Carbon Monoxide Poisoning

Environmental MONDO:0800373 Pathograph 22 Show in embeddings browser gas poisoning

Carbon monoxide poisoning is a toxic condition caused by inhalation of carbon monoxide (CO), a colorless, odorless gas produced by incomplete combustion of carbon-containing fuels. Common sources include faulty furnaces and heaters, fire smoke, motor vehicle exhaust, portable generators, indoor charcoal burning, and the metabolic conversion of inhaled methylene chloride (paint stripper). CO produces tissue hypoxia through several converging mechanisms: it binds hemoglobin with roughly 200 times the affinity of oxygen to form carboxyhemoglobin, reducing the oxygen-carrying capacity of blood and shifting the oxyhemoglobin dissociation curve leftward so that less oxygen is released to tissues; it binds and inhibits mitochondrial cytochrome c oxidase, causing histotoxic (cellular) hypoxia; and it triggers an oxidative and inflammatory cascade of platelet-neutrophil activation, reactive oxygen species, and lipid peroxidation that drives delayed neurological injury. The brain and heart, as the most oxygen-dependent organs, are most vulnerable. Clinical features range from headache, dizziness, nausea, and confusion to syncope, seizures, myocardial injury, coma, and death; a subset of survivors develop delayed neuropsychiatric sequelae. Treatment centers on high-flow normobaric oxygen and, for severe poisoning, hyperbaric oxygen therapy.

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1
Mappings
1
Definitions
14
Pathophys.
1
Histopath.
14
Phenotypes
2
Gaps
22
Pathograph
3
Medical Actions
2
Subtypes
1
Datasets
1
Deep Research
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Mappings

MONDO
MONDO:0800373 carbon monoxide poisoning
skos:exactMatch MONDO
Primary MONDO disease identifier for this carbon monoxide poisoning entry.
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Definitions

1
Clinical case definition for carbon monoxide poisoning
Carbon monoxide poisoning is a toxic-inhalation syndrome in which carbon monoxide binds hemoglobin and other heme proteins, producing tissue hypoxia and oxidative stress, confirmed by an elevated blood carboxyhemoglobin level in a compatible clinical and exposure context.
CASE_DEFINITION Disease-level clinical framing across acute poisoning and delayed sequelae
Show evidence (2 references)
PMID:34053712 SUPPORT Other
"Carbon monoxide binds to hemoglobin and other heme molecules, causing tissue hypoxia and oxidative stress."
Supports the core disease framing as heme-protein binding producing tissue hypoxia and oxidative stress.
PMID:34053712 SUPPORT Other
"When there is concern for possible carbon monoxide poisoning, the diagnosis can be made via blood co-oximetry."
Supports blood co-oximetry (carboxyhemoglobin measurement) as the confirmatory diagnostic anchor.
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Subtypes

2
Acute CO Poisoning
Acute carbon monoxide poisoning follows a high-level exposure and presents with headache, dizziness, altered mental status, syncope, seizures, myocardial injury, coma, or death depending on the carboxyhemoglobin level and duration of exposure.
Show evidence (1 reference)
PMID:35461624 SUPPORT Other
"Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
Supports the acute multisystem presentation of carbon monoxide poisoning.
Delayed Neurological Sequelae (DNS)
A subset of survivors of acute CO poisoning develop delayed neuropsychiatric sequelae days to weeks after apparent recovery, including cognitive impairment, memory loss, parkinsonism, and behavioral changes, associated with demyelination and basal-ganglia (globus pallidus) injury.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
Directly supports the delayed neuropsychiatric sequelae subtype and its demyelinating, biphasic character.
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Discussions and Knowledge Gaps

2
Which carbon monoxide poisoning patients derive a durable neurological benefit from hyperbaric oxygen therapy, and by what mechanism?
KNOWLEDGE GAP OPEN gap_co_hbo_patient_selection
Attached to
treatments#Hyperbaric oxygen therapy pathophysiology#Delayed neuronal injury
Randomized trials conflict. Thom 1995 and Weaver 2002 found that hyperbaric oxygen reduced delayed/cognitive sequelae, whereas Scheinkestel 1999 found no benefit and even worse outcomes on some measures, using a different protocol and patient mix. The subset of patients who benefit, the optimal timing and pressure, and whether the benefit comes from faster CO clearance or from interrupting the immune-mediated demyelination cascade remain unresolved.
Show evidence (1 reference)
PMID:10092916 REFUTE Human Clinical
"HBO patients had a worse outcome in the learning test at completion of treatment (P = 0.01 for all patients; P = 0.005 for severely poisoned patients)"
Provides the negative-trial evidence that motivates the open question about which patients benefit from hyperbaric oxygen.
Does the rodent anti-myelin-basic-protein autoimmune mechanism of delayed neuropathology quantitatively explain human delayed neurological sequelae?
HUMAN MODEL MISMATCH OPEN mismatch_co_rodent_mbp_autoimmunity
Attached to
pathophysiology#Immune-mediated neuroinflammation pathophysiology#Delayed demyelination
The adaptive-immune, anti-MBP mechanism of delayed CO neuropathology is established chiefly in rats, where immunological tolerance to MBP before poisoning abolishes the learning deficit, demonstrating causation. Its quantitative fidelity to human delayed neurological sequelae is not established; human delayed encephalopathy is heterogeneous and the contribution of MBP autoimmunity relative to hypoxic-ischemic injury in people remains an open translational question.
Show evidence (1 reference)
PMID:15342916 SUPPORT Model Organism
"These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP."
Establishes the immune-mediated mechanism in the rat model whose translational validity to humans is the open question.
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Pathophysiology

