poisoning (Panels C and D). Each image is a fractional anisotropy map obtained by acquiring data in 32 diffusion directions. The average variances of the fractional anisotropy values and the apparent diffusion coefficient values of the corpus callosum differed significantly more in the patient with carbon monoxide poisoning than in the normal subject. Panels E and F show coronal T2-weighted images of the hippocampus in a normal volunteer and in a patient after carbon monoxide poisoning, respectively. Hippocampal atrophy (Panel F, arrows) was found in the patient. In a patient with carbon monoxide poisoning, abnormally increased T2 signals are revealed on axial T2-weighted images of the globus pallidus (Panel G, arrows) and on spin-echo imaging of subcortical structures (Panel H, arrows). The results of auditory functional MRI after carbon monoxide poisoning in a patient with previously normal auditory acuity shows normal activation after auditory stimulation of the right ear (Panel I, arrows) and no activation after auditory stimulation of the left ear (Panel J). This pattern is consistent with normal auditory processing on one side (the right, in this case) but suppression of processing on the other side, presumably in relation to brain injury from carbon monoxide poisoning.

Strategies and Evidence

Short-Term Management

If emergency medical personnel are called, they should administer normobaric oxygen to the poisoned patient, by means of a nonrebreather reservoir face mask supplied with high-flow oxygen, or 100% oxygen, by means of an artificial airway, if appropriate. Poisoned patients should then be transported to an emergency department for evaluation.

Although the administration of normobaric oxygen hastens the elimination of carbon monoxide,^2,26 one trial did not show a reduction of cognitive sequelae after the inhalation of normobaric oxygen, as compared with no supplemental oxygen therapy.¹⁸ However, since normobaric oxygen is safe, readily available, and inexpensive, it should be provided until the carboxyhemoglobin level is less than 5%.

Evaluation of the poisoned patient should emphasize the adequacy of ventilation and perfusion, the neurologic examination, and the exposure history (duration, source, and whether others were exposed). The measurement of arterial blood gases by co-oximetry provides information about the adequacy of gas exchange, metabolic acidosis, and carboxyhemoglobin and should be performed in poisoned patients if clinically indicated. However, measurement of venous carboxyhemoglobin levels is adequate for diagnostic purposes.²⁷ Carboxyhemoglobin levels depend on multiple factors, including the magnitude of exposure, the degree of alveolar ventilation, the blood volume, and metabolic activity,¹⁴ but in adult men at rest, the levels are determined predominantly by the ambient carbon monoxide level and the duration of exposure.²⁸ A carboxyhemoglobin level greater than 3% in nonsmokers or greater than 10% in smokers confirms exposure to carbon monoxide, but the level does not correlate with the presence or absence of initial symptoms²⁹ or with later outcomes,¹⁸ which may be more attributable to inflammatory aspects of poisoning than to hypoxia.

Carbon monoxide poisoning can exacerbate angina³⁰ and cause cardiac injury,³¹ even in persons with normal coronary arteries.³² Therefore, poisoned patients should undergo a cardiovascular investigation, including electrocardiography and measurement of cardiac enzymes. If cardiac injury is present, a cardiology consultation is indicated.³¹

For cases of intentional carbon monoxide poisoning, laboratory toxicologic investigations should be performed for the detection of alcohol, benzodiazepines, narcotics, amphetamines, or other such agents. Emergency department personnel should facilitate access to mental health resources.

Use of Hyperbaric Oxygen

Health care providers in the emergency department should consider using hyperbaric oxygen for treating poisoned patients.^{2,14,17,18,33,34,35} Hyperbaric-oxygen therapy is defined as the breathing of 100% oxygen by patients within hyperbaric chambers compressed to greater than 1.4 atm of absolute pressure.³³ Clinicians who use carboxyhemoglobin levels as criteria for whether hyperbaric oxygen should be administered should consider that the level on presentation may underestimate earlier levels because of carboxyhemoglobin elimination over time, which is hastened by the application of supplemental oxygen by emergency medical personnel before arrival at the emergency department.^2,14,26,28

The role of hyperbaric oxygen in the management of carbon monoxide poisoning remains controversial, although both physiological data and some randomized-trial data suggest a potential benefit.^17,35,36 Hyperbaric-oxygen therapy elevates arterial and tissue oxygen tensions, promoting carbon monoxide elimination,^2,14 and also increases adenosine triphosphate production³⁷ and reduces oxidative stress and inflammation.¹⁴

Among published randomized clinical trials of hyperbaric oxygen,^{17,35,36,38,39} only one satisfied all Consolidated Standards for the Reporting of Trials (CONSORT) guidelines,⁴⁰ including double-blinding, enrollment of all eligible patients, a priori definitions of outcomes, and high rates of follow-up.¹⁷ This single-center, prospective trial showed that the incidence of cognitive sequelae was lower among patients who underwent three hyperbaric-oxygen sessions (an initial session of 150 minutes, followed by two sessions of 120 minutes each, separated by an interval of 6 to 12 hours) within 24 hours after acute carbon monoxide poisoning than among patients treated with normobaric oxygen (25% vs. 46%, P=0.007 and P=0.03 after adjustment for cerebellar dysfunction and stratification variables). In addition, the use of hyperbaric oxygen reduced the rate of cognitive sequelae at 12 months (18%, vs. 33% with normobaric oxygen; P=0.04).¹⁷ However, this trial did not clearly identify subgroups of patients in whom hyperbaric oxygen was appreciably more or less beneficial. A post hoc analysis of 86 patients suggested an interaction between the apolipoprotein genotype and the use of hyperbaric oxygen. In patients lacking the apolipoprotein E4 allele, hyperbaric oxygen reduced the rate of cognitive sequelae at 6 weeks, whereas in patients who had the E4 allele (which is present in 30% of the general population), the use of hyperbaric oxygen did not reduce the rate of cognitive sequelae.³⁴

A Cochrane review of six trials, including two published only in abstract form, did not support the use of hyperbaric oxygen for patients with carbon monoxide poisoning.⁴¹ However, the reviewed trials were heterogeneous with respect to the methods used and differed in the selection of patients, dosing of hyperbaric oxygen and normobaric oxygen, and long-term outcome measures; lack of follow-up was a limitation in some trials. Because the trial described above¹⁷ showed a significant benefit of hyperbaric oxygen, and because of the methodologic limitations of the trials in which a benefit was not shown, the review's conclusions have been controversial.

Long-Term Management

Patients with carbon monoxide poisoning should be followed medically after discharge. The extent and rate of recovery after poisoning are variable, and recovery is often complicated by the development of sequelae, which can persist after exposure or develop weeks after poisoning² and which can be permanent.

Specific therapy for sequelae after carbon monoxide poisoning is not available. Clinical experience suggests that patients with sequelae should have their symptoms treated, through cognitive, psychiatric, vocational, speech, occupational, and physical rehabilitation, although data on the effects of these interventions in patients with carbon monoxide–related sequelae are lacking. Patients with persistent headaches may benefit from evaluation by a headache specialist.

Prevention

Governmental air-quality limits for exposure to carbon monoxide are intended to keep carboxyhemoglobin levels in nonsmokers below 3%.⁴² Carboxyhemoglobin levels of 3% or more can adversely affect high-risk groups such as the elderly, pregnant women, fetuses, infants, and patients with cardiovascular or respiratory diseases.

Accidental carbon monoxide poisoning is preventable. Carbon monoxide alarms are designed to go off at exposure levels that would result in carboxyhemoglobin levels exceeding 10%.⁴³

Steps such as avoiding the operation of combustion engines indoors and performing periodic furnace inspections can prevent many cases of carbon monoxide poisoning, as can proper use of alternative heating and cooking sources and generators after natural disasters. A helpful online resource for the prevention of carbon monoxide poisoning is available from the Centers for Disease Control and Prevention (www.cdc.gov/co/).

Areas of Uncertainty

Sequelae

Although carbon monoxide poisoning can cause myriad neurologic and neuropsychological problems, the incidence of sequelae after carbon monoxide poisoning is not clearly known. Prospective studies of patients treated with normobaric oxygen showed that 34% reported symptoms such as headaches or memory problems at 4 weeks³⁸ and 46% had neuropsychological sequelae at 6 weeks.¹⁷ However, among all poisoned patients, the number in whom carbon monoxide-related sequelae will develop is unknown. Studies of long-term outcomes in poisoned patients have not typically involved nonpoisoned, matched controls, nor have they included information about functional and cognitive status before poisoning occurred; rather, such information is inferred from educational level, scholastic performance, vocation, IQ testing, and collateral interviews after poisoning.