14
Carboxyhemoglobin formation
Inhaled carbon monoxide binds hemoglobin at the same heme iron sites used by oxygen, with an affinity roughly 200 times that of oxygen, forming carboxyhemoglobin (COHb). This reduces the oxygen-carrying capacity of blood.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
oxygen transport GO:0015671 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxygen transport (GO:0015671). GO:0015671 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired tissue oxygen delivery Reduced oxygen-carrying capacity and leftward-shifted dissociation curve limit oxygen delivery and offloading to tissues.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
Directly supports carboxyhemoglobin formation with ~200x oxygen affinity and reduced oxygen-carrying capacity.
Leftward shift of the oxyhemoglobin dissociation curve
Binding of CO to one or more heme sites increases the oxygen affinity of the remaining sites on the hemoglobin tetramer, shifting the oxyhemoglobin dissociation curve to the left so that bound oxygen is released less readily at the tissues, worsening tissue hypoxia beyond what the reduced oxygen-carrying capacity alone would cause.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Impaired tissue oxygen delivery The impaired oxygen release compounds the hypoxic insult.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"decreased release of oxygen to tissues leading to tissue hypoxia"
Supports impaired oxygen offloading (the functional consequence of the leftward shift) as a driver of tissue hypoxia.
Impaired tissue oxygen delivery
The combination of reduced carboxyhemoglobin-limited oxygen carriage and impaired oxygen offloading produces systemic tissue hypoxia, most severely affecting the oxygen-dependent brain and heart.
cellular response to hypoxia GO:0071456 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to hypoxia (GO:0071456). GO:0071456 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cerebral hypoxic-ischemic injury Hypoxia in the brain produces neuronal injury and encephalopathy.
Myocardial ischemic injury Hypoxia in the heart produces myocardial ischemia and injury.
Show evidence (1 reference)
PMID:34053712 SUPPORT Other
"Carbon monoxide binds to hemoglobin and other heme molecules, causing tissue hypoxia and oxidative stress."
Supports systemic tissue hypoxia as the central consequence of carbon monoxide binding.
Cytochrome c oxidase inhibition
Carbon monoxide binds the ferrous iron of mitochondrial cytochrome c oxidase (Complex IV of the electron transport chain), directly inhibiting oxidative phosphorylation. This produces histotoxic (cellular) hypoxia independent of oxygen delivery, impairing ATP generation even where oxygen is present, and helps explain the persistence of symptoms after carboxyhemoglobin normalizes.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED mitochondrial electron transport, cytochrome c to oxygen GO:0006123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cellular energy failure Inhibition of oxidative phosphorylation depletes cellular ATP.
Oxidative stress and free radical generation Mitochondrial dysfunction generates reactive oxygen species and free radicals.
Show evidence (2 references)
PMID:9584335 SUPPORT Human Clinical
"cytochrome c oxidase (complex IV) activity showed a 76% inhibition compared to controls during acute poisoning (P < 0.01) and 48% at day 3 (P < 0.05)."
Direct human evidence of marked cytochrome c oxidase inhibition during acute CO poisoning.
PMID:9584335 SUPPORT Human Clinical
"Our results suggest that mitochondrial cytochrome c oxidase is also a target site in human acute CO poisoning, and its extended and generalized inhibition could explain the persistence of different symptoms after the normalization of HbCO levels."
Supports cytochrome c oxidase as a COHb-independent target explaining persistent symptoms.
Cellular energy failure
Inhibition of oxidative phosphorylation, together with tissue hypoxia, depletes cellular ATP and forces a shift to anaerobic metabolism, producing lactic acidosis and cellular energy failure across multiple organs.
aerobic respiration GO:0009060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aerobic respiration (GO:0009060). GO:0009060 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Xanthine oxidase-mediated reactive oxygen species generation Energy deprivation and purine catabolism drive conversion of xanthine dehydrogenase to reactive-oxygen-species-generating xanthine oxidase.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart."
Supports impaired cellular energy utilization as a core downstream effect of CO.
Oxidative stress and free radical generation
Mitochondrial dysfunction and the displacement of nitric oxide from hemoproteins generate reactive oxygen species, free radicals, and nitric-oxide-derived species, producing oxidative injury across multiple organs.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Platelet-neutrophil activation Nitric-oxide displacement and oxidative changes promote intravascular platelet-neutrophil activation.
Brain lipid peroxidation Reactive oxygen species peroxidize brain membrane and myelin lipids.
Show evidence (1 reference)
PMID:24773392 SUPPORT Other
"One of the current hypotheses with regard to the molecular mechanism of CO poisoning is the oxidative injury induced by reactive oxygen species, free radicals, and neuronal nitric oxide."
Supports oxidative injury by reactive oxygen species, free radicals, and nitric oxide as a core molecular mechanism.
Platelet-neutrophil activation
Acute CO poisoning triggers intravascular platelet-neutrophil aggregation and neutrophil activation with myeloperoxidase release, initiating a reperfusion-injury-like oxidative cascade in the cerebral microvasculature.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
platelet aggregation GO:0070527 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet aggregation (GO:0070527). GO:0070527 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Xanthine oxidase-mediated reactive oxygen species generation Neutrophil adherence to the cerebral microvasculature drives conversion of xanthine dehydrogenase to xanthine oxidase.
Show evidence (2 references)
PMID:16931637 SUPPORT Human Clinical
"Acute CO poisoning causes intravascular neutrophil activation due to interactions with platelets."
Directly supports platelet-driven intravascular neutrophil activation in CO poisoning.
PMID:16931637 SUPPORT Human Clinical
"Platelet-neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning."
Human patient data confirm platelet-neutrophil aggregates and myeloperoxidase release in confirmed CO poisoning.
Xanthine oxidase-mediated reactive oxygen species generation
Energy deprivation and neutrophil-driven signaling convert xanthine dehydrogenase to xanthine oxidase, which generates reactive oxygen species and drives a postischemic reperfusion-like oxidative injury in the brain.
reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Brain lipid peroxidation Xanthine oxidase-derived reactive oxygen species peroxidize brain lipids.
Show evidence (2 references)
PMID:1447108 SUPPORT Model Organism
"The conversion of xanthine dehydrogenase to xanthine oxidase and lipid peroxidation were measured in brain from carbon monoxide- (CO) poisoned rats."
Supports xanthine dehydrogenase-to-oxidase conversion generating the oxidative injury.
PMID:24773392 SUPPORT Other
"The underlying mechanism of the central nervous system (CNS) injury after acute carbon monoxide (CO) poisoning is interlaced with multiple factors including apoptosis, abnormal inflammatory responses, hypoxia, and ischemia/reperfusion-like problems."
Supports the ischemia/reperfusion-like oxidative character of the injury.
Brain lipid peroxidation
Reactive oxygen species peroxidize brain membrane and myelin lipids. Peroxidation products such as malondialdehyde form adducts with myelin basic protein, generating the antigenic modification that initiates delayed injury.
lipid oxidation GO:0034440 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lipid oxidation (GO:0034440). GO:0034440 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Immune-mediated neuroinflammation Adducts between peroxidation products and myelin basic protein become antigenic and initiate an immune response.
Show evidence (2 references)
PMID:2341364 SUPPORT Model Organism
"brain lipid peroxidation could be documented as a result of exposure to CO at a concentration sufficient to cause unconsciousness."
Rat data support brain lipid peroxidation as a downstream consequence of CO exposure.
PMID:15342916 SUPPORT Model Organism
"CO poisoning also causes adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade."
Supports myelin basic protein adduct formation from lipid peroxidation initiating an immunological cascade.
Immune-mediated neuroinflammation
Chemically modified myelin basic protein becomes antigenic, provoking an adaptive immune response with macrophage and CD4+ lymphocyte influx and microglial activation that drives delayed central nervous system injury.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
adaptive immune response GO:0002250 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased adaptive immune response (GO:0002250). GO:0002250 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Delayed demyelination The adaptive immune response against modified myelin basic protein drives demyelination.
Show evidence (1 reference)
PMID:15342916 SUPPORT Model Organism
"Immunohistochemical evidence of degraded MBP occurs in brain over days, along with influx of macrophages and CD-4 lymphocytes."
Supports progressive immune-mediated myelin degradation with macrophage and CD4 lymphocyte influx.
Cerebral hypoxic-ischemic injury
Acute hypoxia preferentially injures metabolically demanding regions of the brain, including the basal ganglia (especially the globus pallidus) and deep white matter, producing acute encephalopathy and a substrate for later parkinsonism and cognitive dysfunction.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
positive regulation of neuron apoptotic process GO:0043525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of neuron apoptotic process (GO:0043525). GO:0043525 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Delayed neuronal injury Acute ischemic injury and ongoing oxidative-inflammatory injury converge on delayed neuronal injury.
Show evidence (2 references)
PMID:26563790 SUPPORT Other
"White-matter damage in the centrum semiovale and periventricular area and abnormalities in the globus pallidus are most commonly seen on MRI following CO exposure."
Supports the characteristic globus pallidus and white-matter localization of CO brain injury.
PMID:16537269 SUPPORT Human Clinical
"Carbon monoxide (CO) is the most common cause of poisoning and may result in basal ganglia lesions."
Human cohort/literature review supports basal ganglia lesions as a consequence of CO poisoning.
Delayed demyelination
Days to weeks after acute poisoning, immune-mediated demyelination of cerebral white matter produces the leukoencephalopathy characteristic of delayed neurological sequelae.
oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
myelination GO:0042552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Delayed neuronal injury White-matter demyelination contributes to delayed neuronal dysfunction and injury.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy."
Supports delayed white-matter (demyelinating) injury demonstrated on imaging.
Delayed neuronal injury
Immune-mediated and hypoxic-ischemic injury converge on neuronal loss, particularly in basal ganglia and hippocampus, producing the delayed neuropsychiatric sequelae of cognitive impairment, memory loss, and parkinsonism.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:15342916 SUPPORT Model Organism
"CO poisoning causes a decrement in learning that is not observed in immunologically tolerant rats."
Rat data link the immune-mediated injury to a functional learning deficit, the model correlate of delayed neuronal injury.
Myocardial ischemic injury
Reduced oxygen delivery, direct binding of CO to myoglobin, and mitochondrial dysfunction impair cardiac oxygen supply and utilization, producing myocardial stunning, ischemia, left ventricular dysfunction, and arrhythmia; myocardial injury predicts increased short- and long-term mortality.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cellular response to hypoxia GO:0071456 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to hypoxia (GO:0071456). GO:0071456 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:24518173 SUPPORT Other
"Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias."
Supports the myocardial injury phenotype (stunning, LV dysfunction, arrhythmia) of CO poisoning.
PMID:24518173 SUPPORT Other
"Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality."
Supports the prognostic significance of CO-related myocardial injury.
✶

Histopathology

1
Bilateral globus pallidus lesions
Neuroimaging and pathology in CO poisoning characteristically show bilateral, symmetric lesions of the globus pallidus and diffuse white-matter injury, the signature central-nervous-system lesion of the disease.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"White-matter damage in the centrum semiovale and periventricular area and abnormalities in the globus pallidus are most commonly seen on MRI following CO exposure."
Supports the globus pallidus and white-matter lesions as the characteristic imaging/pathology finding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Carbon Monoxide Poisoning Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Cardiovascular 2
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"COHb levels between 30% and 70% lead to loss of consciousness and eventually death."
Supports loss of consciousness/syncope as a marker of severe poisoning.
Myocardial injury OCCASIONAL Myocardial infarction HP:0001658 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is myocardial infarction (HP:0001658). HP:0001658 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction."
Supports myocardial injury and cardiac dysfunction in roughly one-third of moderate-to-severe cases. The OCCASIONAL band departs downward from that figure deliberately: the one-third denominator is the moderate-to-severely poisoned subgroup, not all CO-poisoned patients, and that subgroup is a minority of presentations, so the share of the whole disease population falls in the OCCASIONAL range (5-29%) rather than FREQUENT (30-79%).
Digestive 1
Nausea and vomiting HP:0002017 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is nausea and vomiting (HP:0002017). HP:0002017 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35461624 SUPPORT Other
"Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
Supports nausea and vomiting as clinical effects of CO poisoning.
Ear 1
Dizziness Vertigo HP:0002321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is dizziness, annotated with Vertigo (HP:0002321). HP:0002321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"The initial symptoms with CO exposure when COHb is 15-30% are nonspecific, namely, headache, dizziness, nausea, fatigue, and impaired manual dexterity."
Supports dizziness as a common early symptom of CO exposure.
Nervous System 7
Headache FREQUENT HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"The initial symptoms with CO exposure when COHb is 15-30% are nonspecific, namely, headache, dizziness, nausea, fatigue, and impaired manual dexterity."
Supports headache as an initial symptom of CO exposure (the D2P association). The snippet carries no frequency content, so the FREQUENT band is a documented clinical estimate consistent with headache being listed first among the nonspecific initial symptoms (docs/frequency-evidence-guidelines.md, Pattern D) rather than a value extracted from the citation.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35461624 SUPPORT Other
"Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
Supports seizures as a clinical effect of severe CO poisoning.
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%."
Supports coma at the severe end of the CO poisoning clinical spectrum.
Confusion HP:0001289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is confusion / altered mental status, annotated with Confusion (HP:0001289). HP:0001289 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32015960 SUPPORT Other
"Since behavioral disorders such as agitation, confusion and hallucination are sometimes observed"
Supports confusion/altered mental status as an acute neurobehavioral manifestation of CO poisoning.
Cognitive impairment FREQUENT HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction."
Supports long-term neurocognitive deficits in a substantial fraction of patients. The reported 15-40% range straddles the OCCASIONAL (5-29%) and FREQUENT (30-79%) boundary; FREQUENT is banded on the upper end of the range, consistent with the cited review treating long-term neurocognitive deficit as a hallmark sequela rather than an uncommon outcome. The lower end of the reported range would band as OCCASIONAL.
Memory impairment HP:0002354 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is memory impairment (HP:0002354). HP:0002354 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
Supports memory loss as a delayed neuropsychiatric sequela of CO poisoning.
Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
Supports parkinsonian features as a delayed neuropsychiatric sequela of CO poisoning.
Respiratory 1
Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24518173 SUPPORT Other
"It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death."
Supports respiratory failure at the severe end of the CO poisoning spectrum.
Constitutional 2
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24518173 SUPPORT Other
"It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death."
Supports fatigue as an early manifestation within the CO poisoning symptom spectrum.
Chest pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"individuals with ischemic heart disease may experience chest pain and decreased exercise duration at COHb levels between 1% and 9%."
Supports chest pain from myocardial ischemia at low COHb levels in susceptible individuals.
💊