A patient's initial presentation does not predict later outcomes with certainty, but particular variables known at the time of poisoning are predictive of risks for subsequent sequelae.^17,18 In one study, patients who were 36 years of age or older or who had been exposed to carbon monoxide for at least 24 hours, who did not receive hyperbaric oxygen,¹⁸ or who had cerebellar abnormalities on presentation¹⁷ had an increased risk of cognitive sequelae at 6 weeks as compared with those without these characteristics. In another study, patients with dizziness before hospital admission or headaches at the time of admission had an increased risk of minor neurologic problems 1 month after poisoning.⁴⁴ Given the role of inflammation in carbon monoxide–associated injury (Figure 2), levels of inflammatory markers might predict the risk of sequelae, but this possibility requires further study.

Information about sequelae beyond the first year after poisoning is limited.^17,18,19 In one cohort, approximately 6 years after poisoning, 19% of patients had cognitive problems⁴⁵ and 37% had abnormal neurologic evaluations.⁴⁶

In patients without a history of carbon monoxide poisoning, abnormalities found on neuroimaging that are consistent with those reported after carbon monoxide poisoning — such as hippocampal atrophy⁴⁷ or white-matter hyperintensities⁴⁸ — are associated with an increased risk of early cognitive decline. It is unknown whether patients with carbon monoxide poisoning who have such abnormalities are also at increased risk for early cognitive decline or Alzheimer's disease.

Variability among Patients

Responses to carbon monoxide exposures are variable. Exposed children often become symptomatic earlier, and recover faster, than similarly exposed adults, because of their lesser blood volume and increased minute ventilation per unit of body mass as compared with adults. Prospective studies of children exposed to carbon monoxide have reported variable rates of sequelae.^49,50 The unborn fetus is highly susceptible to the adverse effects of carbon monoxide. The period required to eliminate carbon monoxide is prolonged for fetal blood as compared with adult blood, and maternal poisoning and hypoxemia contribute to fetal hypoxia.⁵¹ Fetal mortality exceeds 50% in cases of severe poisoning.⁵² Hyperbaric-oxygen therapy should be considered in women with acute carbon monoxide poisoning,¹⁷ including pregnant women, and in particular if the fetus shows signs of distress.⁵¹ The role of hyperbaric oxygen in treating a fetus with carbon monoxide poisoning remains unclear, although there has been at least one case report of a favorable outcome.⁵¹

Hyperbaric-Oxygen Therapy

It is not clear which patients should receive hyperbaric-oxygen therapy. Additional uncertainties about this therapy include the optimal chamber pressure, the optimal number of hyperbaric-oxygen sessions, and the maximal interval after poisoning during which hyperbaric oxygen may still have a favorable effect. Case reports describe improvement of sequelae with a series of hyperbaric-oxygen sessions beginning days after poisoning,⁵³ although mechanisms of possible benefit are unknown, and most clinicians do not administer hyperbaric oxygen if more than 24 hours has elapsed since carbon monoxide poisoning.⁵⁴ A single-center, double-blind clinical trial (ClinicalTrials.gov number, NCT00465855 [ClinicalTrials.gov] ) is under way to determine the effect of one or three hyperbaric-oxygen sessions on rates of cognitive sequelae at 6 weeks among accidentally poisoned patients presenting less than 24 hours after exposure.

Other Therapy

Inflammation caused by carbon monoxide results in tissue injury. Whether antiinflammatory therapy or the use of other neuroprotective interventions, such as induced hypothermia, could improve outcomes after poisoning is unknown.

Guidelines

The Undersea and Hyperbaric Medical Society recommends hyperbaric-oxygen therapy for patients with serious carbon monoxide poisoning — as manifested by transient or prolonged unconsciousness, abnormal neurologic signs, cardiovascular dysfunction, or severe acidosis — or patients who are 36 years of age or older, were exposed for 24 hours or more (including intermittent exposures), or have a carboxyhemoglobin level of 25% or more.³³

A Clinical Policies Subcommittee of the American College of Emergency Physicians states that hyperbaric oxygen "is a therapeutic option for [carbon monoxide–]poisoned patients; however, its use cannot be mandated. . . . No clinical variables, including carboxyhemoglobin levels, identify a subgroup of [carbon monoxide–]poisoned patients for whom [hyperbaric oxygen] is most likely to provide benefit or cause harm."⁵⁵ The subcommittee advocates a large, multicenter clinical trial with elements identical to those incorporated in a previous single-center trial.¹⁷ My recommendations diverge from this policy statement in that I more strongly recommend that hyperbaric-oxygen therapy be considered for patients with carbon monoxide poisoning, on the basis of the available data, including biochemical studies, studies in animals, and at least one rigorous clinical trial.

Conclusions and Recommendations

Patients who have had carbon monoxide poisoning, such as the patient in the vignette, should be treated immediately with normobaric oxygen (with a fraction of inspired oxygen as high as possible), which speeds up the excretion of carbon monoxide. The source of carbon monoxide should be identified and removed.

Carbon monoxide poisoning can result in permanent sequelae. Clinicians evaluating patients with acute poisoning should consider hyperbaric-oxygen therapy. Although some randomized trials did not show efficacy, in the most rigorous trial, the rate of cognitive sequelae at 6 weeks was 25%, a 46% reduction from the rate of sequelae among patients receiving normobaric oxygen.¹⁷ Patients should be informed that they may not fully recover after poisoning, and they should be given referrals as appropriate for their sequelae.

The case of carbon monoxide poisoning described in the vignette was caused by a faulty home furnace. Patients should be educated to minimize the risks of carbon monoxide exposure, including by avoiding the operation of combustion engines indoors and performing periodic furnace inspections. Patients should also be encouraged to obtain, install, and heed carbon monoxide alarms.

Dr. Weaver reports serving as an expert witness for both the plaintiff and defense in cases involving carbon monoxide and receiving grants for carbon monoxide research from the Centers for Disease Control and Prevention and the Deseret Foundation. No other potential conflict of interest relevant to this article was reported.

I thank William W. Orrison, M.D., of Nevada Imaging Centers, Las Vegas, for providing the brain MRI images, and Kayla Deru, of Intermountain Healthcare, Salt Lake City, for assistance with a previous version of the manuscript.

Source Information

From the Department of Hyperbaric Medicine, LDS Hospital; and the Department of Medicine, University of Utah School of Medicine — both in Salt Lake City; and the Department of Hyperbaric Medicine, Intermountain Medical Center, Murray, Utah.

An audio version of this article is available at NEJM.org.

Address reprint requests to Dr. Weaver at the Department of Hyperbaric Medicine, LDS Hospital, Eighth Ave. and C St., Salt Lake City, UT 84143, or at lindell.weaver@imail.org.