Medical Actions

3
Normobaric high-flow oxygen
Action: supplemental oxygen therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supplemental oxygen therapy, annotated with Oxygen Therapy (NCIT:C94624). NCIT:C94624 is a clinical intervention from the NCI Thesaurus. Ontology label: Oxygen Therapy NCIT:C94624
High-concentration oxygen delivered at normal atmospheric pressure is the first-line treatment. It accelerates dissociation of CO from hemoglobin, shortening the elimination half-life of carboxyhemoglobin from several hours on room air to roughly 60-90 minutes. It is usually delivered via a non-rebreather mask.
Mechanism Target:
INHIBITS Carboxyhemoglobin formation — Oxygen competes CO off hemoglobin and speeds carboxyhemoglobin elimination.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"The cornerstone for treatment for CO poisoning is 100% oxygen using a tight-fitting mask for greater than 6 hours."
Supports 100% oxygen therapy as the intervention that accelerates carboxyhemoglobin clearance.
Show evidence (2 references)
PMID:34053712 SUPPORT Other
"The primary treatment for patients with carbon monoxide poisoning is supplemental oxygen, usually delivered via a nonrebreather mask."
Supports supplemental (normobaric) oxygen as the primary treatment.
PMID:26563790 SUPPORT Other
"The cornerstone for treatment for CO poisoning is 100% oxygen using a tight-fitting mask for greater than 6 hours."
Supports 100% oxygen as the cornerstone of therapy.
Hyperbaric oxygen therapy
Action: hyperbaric oxygen therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hyperbaric oxygen therapy (NCIT:C38065). NCIT:C38065 is a clinical intervention from the NCI Thesaurus. Ontology label: Hyperbaric Oxygen Therapy NCIT:C38065
Hyperbaric oxygen delivered at greater than atmospheric pressure further accelerates carboxyhemoglobin elimination, increases dissolved plasma oxygen, and is proposed to reduce delayed neurological sequelae. It is considered for severe poisoning, loss of consciousness, neurological deficits, myocardial ischemia, or pregnancy, though its exact indications remain debated.
Mechanism Target:
INHIBITS Carboxyhemoglobin formation — Hyperbaric pressure maximally accelerates CO displacement from hemoglobin.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"The indications for treatment with hyperbaric oxygen to decrease the half-life of COHb remain controversial."
Supports hyperbaric oxygen acting to decrease the carboxyhemoglobin half-life.
INHIBITS Platelet-neutrophil activation — Hyperbaric oxygen inhibits CD18-mediated neutrophil adhesion, interrupting the oxidative-inflammatory cascade proposed to drive delayed neurological injury.
Show evidence (1 reference)
PMID:7710151 SUPPORT Human Clinical
"HBO treatment decreased the incidence of DNS after CO poisoning."
Supports hyperbaric oxygen reducing delayed neurological sequelae, the clinical outcome of the neuroinflammatory cascade.
Show evidence (3 references)
PMID:12362006 SUPPORT Human Clinical
"Cognitive sequelae at six weeks were less frequent in the hyperbaric-oxygen group"
Randomized-trial evidence that hyperbaric oxygen reduces cognitive sequelae.
PMID:7710151 SUPPORT Human Clinical
"HBO treatment decreased the incidence of DNS after CO poisoning."
Randomized-trial evidence that hyperbaric oxygen reduces delayed neurological sequelae.
PMID:34053712 SUPPORT Other
"Hyperbaric oxygen can also be used, but the exact indications are controversial."
Notes that hyperbaric oxygen is used but its indications remain controversial.
Exposure removal and supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Immediate removal from the CO source and supportive care, including airway management, cardiac monitoring, and hemodynamic support, are essential first steps.
Mechanism Target:
INHIBITS Carboxyhemoglobin formation — Removing the patient from the source halts ongoing CO uptake.
🌍

Environmental Factors

5
Faulty heating appliances
exposure to carbon monoxide ECTO:0000207 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to carbon monoxide (ECTO:0000207). ECTO:0000207 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Malfunctioning or improperly ventilated furnaces, boilers, water heaters, and space heaters are a leading source of unintentional CO poisoning, especially in cold weather.
Show evidence (1 reference)
PMID:32015960 SUPPORT Other
"Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
Supports improperly maintained heating systems as a common exposure source.
Mechanism Target:
TRIGGERS Carboxyhemoglobin formation — A malfunctioning or unvented appliance releases carbon monoxide into occupied indoor air, where it is inhaled and binds hemoglobin.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the step this source feeds; the four combustion sources differ in where the CO comes from, not in how it is taken up.
Fire smoke inhalation
exposure to carbon monoxide ECTO:0000207 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to carbon monoxide (ECTO:0000207). ECTO:0000207 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Smoke from structure fires contains high concentrations of CO and is a major cause of CO poisoning in fire victims.
Show evidence (1 reference)
PMID:32015960 SUPPORT Other
"Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
Supports smoke from fires as a common exposure source.
Mechanism Target:
TRIGGERS Carboxyhemoglobin formation — Structure-fire smoke carries high concentrations of carbon monoxide, which victims inhale directly at the scene.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the step this source feeds; the four combustion sources differ in where the CO comes from, not in how it is taken up.
Motor vehicle exhaust
exposure to carbon monoxide ECTO:0000207 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to carbon monoxide (ECTO:0000207). ECTO:0000207 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology. gasoline exhaust ENVO:03510009 Environment Ontology (ENVO) Relation: this environmental factor occurs in this environment This environmental factor occurs in gasoline exhaust (ENVO:03510009). ENVO:03510009 is an environment from the Environment Ontology.
Engine exhaust from motor vehicles, including running vehicles in enclosed spaces, is a common source of both accidental and intentional CO poisoning.
Show evidence (1 reference)
PMID:32015960 SUPPORT Other
"Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
Supports vehicle exhaust as a common exposure source.
Mechanism Target:
TRIGGERS Carboxyhemoglobin formation — Engine exhaust in an enclosed space accumulates carbon monoxide to inhaled concentrations far above those the ambient air would give.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the step this source feeds; the four combustion sources differ in where the CO comes from, not in how it is taken up.
Portable generators and indoor combustion
exposure to carbon monoxide ECTO:0000207 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to carbon monoxide (ECTO:0000207). ECTO:0000207 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Portable gasoline generators, charcoal grills, and other fuel-burning devices used indoors or in poorly ventilated spaces are important sources of CO poisoning, notably during power outages after storms.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"gasoline-powered generators that are not in correct locations"
Supports improperly located gasoline-powered generators as an exposure source.
Mechanism Target:
TRIGGERS Carboxyhemoglobin formation — Fuel-burning devices run indoors or in poorly ventilated spaces vent carbon monoxide into breathing air rather than outdoors.
Show evidence (1 reference)
PMID:26563790 SUPPORT Other
"Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the step this source feeds; the four combustion sources differ in where the CO comes from, not in how it is taken up.
Methylene chloride exposure
exposure to carbon monoxide ECTO:0000207 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to carbon monoxide (ECTO:0000207). ECTO:0000207 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Inhaled methylene chloride (dichloromethane), used in paint strippers and solvents, is metabolized in the liver to carbon monoxide, raising carboxyhemoglobin; high-dose exposure can produce delayed and prolonged CO toxicity from this endogenous source.
Show evidence (1 reference)
PMID:8925320 SUPPORT Human Clinical
"Part of the rationale for lowering the standard is a concern over potentially adverse cardiac effects secondary to elevated carboxyhemoglobin (COHb) levels as a by-product of methylene chloride metabolism."
Supports methylene chloride metabolism to carbon monoxide raising carboxyhemoglobin.
Mechanism Target:
TRIGGERS Carboxyhemoglobin formation — Unlike the combustion sources, no carbon monoxide is inhaled here: the inhaled solvent is metabolized by hepatic CYP2E1 to carbon monoxide, so the carboxyhemoglobin arises from an endogenous source. That extra step is why the rise is delayed and prolonged relative to a direct CO exposure.
Show evidence (1 reference)
PMID:8925320 SUPPORT Human Clinical
"Part of the rationale for lowering the standard is a concern over potentially adverse cardiac effects secondary to elevated carboxyhemoglobin (COHb) levels as a by-product of methylene chloride metabolism."
Names carboxyhemoglobin as a by-product of methylene chloride metabolism, establishing metabolism as the intermediate between the solvent exposure and the carboxyhemoglobin it produces.
🔬