References

1. Hampson NB, Weaver LK. Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med 2007;34:163-168. [ISI][Medline]
2. Ernst A, Zibrak JD. Carbon monoxide poisoning. N Engl J Med 1998;339:1603-1608. [Free Full Text]
3. Amitai Y, Zlotogorski Z, Golan-Katzav V, Wexler A, Gross D. Neuropsychological impairment from acute low-level exposure to carbon monoxide. Arch Neurol 1998;55:845-848. [Free Full Text]
4. Boehning D, Moon C, Sharma S, et al. Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. Neuron 2003;40:129-137. [CrossRef][ISI][Medline]
5. Mannaioni PF, Vannacci A, Masini E. Carbon monoxide: the bad and the good side of the coin, from neuronal death to anti-inflammatory activity. Inflamm Res 2006;55:261-273. [CrossRef][ISI][Medline]
6. Zhang X, Shan P, Otterbein LE, et al. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem 2003;278:1248-1258. [Free Full Text]
7. Taillé C, Almolki A, Benhamed M, et al. Heme oxygenase inhibits human airway smooth muscle proliferation via a bilirubin-dependent modulation of ERK1/2 phosphorylation. J Biol Chem 2003;278:27160-27168. [Free Full Text]
8. Suliman HB, Carraway MS, Tatro LG, Piantadosi CA. A new activating role for CO in cardiac mitochondrial biogenesis. J Cell Sci 2007;120:299-308. [Free Full Text]
9. Alonso JR, Cardellach F, López S, Casademont J, Miró O. Carbon monoxide specifically inhibits cytochrome c oxidase of human mitochondrial respiratory chain. Pharmacol Toxicol 2003;93:142-146. [CrossRef][ISI][Medline]
10. Piantadosi CA. Toxicity of carbon monoxide: hemoglobin vs. histotoxic mechanisms. In: Penney DG, ed. Carbon monoxide. Boca Raton, FL: CRC Press, 1996:163-86.
11. Piantadosi CA, Zhang J, Levin ED, Folz RJ, Schmechel DE. Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat. Exp Neurol 1997;147:103-114. [CrossRef][ISI][Medline]
12. Cronje FJ, Carraway MS, Freiberger JJ, Suliman HB, Piantadosi CA. Carbon monoxide actuates O(2)-limited heme degradation in the rat brain. Free Radic Biol Med 2004;37:1802-1812. [CrossRef][ISI][Medline]
13. Thom SR, Bhopale VM, Han ST, Clark JM, Hardy KR. Intravascular neutrophil activation due to carbon monoxide poisoning. Am J Respir Crit Care Med 2006;174:1239-1248. [Free Full Text]
14. Thom SR. Carbon monoxide pathophysiology and treatment. In: Neuman TS, Thom SR, eds. Physiology and medicine of hyperbaric oxygen therapy. Philadelphia: Saunders Elsevier, 2008:321-47.
15. Chin BY, Jiang G, Wegiel B, et al. Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A 2007;104:5109-5114. [Free Full Text]
16. Penney DG. Chronic carbon monoxide poisoning: a case series. In: Penney DG, ed. Carbon monoxide poisoning. Boca Raton, FL: CRC Press, 2008:551-67.
17. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002;347:1057-1067. [Free Full Text]
18. Weaver LK, Valentine KJ, Hopkins RO. Carbon monoxide poisoning: risk factors for cognitive sequelae and the role of hyperbaric oxygen. Am J Respir Crit Care Med 2007;176:491-497. [Free Full Text]
19. Jasper BW, Hopkins RO, Duker HV, Weaver LK. Affective outcome following carbon monoxide poisoning: a prospective longitudinal study. Cogn Behav Neurol 2005;18:127-134. [CrossRef][ISI][Medline]
20. Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 1983;40:433-435. [Free Full Text]
21. Parkinson RB, Hopkins RO, Cleavinger HB, et al. White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning. Neurology 2002;58:1525-1532. [ISI][Medline]
22. Pulsipher DT, Hopkins RO, Weaver LK. Basal ganglia volumes following CO poisoning: a prospective longitudinal study. Undersea Hyperb Med 2006;33:245-256. [ISI][Medline]
23. Gale SD, Hopkins RO, Weaver LK, Bigler ED, Booth EJ, Blatter DD. MRI, quantitative MRI, SPECT, and neuropsychological findings following carbon monoxide poisoning. Brain Inj 1999;13:229-243. [CrossRef][ISI][Medline]
24. Durak AC, Coskun A, Yikilmaz A, Erdogan F, Mavili E, Guven M. Magnetic resonance imaging findings in chronic carbon monoxide intoxication. Acta Radiol 2005;46:322-327. [ISI][Medline]
25. Terajima K, Igarashi H, Hirose M, Matsuzawa H, Nishizawa M, Nakada T. Serial assessments of delayed encephalopathy after carbon monoxide poisoning using magnetic resonance spectroscopy and diffusion tensor imaging on 3.0T system. Eur Neurol 2008;59:55-61. [CrossRef][ISI][Medline]
26. Weaver LK, Howe S, Hopkins R, Chan KJ. Carboxyhemoglobin half-life in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest 2000;117:801-808. [CrossRef][ISI][Medline]
27. Touger M, Gallagher EJ, Tyrell J. Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Ann Emerg Med 1995;25:481-483. [CrossRef][ISI][Medline]