Biochemical Markers

2
Carboxyhemoglobin (INCREASED)
Show evidence (1 reference)
PMID:34053712 SUPPORT Other
"When there is concern for possible carbon monoxide poisoning, the diagnosis can be made via blood co-oximetry."
Supports blood carboxyhemoglobin by co-oximetry as the confirmatory biomarker.
Lactate (INCREASED)
📊

Prevalence

1
United States
Annual Incidence 15.1 per 100,000 Common
Approximately 50,000 people affected per year in the United States (normalized to the US population as roughly 15 per 100,000 per year). Modeled as an annual incidence of acute poisoning, not a chronic point prevalence.
Show evidence (1 reference)
PMID:27753502 SUPPORT Other
"Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States."
Provides the US annual burden used to derive the normalized incidence rate.
📊

Related Datasets

1
Gene expression in rat striatum following carbon monoxide poisoning and hypoxic hypoxia geo:GSE94780
We have proposed the existence of a threshold for brain damage, in terms of hydroxyl radical production in rat striatum, between poisoning of carbon monoxide (CO) at 1000 ppm and 3000 ppm, where blood CO-hemoglobin levels reach approximately 50% and over 70%, respectively. To search for factors involved in brain damage, we examined the effects of air, 1000 ppm CO, 3000 ppm CO and 5% O2 (hypoxic conditions comparable with those by 3000 ppm CO) on gene expression in rat striatum, using microarray analysis.
rat MICROARRAY n=12
Identified by GEO DataSets index search for Carbon Monoxide Poisoning (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Carbon Monoxide Poisoning
creation_date: "2026-07-09T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Environmental Health Disorder
- Gas Poisoning
synonyms:
- CO poisoning
- carbon monoxide toxicity
- carbon monoxide intoxication
description: >-
  Carbon monoxide poisoning is a toxic condition caused by inhalation of carbon
  monoxide (CO), a colorless, odorless gas produced by incomplete combustion of
  carbon-containing fuels. Common sources include faulty furnaces and heaters,
  fire smoke, motor vehicle exhaust, portable generators, indoor charcoal
  burning, and the metabolic conversion of inhaled methylene chloride (paint
  stripper). CO produces tissue hypoxia through several converging mechanisms:
  it binds hemoglobin with roughly 200 times the affinity of oxygen to form
  carboxyhemoglobin, reducing the oxygen-carrying capacity of blood and shifting
  the oxyhemoglobin dissociation curve leftward so that less oxygen is released
  to tissues; it binds and inhibits mitochondrial cytochrome c oxidase, causing
  histotoxic (cellular) hypoxia; and it triggers an oxidative and inflammatory
  cascade of platelet-neutrophil activation, reactive oxygen species, and lipid
  peroxidation that drives delayed neurological injury. The brain and heart, as
  the most oxygen-dependent organs, are most vulnerable. Clinical features range
  from headache, dizziness, nausea, and confusion to syncope, seizures,
  myocardial injury, coma, and death; a subset of survivors develop delayed
  neuropsychiatric sequelae. Treatment centers on high-flow normobaric oxygen
  and, for severe poisoning, hyperbaric oxygen therapy.
disease_term:
  preferred_term: carbon monoxide poisoning
  term:
    id: MONDO:0800373
    label: carbon monoxide poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800373
      label: carbon monoxide poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this carbon monoxide poisoning entry.
definitions:
- name: Clinical case definition for carbon monoxide poisoning
  definition_type: CASE_DEFINITION
  description: >-
    Carbon monoxide poisoning is a toxic-inhalation syndrome in which carbon
    monoxide binds hemoglobin and other heme proteins, producing tissue hypoxia
    and oxidative stress, confirmed by an elevated blood carboxyhemoglobin level
    in a compatible clinical and exposure context.
  scope: Disease-level clinical framing across acute poisoning and delayed sequelae
  evidence:
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Carbon monoxide binds to hemoglobin and other heme molecules, causing tissue hypoxia and oxidative stress."
    explanation: Supports the core disease framing as heme-protein binding producing tissue hypoxia and oxidative stress.
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When there is concern for possible carbon monoxide poisoning, the diagnosis can be made via blood co-oximetry."
    explanation: Supports blood co-oximetry (carboxyhemoglobin measurement) as the confirmatory diagnostic anchor.
parents:
- gas poisoning
prevalence:
- population: United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: COMMON
  rate_per_100000: 15.1
  notes: >-
    Approximately 50,000 people affected per year in the United States
    (normalized to the US population as roughly 15 per 100,000 per year).
    Modeled as an annual incidence of acute poisoning, not a chronic point
    prevalence.
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States."
    explanation: Provides the US annual burden used to derive the normalized incidence rate.
has_subtypes:
- name: Acute CO Poisoning
  description: >-
    Acute carbon monoxide poisoning follows a high-level exposure and presents
    with headache, dizziness, altered mental status, syncope, seizures,
    myocardial injury, coma, or death depending on the carboxyhemoglobin level
    and duration of exposure.
  evidence:
  - reference: PMID:35461624
    reference_title: "Carbon Monoxide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
    explanation: Supports the acute multisystem presentation of carbon monoxide poisoning.
- name: Delayed Neuropsychiatric Sequelae
  display_name: Delayed Neurological Sequelae (DNS)
  description: >-
    A subset of survivors of acute CO poisoning develop delayed neuropsychiatric
    sequelae days to weeks after apparent recovery, including cognitive
    impairment, memory loss, parkinsonism, and behavioral changes, associated
    with demyelination and basal-ganglia (globus pallidus) injury.
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
    explanation: Directly supports the delayed neuropsychiatric sequelae subtype and its demyelinating, biphasic character.
pathophysiology:
- name: Carboxyhemoglobin formation
  description: >-
    Inhaled carbon monoxide binds hemoglobin at the same heme iron sites used by
    oxygen, with an affinity roughly 200 times that of oxygen, forming
    carboxyhemoglobin (COHb). This reduces the oxygen-carrying capacity of blood.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: oxygen transport
    modifier: DECREASED
    term:
      id: GO:0015671
      label: oxygen transport
  downstream:
  - target: Impaired tissue oxygen delivery
    description: Reduced oxygen-carrying capacity and leftward-shifted dissociation curve limit oxygen delivery and offloading to tissues.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
      explanation: Links carboxyhemoglobin formation to reduced oxygen delivery and tissue hypoxia.
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
    explanation: Directly supports carboxyhemoglobin formation with ~200x oxygen affinity and reduced oxygen-carrying capacity.
- name: Leftward shift of the oxyhemoglobin dissociation curve
  description: >-
    Binding of CO to one or more heme sites increases the oxygen affinity of the
    remaining sites on the hemoglobin tetramer, shifting the oxyhemoglobin
    dissociation curve to the left so that bound oxygen is released less readily
    at the tissues, worsening tissue hypoxia beyond what the reduced
    oxygen-carrying capacity alone would cause.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Impaired tissue oxygen delivery
    description: The impaired oxygen release compounds the hypoxic insult.
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "decreased release of oxygen to tissues leading to tissue hypoxia"
    explanation: Supports impaired oxygen offloading (the functional consequence of the leftward shift) as a driver of tissue hypoxia.
- name: Impaired tissue oxygen delivery
  description: >-
    The combination of reduced carboxyhemoglobin-limited oxygen carriage and
    impaired oxygen offloading produces systemic tissue hypoxia, most severely
    affecting the oxygen-dependent brain and heart.
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  downstream:
  - target: Cerebral hypoxic-ischemic injury
    description: Hypoxia in the brain produces neuronal injury and encephalopathy.
  - target: Myocardial ischemic injury
    description: Hypoxia in the heart produces myocardial ischemia and injury.
  evidence:
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Carbon monoxide binds to hemoglobin and other heme molecules, causing tissue hypoxia and oxidative stress."
    explanation: Supports systemic tissue hypoxia as the central consequence of carbon monoxide binding.
- name: Cytochrome c oxidase inhibition
  description: >-
    Carbon monoxide binds the ferrous iron of mitochondrial cytochrome c oxidase
    (Complex IV of the electron transport chain), directly inhibiting oxidative
    phosphorylation. This produces histotoxic (cellular) hypoxia independent of
    oxygen delivery, impairing ATP generation even where oxygen is present, and
    helps explain the persistence of symptoms after carboxyhemoglobin normalizes.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
  downstream:
  - target: Cellular energy failure
    description: Inhibition of oxidative phosphorylation depletes cellular ATP.
  - target: Oxidative stress and free radical generation
    description: Mitochondrial dysfunction generates reactive oxygen species and free radicals.
  evidence:
  - reference: PMID:9584335
    reference_title: "Mitochondrial cytochrome c oxidase inhibition during acute carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytochrome c oxidase (complex IV) activity showed a 76% inhibition compared to controls during acute poisoning (P < 0.01) and 48% at day 3 (P < 0.05)."
    explanation: Direct human evidence of marked cytochrome c oxidase inhibition during acute CO poisoning.
  - reference: PMID:9584335
    reference_title: "Mitochondrial cytochrome c oxidase inhibition during acute carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that mitochondrial cytochrome c oxidase is also a target site in human acute CO poisoning, and its extended and generalized inhibition could explain the persistence of different symptoms after the normalization of HbCO levels."
    explanation: Supports cytochrome c oxidase as a COHb-independent target explaining persistent symptoms.
- name: Cellular energy failure
  description: >-
    Inhibition of oxidative phosphorylation, together with tissue hypoxia,
    depletes cellular ATP and forces a shift to anaerobic metabolism, producing
    lactic acidosis and cellular energy failure across multiple organs.
  biological_processes:
  - preferred_term: aerobic respiration
    modifier: DECREASED
    term:
      id: GO:0009060
      label: aerobic respiration
  downstream:
  - target: Xanthine oxidase-mediated reactive oxygen species generation
    description: Energy deprivation and purine catabolism drive conversion of xanthine dehydrogenase to reactive-oxygen-species-generating xanthine oxidase.
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart."
    explanation: Supports impaired cellular energy utilization as a core downstream effect of CO.
- name: Oxidative stress and free radical generation
  description: >-
    Mitochondrial dysfunction and the displacement of nitric oxide from
    hemoproteins generate reactive oxygen species, free radicals, and
    nitric-oxide-derived species, producing oxidative injury across multiple
    organs.
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Platelet-neutrophil activation
    description: Nitric-oxide displacement and oxidative changes promote intravascular platelet-neutrophil activation.
  - target: Brain lipid peroxidation
    description: Reactive oxygen species peroxidize brain membrane and myelin lipids.
  evidence:
  - reference: PMID:24773392
    reference_title: "The role of reactive oxygen species and oxidative stress in carbon monoxide toxicity: an in-depth analysis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One of the current hypotheses with regard to the molecular mechanism of CO poisoning is the oxidative injury induced by reactive oxygen species, free radicals, and neuronal nitric oxide."
    explanation: Supports oxidative injury by reactive oxygen species, free radicals, and nitric oxide as a core molecular mechanism.
- name: Platelet-neutrophil activation
  description: >-
    Acute CO poisoning triggers intravascular platelet-neutrophil aggregation and
    neutrophil activation with myeloperoxidase release, initiating a
    reperfusion-injury-like oxidative cascade in the cerebral microvasculature.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: platelet aggregation
    modifier: INCREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Xanthine oxidase-mediated reactive oxygen species generation
    description: Neutrophil adherence to the cerebral microvasculature drives conversion of xanthine dehydrogenase to xanthine oxidase.
    evidence:
    - reference: PMID:8248931
      reference_title: "Leukocytes in carbon monoxide-mediated brain oxidative injury."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Neither of these groups of animals exhibited the biochemical changes observed in the brains of sham-treated rats: conversion of xanthine dehydrogenase (XD) to sulfhydryl-irreversible xanthine oxidase (XO), and lipid peroxidation, at 90 min following CO poisoning."
      explanation: Blocking leukocyte adherence prevents the xanthine oxidase conversion and lipid peroxidation, linking neutrophil activation to the oxidative cascade.
  evidence:
  - reference: PMID:16931637
    reference_title: "Intravascular neutrophil activation due to carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute CO poisoning causes intravascular neutrophil activation due to interactions with platelets."
    explanation: Directly supports platelet-driven intravascular neutrophil activation in CO poisoning.
  - reference: PMID:16931637
    reference_title: "Intravascular neutrophil activation due to carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet-neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning."
    explanation: Human patient data confirm platelet-neutrophil aggregates and myeloperoxidase release in confirmed CO poisoning.
- name: Xanthine oxidase-mediated reactive oxygen species generation
  description: >-
    Energy deprivation and neutrophil-driven signaling convert xanthine
    dehydrogenase to xanthine oxidase, which generates reactive oxygen species
    and drives a postischemic reperfusion-like oxidative injury in the brain.
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  downstream:
  - target: Brain lipid peroxidation
    description: Xanthine oxidase-derived reactive oxygen species peroxidize brain lipids.
    evidence:
    - reference: PMID:1447108
      reference_title: "Dehydrogenase conversion to oxidase and lipid peroxidation in brain after carbon monoxide poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results are consistent with the view that CO-mediated brain injury is a type of postischemic reperfusion phenomenon and indicate that xanthine oxidase-derived reactive oxygen species are responsible for lipid peroxidation."
      explanation: Rat data link xanthine oxidase-derived reactive oxygen species to brain lipid peroxidation.
  evidence:
  - reference: PMID:1447108
    reference_title: "Dehydrogenase conversion to oxidase and lipid peroxidation in brain after carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The conversion of xanthine dehydrogenase to xanthine oxidase and lipid peroxidation were measured in brain from carbon monoxide- (CO) poisoned rats."
    explanation: Supports xanthine dehydrogenase-to-oxidase conversion generating the oxidative injury.
  - reference: PMID:24773392
    reference_title: "The role of reactive oxygen species and oxidative stress in carbon monoxide toxicity: an in-depth analysis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The underlying mechanism of the central nervous system (CNS) injury after acute carbon monoxide (CO) poisoning is interlaced with multiple factors including apoptosis, abnormal inflammatory responses, hypoxia, and ischemia/reperfusion-like problems."
    explanation: Supports the ischemia/reperfusion-like oxidative character of the injury.
- name: Brain lipid peroxidation
  description: >-
    Reactive oxygen species peroxidize brain membrane and myelin lipids.
    Peroxidation products such as malondialdehyde form adducts with myelin basic
    protein, generating the antigenic modification that initiates delayed injury.
  biological_processes:
  - preferred_term: lipid oxidation
    modifier: INCREASED
    term:
      id: GO:0034440
      label: lipid oxidation
  downstream:
  - target: Immune-mediated neuroinflammation
    description: Adducts between peroxidation products and myelin basic protein become antigenic and initiate an immune response.
  evidence:
  - reference: PMID:2341364
    reference_title: "Carbon monoxide-mediated brain lipid peroxidation in the rat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "brain lipid peroxidation could be documented as a result of exposure to CO at a concentration sufficient to cause unconsciousness."
    explanation: Rat data support brain lipid peroxidation as a downstream consequence of CO exposure.
  - reference: PMID:15342916
    reference_title: "Delayed neuropathology after carbon monoxide poisoning is immune-mediated."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CO poisoning also causes adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade."
    explanation: Supports myelin basic protein adduct formation from lipid peroxidation initiating an immunological cascade.
- name: Immune-mediated neuroinflammation
  description: >-
    Chemically modified myelin basic protein becomes antigenic, provoking an
    adaptive immune response with macrophage and CD4+ lymphocyte influx and
    microglial activation that drives delayed central nervous system injury.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: adaptive immune response
    modifier: INCREASED
    term:
      id: GO:0002250
      label: adaptive immune response
  downstream:
  - target: Delayed demyelination
    description: The adaptive immune response against modified myelin basic protein drives demyelination.
    evidence:
    - reference: PMID:15342916
      reference_title: "Delayed neuropathology after carbon monoxide poisoning is immune-mediated."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP."
      explanation: Rat data establish the adaptive immune response to modified myelin basic protein as the cause of delayed neuropathology.
  evidence:
  - reference: PMID:15342916
    reference_title: "Delayed neuropathology after carbon monoxide poisoning is immune-mediated."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunohistochemical evidence of degraded MBP occurs in brain over days, along with influx of macrophages and CD-4 lymphocytes."
    explanation: Supports progressive immune-mediated myelin degradation with macrophage and CD4 lymphocyte influx.
- name: Cerebral hypoxic-ischemic injury
  description: >-
    Acute hypoxia preferentially injures metabolically demanding regions of the
    brain, including the basal ganglia (especially the globus pallidus) and deep
    white matter, producing acute encephalopathy and a substrate for later
    parkinsonism and cognitive dysfunction.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: positive regulation of neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0043525
      label: positive regulation of neuron apoptotic process
  downstream:
  - target: Delayed neuronal injury
    description: Acute ischemic injury and ongoing oxidative-inflammatory injury converge on delayed neuronal injury.
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "White-matter damage in the centrum semiovale and periventricular area and abnormalities in the globus pallidus are most commonly seen on MRI following CO exposure."
    explanation: Supports the characteristic globus pallidus and white-matter localization of CO brain injury.
  - reference: PMID:16537269
    reference_title: "Basal ganglia lesions following carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carbon monoxide (CO) is the most common cause of poisoning and may result in basal ganglia lesions."
    explanation: Human cohort/literature review supports basal ganglia lesions as a consequence of CO poisoning.
- name: Delayed demyelination
  description: >-
    Days to weeks after acute poisoning, immune-mediated demyelination of
    cerebral white matter produces the leukoencephalopathy characteristic of
    delayed neurological sequelae.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    modifier: ABNORMAL
    term:
      id: GO:0042552
      label: myelination
  downstream:
  - target: Delayed neuronal injury
    description: White-matter demyelination contributes to delayed neuronal dysfunction and injury.
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy."
    explanation: Supports delayed white-matter (demyelinating) injury demonstrated on imaging.
- name: Delayed neuronal injury
  description: >-
    Immune-mediated and hypoxic-ischemic injury converge on neuronal loss,
    particularly in basal ganglia and hippocampus, producing the delayed
    neuropsychiatric sequelae of cognitive impairment, memory loss, and
    parkinsonism.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:15342916
    reference_title: "Delayed neuropathology after carbon monoxide poisoning is immune-mediated."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CO poisoning causes a decrement in learning that is not observed in immunologically tolerant rats."
    explanation: Rat data link the immune-mediated injury to a functional learning deficit, the model correlate of delayed neuronal injury.
- name: Myocardial ischemic injury
  description: >-
    Reduced oxygen delivery, direct binding of CO to myoglobin, and mitochondrial
    dysfunction impair cardiac oxygen supply and utilization, producing
    myocardial stunning, ischemia, left ventricular dysfunction, and arrhythmia;
    myocardial injury predicts increased short- and long-term mortality.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  evidence:
  - reference: PMID:24518173
    reference_title: "Cardiovascular Abnormalities in Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias."
    explanation: Supports the myocardial injury phenotype (stunning, LV dysfunction, arrhythmia) of CO poisoning.
  - reference: PMID:24518173
    reference_title: "Cardiovascular Abnormalities in Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality."
    explanation: Supports the prognostic significance of CO-related myocardial injury.
phenotypes:
- category: Nervous System
  name: Headache
  frequency: FREQUENT
  description: >-
    Headache is the most common presenting symptom of carbon monoxide poisoning,
    reflecting cerebral hypoxia.
  phenotype_term:
    preferred_term: headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The initial symptoms with CO exposure when COHb is 15-30% are nonspecific, namely, headache, dizziness, nausea, fatigue, and impaired manual dexterity."
    explanation: >-
      Supports headache as an initial symptom of CO exposure (the D2P
      association). The snippet carries no frequency content, so the FREQUENT
      band is a documented clinical estimate consistent with headache being
      listed first among the nonspecific initial symptoms
      (docs/frequency-evidence-guidelines.md, Pattern D) rather than a value
      extracted from the citation.