28. Peterson JE, Stewart RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health 1970;21:165-171. [ISI][Medline]
29. Hampson NB, Hauff NM. Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture? Am J Emerg Med 2008;26:665-669. [CrossRef][ISI][Medline]
30. Balzan MV, Cacciottolo JM, Mifsud S. Unstable angina and exposure to carbon monoxide. Postgrad Med J 1994;70:699-702. [Free Full Text]
31. Satran D, Henry CR, Adkinson C, Nicholson CI, Bracha Y, Henry TD. Cardiovascular manifestations of moderate to severe carbon monoxide poisoning. J Am Coll Cardiol 2005;45:1513-1516. [Free Full Text]
32. Kalay N, Ozdogru I, Cetinkaya Y, et al. Cardiovascular effects of carbon monoxide poisoning. Am J Cardiol 2007;99:322-324. [CrossRef][ISI][Medline]
33. Gesell LB, ed. Hyperbaric oxygen 2009: indications and results: the Hyperbaric Oxygen Therapy Committee report. Durham, NC: Undersea and Hyperbaric Medical Society, 2008.
34. Hopkins RO, Weaver LK, Valentine KJ, Mower C, Churchill S, Carlquist J. Apolipoprotein E genotype and response of carbon monoxide poisoning to hyperbaric oxygen treatment. Am J Respir Crit Care Med 2007;176:1001-1006. [Free Full Text]
35. Thom SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB. Delayed neuropsychologic sequelae following carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995;25:474-480. [CrossRef][ISI][Medline]
36. Ducassé JL, Celsis P, Marc-Vergnes JP. Non-comatose patients with acute carbon monoxide poisoning: hyperbaric or normobaric oxygenation? Undersea Hyperb Med 1995;22:9-15. [ISI][Medline]
37. Brown SD, Piantadosi CA. Recovery of energy metabolism in rat brain after carbon monoxide hypoxia. J Clin Invest 1992;89:666-672. [ISI][Medline]
38. Raphael JC, Elkharrat D, Jars-Guincestre MC, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;2:414-419. [CrossRef][ISI][Medline]
39. Scheinkestel CD, Bailey M, Myles PS, et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial. Med J Aust 1999;170:203-210. [ISI][Medline]
40. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001;285:1987-1991. [Free Full Text]
41. Juurlink DN, Buckley NA, Stanbrook MB, Isbister GK, Bennett M, McGuigan MA. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev 2005;1:CD002041-CD002041. [Medline]
42. Office of Research and Development, National Center for Environmental Assessment. Air quality criteria for carbon monoxide: final report. Washington, DC: Environmental Protection Agency, 2000. (EPA publication no. 600/P-99/001F.)
43. UL 2034: standard for single and multiple station carbon monoxide alarms. 2nd ed. Northbrook, IL: Underwriters Laboratories, 1996.
44. Annane D, Chevret S, Jars-Guincestre C, et al. Prognostic factors in unintentional mild carbon monoxide poisoning. Intensive Care Med 2001;27:1776-1781. [CrossRef][ISI][Medline]
45. Hopkins RO, Weaver LK. Cognitive outcomes 6 years after acute carbon monoxide poisoning. Undersea Hyperb Med 2008;35:258-258.
46. Weaver LK, Hopkins RO, Churchill S, Deru K. Neurological outcomes 6 years after acute carbon monoxide poisoning. Undersea Hyperb Med 2008;35:258-259.
47. den Heijer T, Sijens PE, Prins ND, et al. MR spectroscopy of brain white matter in the prediction of dementia. Neurology 2006;66:540-544. [Free Full Text]
48. Smith EE, Egorova S, Blacker D, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol 2008;65:94-100. [Free Full Text]
49. Kim JK, Coe CJ. Clinical study on carbon monoxide intoxication in children. Yonsei Med J 1987;28:266-273. [Medline]
50. Klees M, Heremans M, Dougan S. Psychological sequelae to carbon monoxide intoxication in the child. Sci Total Environ 1985;44:165-176. [CrossRef][Medline]
51. Van Hoesen KB, Camporesi EM, Moon RE, Hage ML, Piantadosi CA. Should hyperbaric oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? A case report and literature review. JAMA 1989;261:1039-1043. [Erratum, JAMA 1990;273:2750.] [Abstract]
52. Koren G, Sharav T, Pastuszak A, et al. A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol 1991;5:397-403. [CrossRef][ISI][Medline]
53. Myers RA, Snyder SK, Emhoff TA. Subacute sequelae of carbon monoxide poisoning. Ann Emerg Med 1985;14:1163-1167. [CrossRef][ISI][Medline]
54. Hampson NB, Dunford RG, Kramer CC, Norkool DM. Selection criteria utilized for hyperbaric oxygen treatment of carbon monoxide poisoning. J Emerg Med 1995;13:227-231. [CrossRef][ISI][Medline]
55. Wolf SJ, Lavonas EJ, Sloan EP, Jagoda AS, American College of Emergency Physicians. Critical issues in the management of adult patients presenting to the emergency department with acute carbon monoxide poisoning. Ann Emerg Med 2008;51:138-152. [CrossRef][ISI][Medline]

Source : http://content.nejm.org/cgi/content/full/360/12/1217