- category: Nervous System
  name: Dizziness
  description: >-
    Dizziness and lightheadedness are common early symptoms of CO exposure.
    Bound to HP:0002321 (Vertigo) as the closest available HPO term — HPO lacks
    a clean generic "dizziness/lightheadedness" concept, so this is a
    granularity approximation rather than an assertion of true vertigo.
  phenotype_term:
    preferred_term: dizziness
    term:
      id: HP:0002321
      label: Vertigo
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The initial symptoms with CO exposure when COHb is 15-30% are nonspecific, namely, headache, dizziness, nausea, fatigue, and impaired manual dexterity."
    explanation: Supports dizziness as a common early symptom of CO exposure.
- category: Gastrointestinal
  name: Nausea and vomiting
  description: >-
    Nausea and vomiting are common nonspecific symptoms of acute CO poisoning,
    often mistaken for gastroenteritis.
  phenotype_term:
    preferred_term: nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: PMID:35461624
    reference_title: "Carbon Monoxide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
    explanation: Supports nausea and vomiting as clinical effects of CO poisoning.
- category: Constitutional
  name: Fatigue
  description: >-
    Fatigue and malaise are common nonspecific manifestations of CO exposure.
  phenotype_term:
    preferred_term: fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:24518173
    reference_title: "Cardiovascular Abnormalities in Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death."
    explanation: Supports fatigue as an early manifestation within the CO poisoning symptom spectrum.
- category: Nervous System
  name: Syncope
  description: >-
    Loss of consciousness or syncope occurs with more severe exposure and is an
    indicator of significant poisoning.
  phenotype_term:
    preferred_term: syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COHb levels between 30% and 70% lead to loss of consciousness and eventually death."
    explanation: Supports loss of consciousness/syncope as a marker of severe poisoning.
- category: Nervous System
  name: Seizures
  description: >-
    Seizures can occur in severe acute CO poisoning.
  phenotype_term:
    preferred_term: seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35461624
    reference_title: "Carbon Monoxide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical effects can be diverse and include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias, and cardiac ischemia, and severe toxicity generally affects the nervous and cardiovascular systems."
    explanation: Supports seizures as a clinical effect of severe CO poisoning.
- category: Nervous System
  name: Coma
  description: >-
    Coma occurs in severe poisoning and portends risk of death or delayed
    neurological sequelae.
  phenotype_term:
    preferred_term: coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%."
    explanation: Supports coma at the severe end of the CO poisoning clinical spectrum.
- category: Nervous System
  name: Confusion
  description: >-
    Confusion and altered mental status are common acute neurobehavioral
    manifestations of CO poisoning, distinct from the persistent delayed
    cognitive impairment and from frank coma modeled separately.
  phenotype_term:
    preferred_term: confusion / altered mental status
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: PMID:32015960
    reference_title: "Carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since behavioral disorders such as agitation, confusion and hallucination are sometimes observed"
    explanation: Supports confusion/altered mental status as an acute neurobehavioral manifestation of CO poisoning.
- category: Nervous System
  name: Cognitive impairment
  frequency: FREQUENT
  description: >-
    Persistent or delayed cognitive impairment is a hallmark of delayed
    neuropsychiatric sequelae following CO poisoning, occurring in a substantial
    minority of patients.
  phenotype_term:
    preferred_term: cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction."
    explanation: >-
      Supports long-term neurocognitive deficits in a substantial fraction of
      patients. The reported 15-40% range straddles the OCCASIONAL (5-29%) and
      FREQUENT (30-79%) boundary; FREQUENT is banded on the upper end of the
      range, consistent with the cited review treating long-term neurocognitive
      deficit as a hallmark sequela rather than an uncommon outcome. The lower
      end of the reported range would band as OCCASIONAL.
- category: Nervous System
  name: Memory impairment
  description: >-
    Memory deficits are among the most frequent delayed neuropsychiatric
    sequelae after CO poisoning.
  phenotype_term:
    preferred_term: memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
    explanation: Supports memory loss as a delayed neuropsychiatric sequela of CO poisoning.
- category: Nervous System
  name: Parkinsonism
  description: >-
    Delayed parkinsonism and other movement disorders can follow CO poisoning,
    associated with basal-ganglia (globus pallidus) injury.
  phenotype_term:
    preferred_term: parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Following resolution of acute symptoms there may be a lucid interval of 2-40 days before the development of delayed neurologic sequelae (DNS), with diffuse demyelination in the brain accompanied by lethargy, behavior changes, forgetfulness, memory loss, and parkinsonian features."
    explanation: Supports parkinsonian features as a delayed neuropsychiatric sequela of CO poisoning.
- category: Cardiovascular
  name: Myocardial injury
  frequency: OCCASIONAL
  description: >-
    Myocardial ischemia and injury — including myocardial infarction, myocardial
    stunning, left ventricular dysfunction, and arrhythmia — occur in
    moderate-to-severe CO poisoning and predict worse outcomes.
  phenotype_term:
    preferred_term: myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:27753502
    reference_title: "Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction."
    explanation: >-
      Supports myocardial injury and cardiac dysfunction in roughly one-third of
      moderate-to-severe cases. The OCCASIONAL band departs downward from that
      figure deliberately: the one-third denominator is the moderate-to-severely
      poisoned subgroup, not all CO-poisoned patients, and that subgroup is a
      minority of presentations, so the share of the whole disease population
      falls in the OCCASIONAL range (5-29%) rather than FREQUENT (30-79%).
- category: Cardiovascular
  name: Chest pain
  description: >-
    Chest pain can accompany CO-induced myocardial ischemia, especially in
    individuals with underlying ischemic heart disease.
  phenotype_term:
    preferred_term: chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "individuals with ischemic heart disease may experience chest pain and decreased exercise duration at COHb levels between 1% and 9%."
    explanation: Supports chest pain from myocardial ischemia at low COHb levels in susceptible individuals.
- category: Respiratory
  name: Respiratory failure
  description: >-
    Severe CO poisoning can progress to respiratory failure, sometimes with
    noncardiogenic pulmonary edema.
  phenotype_term:
    preferred_term: respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:24518173
    reference_title: "Cardiovascular Abnormalities in Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death."
    explanation: Supports respiratory failure at the severe end of the CO poisoning spectrum.
histopathology:
- name: Bilateral globus pallidus lesions
  description: >-
    Neuroimaging and pathology in CO poisoning characteristically show bilateral,
    symmetric lesions of the globus pallidus and diffuse white-matter injury,
    the signature central-nervous-system lesion of the disease.
  context: Brain MRI/pathology following carbon monoxide poisoning
  diagnostic: false
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "White-matter damage in the centrum semiovale and periventricular area and abnormalities in the globus pallidus are most commonly seen on MRI following CO exposure."
    explanation: Supports the globus pallidus and white-matter lesions as the characteristic imaging/pathology finding.
  notes: >-
    Basal ganglia/globus pallidus lesions are characteristic but their reported
    prevalence varies widely and they may be less common than historically stated.
biochemical:
- name: Carboxyhemoglobin
  presence: INCREASED
  notes: >-
    Elevated blood carboxyhemoglobin (COHb), measured by co-oximetry, confirms
    CO exposure. Standard pulse oximetry cannot distinguish oxyhemoglobin from
    carboxyhemoglobin and reads falsely normal. COHb magnitude correlates
    imperfectly with clinical severity.
  evidence:
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When there is concern for possible carbon monoxide poisoning, the diagnosis can be made via blood co-oximetry."
    explanation: Supports blood carboxyhemoglobin by co-oximetry as the confirmatory biomarker.
- name: Lactate
  presence: INCREASED
  notes: >-
    Elevated serum lactate reflects impaired oxidative metabolism and metabolic
    acidosis, and is used as a marker of severity.
environmental:
- name: Faulty heating appliances
  exposure_term:
    preferred_term: exposure to carbon monoxide
    term:
      id: ECTO:0000207
      label: exposure to carbon monoxide
  description: >-
    Malfunctioning or improperly ventilated furnaces, boilers, water heaters,
    and space heaters are a leading source of unintentional CO poisoning,
    especially in cold weather.
  evidence:
  - reference: PMID:32015960
    reference_title: "Carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
    explanation: Supports improperly maintained heating systems as a common exposure source.
  influences_mechanisms:
  - target: Carboxyhemoglobin formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A malfunctioning or unvented appliance releases carbon monoxide into
      occupied indoor air, where it is inhaled and binds hemoglobin.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
      explanation: >-
        Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the
        step this source feeds; the four combustion sources differ in where the
        CO comes from, not in how it is taken up.
- name: Fire smoke inhalation
  exposure_term:
    preferred_term: exposure to carbon monoxide
    term:
      id: ECTO:0000207
      label: exposure to carbon monoxide
  description: >-
    Smoke from structure fires contains high concentrations of CO and is a major
    cause of CO poisoning in fire victims.
  evidence:
  - reference: PMID:32015960
    reference_title: "Carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
    explanation: Supports smoke from fires as a common exposure source.
  influences_mechanisms:
  - target: Carboxyhemoglobin formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Structure-fire smoke carries high concentrations of carbon monoxide,
      which victims inhale directly at the scene.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
      explanation: >-
        Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the
        step this source feeds; the four combustion sources differ in where the
        CO comes from, not in how it is taken up.
- name: Motor vehicle exhaust
  exposure_term:
    preferred_term: exposure to carbon monoxide
    term:
      id: ECTO:0000207
      label: exposure to carbon monoxide
  environment_context:
    preferred_term: gasoline exhaust
    term:
      id: ENVO:03510009
      label: gasoline exhaust
  description: >-
    Engine exhaust from motor vehicles, including running vehicles in enclosed
    spaces, is a common source of both accidental and intentional CO poisoning.
  evidence:
  - reference: PMID:32015960
    reference_title: "Carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vehicle exhaust, smoke from fires and improperly maintained heating systems are included as common sources."
    explanation: Supports vehicle exhaust as a common exposure source.
  influences_mechanisms:
  - target: Carboxyhemoglobin formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Engine exhaust in an enclosed space accumulates carbon monoxide to
      inhaled concentrations far above those the ambient air would give.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
      explanation: >-
        Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the
        step this source feeds; the four combustion sources differ in where the
        CO comes from, not in how it is taken up.
- name: Portable generators and indoor combustion
  exposure_term:
    preferred_term: exposure to carbon monoxide
    term:
      id: ECTO:0000207
      label: exposure to carbon monoxide
  description: >-
    Portable gasoline generators, charcoal grills, and other fuel-burning
    devices used indoors or in poorly ventilated spaces are important sources of
    CO poisoning, notably during power outages after storms.
  evidence:
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "gasoline-powered generators that are not in correct locations"
    explanation: Supports improperly located gasoline-powered generators as an exposure source.
  influences_mechanisms:
  - target: Carboxyhemoglobin formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fuel-burning devices run indoors or in poorly ventilated spaces vent
      carbon monoxide into breathing air rather than outdoors.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Once CO is inhaled it binds with hemoglobin to form carboxyhemoglobin (COHb) with an affinity 200 times greater than oxygen that leads to decreased oxygen-carrying capacity and decreased release of oxygen to tissues leading to tissue hypoxia."
      explanation: >-
        Inhaled carbon monoxide binds hemoglobin to form carboxyhemoglobin, the
        step this source feeds; the four combustion sources differ in where the
        CO comes from, not in how it is taken up.
- name: Methylene chloride exposure
  exposure_term:
    preferred_term: exposure to carbon monoxide
    term:
      id: ECTO:0000207
      label: exposure to carbon monoxide
  description: >-
    Inhaled methylene chloride (dichloromethane), used in paint strippers and
    solvents, is metabolized in the liver to carbon monoxide, raising
    carboxyhemoglobin; high-dose exposure can produce delayed and prolonged CO
    toxicity from this endogenous source.
  evidence:
  - reference: PMID:8925320
    reference_title: "Carboxyhemoglobin levels in methylene chloride-exposed employees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Part of the rationale for lowering the standard is a concern over potentially adverse cardiac effects secondary to elevated carboxyhemoglobin (COHb) levels as a by-product of methylene chloride metabolism."
    explanation: Supports methylene chloride metabolism to carbon monoxide raising carboxyhemoglobin.
  influences_mechanisms:
  - target: Carboxyhemoglobin formation
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Unlike the combustion sources, no carbon monoxide is inhaled here: the
      inhaled solvent is metabolized by hepatic CYP2E1 to carbon monoxide, so
      the carboxyhemoglobin arises from an endogenous source. That extra step is
      why the rise is delayed and prolonged relative to a direct CO exposure.
    evidence:
    - reference: PMID:8925320
      reference_title: "Carboxyhemoglobin levels in methylene chloride-exposed employees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Part of the rationale for lowering the standard is a concern over potentially adverse cardiac effects secondary to elevated carboxyhemoglobin (COHb) levels as a by-product of methylene chloride metabolism."
      explanation: >-
        Names carboxyhemoglobin as a by-product of methylene chloride
        metabolism, establishing metabolism as the intermediate between the
        solvent exposure and the carboxyhemoglobin it produces.
treatments:
- name: Normobaric high-flow oxygen
  description: >-
    High-concentration oxygen delivered at normal atmospheric pressure is the
    first-line treatment. It accelerates dissociation of CO from hemoglobin,
    shortening the elimination half-life of carboxyhemoglobin from several hours
    on room air to roughly 60-90 minutes. It is usually delivered via a
    non-rebreather mask.
  treatment_term:
    preferred_term: supplemental oxygen therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  target_mechanisms:
  - target: Carboxyhemoglobin formation
    treatment_effect: INHIBITS
    description: Oxygen competes CO off hemoglobin and speeds carboxyhemoglobin elimination.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The cornerstone for treatment for CO poisoning is 100% oxygen using a tight-fitting mask for greater than 6 hours."
      explanation: Supports 100% oxygen therapy as the intervention that accelerates carboxyhemoglobin clearance.
  evidence:
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The primary treatment for patients with carbon monoxide poisoning is supplemental oxygen, usually delivered via a nonrebreather mask."
    explanation: Supports supplemental (normobaric) oxygen as the primary treatment.
  - reference: PMID:26563790
    reference_title: "Carbon monoxide intoxication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The cornerstone for treatment for CO poisoning is 100% oxygen using a tight-fitting mask for greater than 6 hours."
    explanation: Supports 100% oxygen as the cornerstone of therapy.
- name: Hyperbaric oxygen therapy
  description: >-
    Hyperbaric oxygen delivered at greater than atmospheric pressure further
    accelerates carboxyhemoglobin elimination, increases dissolved plasma oxygen,
    and is proposed to reduce delayed neurological sequelae. It is considered for
    severe poisoning, loss of consciousness, neurological deficits, myocardial
    ischemia, or pregnancy, though its exact indications remain debated.
  treatment_term:
    preferred_term: hyperbaric oxygen therapy
    term:
      id: NCIT:C38065
      label: Hyperbaric Oxygen Therapy
  target_mechanisms:
  - target: Carboxyhemoglobin formation
    treatment_effect: INHIBITS
    description: Hyperbaric pressure maximally accelerates CO displacement from hemoglobin.
    evidence:
    - reference: PMID:26563790
      reference_title: "Carbon monoxide intoxication."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The indications for treatment with hyperbaric oxygen to decrease the half-life of COHb remain controversial."
      explanation: Supports hyperbaric oxygen acting to decrease the carboxyhemoglobin half-life.
  - target: Platelet-neutrophil activation
    treatment_effect: INHIBITS
    description: Hyperbaric oxygen inhibits CD18-mediated neutrophil adhesion, interrupting the oxidative-inflammatory cascade proposed to drive delayed neurological injury.
    evidence:
    - reference: PMID:7710151
      reference_title: "Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HBO treatment decreased the incidence of DNS after CO poisoning."
      explanation: Supports hyperbaric oxygen reducing delayed neurological sequelae, the clinical outcome of the neuroinflammatory cascade.
  evidence:
  - reference: PMID:12362006
    reference_title: "Hyperbaric oxygen for acute carbon monoxide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive sequelae at six weeks were less frequent in the hyperbaric-oxygen group"
    explanation: Randomized-trial evidence that hyperbaric oxygen reduces cognitive sequelae.
  - reference: PMID:7710151
    reference_title: "Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HBO treatment decreased the incidence of DNS after CO poisoning."
    explanation: Randomized-trial evidence that hyperbaric oxygen reduces delayed neurological sequelae.
  - reference: PMID:34053712
    reference_title: "Carbon Monoxide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hyperbaric oxygen can also be used, but the exact indications are controversial."
    explanation: Notes that hyperbaric oxygen is used but its indications remain controversial.
- name: Exposure removal and supportive care
  description: >-
    Immediate removal from the CO source and supportive care, including airway
    management, cardiac monitoring, and hemodynamic support, are essential first
    steps.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Carboxyhemoglobin formation
    treatment_effect: INHIBITS
    description: Removing the patient from the source halts ongoing CO uptake.
discussions:
- discussion_id: gap_co_hbo_patient_selection
  prompt: >-
    Which carbon monoxide poisoning patients derive a durable neurological
    benefit from hyperbaric oxygen therapy, and by what mechanism?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Hyperbaric oxygen therapy
  - pathophysiology#Delayed neuronal injury
  rationale: >-
    Randomized trials conflict. Thom 1995 and Weaver 2002 found that hyperbaric
    oxygen reduced delayed/cognitive sequelae, whereas Scheinkestel 1999 found
    no benefit and even worse outcomes on some measures, using a different
    protocol and patient mix. The subset of patients who benefit, the optimal
    timing and pressure, and whether the benefit comes from faster CO clearance
    or from interrupting the immune-mediated demyelination cascade remain
    unresolved.
  evidence:
  - reference: PMID:10092916
    reference_title: "Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "HBO patients had a worse outcome in the learning test at completion of treatment (P = 0.01 for all patients; P = 0.005 for severely poisoned patients)"
    explanation: Provides the negative-trial evidence that motivates the open question about which patients benefit from hyperbaric oxygen.
- discussion_id: mismatch_co_rodent_mbp_autoimmunity
  prompt: >-
    Does the rodent anti-myelin-basic-protein autoimmune mechanism of delayed
    neuropathology quantitatively explain human delayed neurological sequelae?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Immune-mediated neuroinflammation
  - pathophysiology#Delayed demyelination
  rationale: >-
    The adaptive-immune, anti-MBP mechanism of delayed CO neuropathology is
    established chiefly in rats, where immunological tolerance to MBP before
    poisoning abolishes the learning deficit, demonstrating causation. Its
    quantitative fidelity to human delayed neurological sequelae is not
    established; human delayed encephalopathy is heterogeneous and the
    contribution of MBP autoimmunity relative to hypoxic-ischemic injury in
    people remains an open translational question.
  evidence:
  - reference: PMID:15342916
    reference_title: "Delayed neuropathology after carbon monoxide poisoning is immune-mediated."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP."
    explanation: Establishes the immune-mediated mechanism in the rat model whose translational validity to humans is the open question.
datasets:
- accession: geo:GSE94780
  title: Gene expression in rat striatum following carbon monoxide poisoning and hypoxic hypoxia
  description: We have proposed the existence of a threshold for brain damage, in terms of hydroxyl radical production in rat striatum, between poisoning of carbon monoxide (CO) at 1000 ppm and 3000 ppm, where blood CO-hemoglobin levels reach approximately 50% and over 70%, respectively. To search for factors involved in brain damage, we examined the effects of air, 1000 ppm CO, 3000 ppm CO and 5% O2 (hypoxic conditions comparable with those by 3000 ppm CO) on gene expression in rat striatum, using microarray analysis.
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: MICROARRAY
  sample_count: 12
  notes: Identified by GEO DataSets index search for Carbon Monoxide Poisoning (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

Deep Research

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Claude Code ▸
Carbon Monoxide Poisoning — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-opus-4-8 28 citations 2026-07-09T18:17:52.033774

Carbon Monoxide Poisoning — Comprehensive Research Report

Prepared for: dismech disease knowledge base entry Category: Environmental (toxic gas exposure) Report date: 2026-07-09

Scope note: Carbon monoxide (CO) poisoning is a toxic-exposure syndrome, not a Mendelian or genetically-defined disease. Sections framed around causal genes, inheritance, penetrance, founder effects, and germline variants are largely Not Applicable; they are retained below with explicit "N/A" annotations and repurposed toward host susceptibility modifiers where evidence exists. The mechanistic, phenotypic, diagnostic, treatment, and prevention sections are the substantive core.

1. Disease Information

Overview. Carbon monoxide poisoning is the clinical syndrome resulting from inhalation of carbon monoxide, a colorless, odorless, tasteless, non-irritating gas produced by incomplete combustion of carbon-containing (hydrocarbon) fuels. It is one of the most common causes of fatal poisoning worldwide. CO produces injury through two convergent mechanisms: (1) hypoxic stress from formation of carboxyhemoglobin (COHb), which reduces oxygen-carrying capacity and shifts the oxyhemoglobin dissociation curve leftward (impairing tissue oxygen offloading); and (2) direct cellular toxicity independent of COHb — binding to mitochondrial cytochrome c oxidase, myoglobin, and other heme proteins, plus oxidative/nitrosative stress and an immune-mediated delayed neuroinflammatory cascade (StatPearls Carboxyhemoglobin Toxicity, NBK557888; Weaver, NEJM 2002, PMID 12362006).

Key identifiers. - MONDO: MONDO:0021113 (carbon monoxide poisoning) — verify against the local sqlite:obo:mondo adapter before committing (runoak -i sqlite:obo:mondo info MONDO:0021113 -O obo); OLS did not render the record in this session, so treat the ID as provisional. A closely related concept is carboxyhemoglobinemia. - ICD-10-CM: T58.- "Toxic effect of carbon monoxide," with source/intent subcodes — e.g., T58.01XA (motor-vehicle exhaust, accidental, initial encounter), T58.11XA (utility gas, accidental), T58.91XA (unspecified source, accidental), and intentional-self-harm variants (T58.-2-). - ICD-11: NE61 / stem for toxic effect of carbon monoxide (foundation "Toxic effect of carbon monoxide"). - MeSH: D002249 "Carbon Monoxide Poisoning." - OMIM/Orphanet: No dedicated Mendelian OMIM entry (not a genetic disease). Not a designated rare disease in Orphanet. - SNOMED CT: 284196006 "Carbon monoxide poisoning" (concept present; verify current ID).

Synonyms / alternative names. CO poisoning; carbon monoxide toxicity; carbon monoxide intoxication; carboxyhemoglobinemia (the biochemical state); "silent killer" (lay). Historically overlapping legacy terms: "coal gas poisoning," "flue gas / smoke inhalation CO component."

Data derivation. Disease-level knowledge here derives from aggregated resources (CDC/WHO surveillance, poison-center data, UHMS/society guidelines, and clinical-trial cohorts) rather than individual EHR records, though large administrative/EHR and forensic cohorts underpin the epidemiology and prognosis figures.

Sources: StatPearls Carboxyhemoglobin Toxicity; MSD/Merck Manual; ICD10Data T58.

2. Etiology

Primary cause (environmental/toxic). Inhalation of CO gas. There is no genetic or infectious primary etiology — this is a pure environmental/toxicological exposure disease. CHEBI: carbon monoxide = CHEBI:17245.

Common exposure sources. - Faulty or unvented fuel-burning appliances: furnaces, gas/oil boilers, water heaters, gas ranges/ovens, space heaters. - Motor-vehicle exhaust (running engines in attached/closed garages; a frequent suicide method). - Portable generators, a major cause of poisoning and death during storm-related power outages (CDC disaster guidance). - Charcoal grills / hibachis used indoors; camping stoves and lanterns in tents. - House fires / smoke inhalation (CO is a leading cause of fire-related death). - Methylene chloride (dichloromethane, CHEBI:15767) — paint strippers and solvents; hepatically metabolized to CO, causing delayed, prolonged COHb elevation. - Indoor use of gasoline-powered tools; ice-rink resurfacers; boating "houseboat/exhaust" exposures. - Tobacco/hookah smoke (chronic low-level source; baseline COHb 3–10% in smokers).

Risk factors (environmental / demographic). - Season: winter months (heating use); poisonings and deaths peak in cold months (CDC/NVSS). - Setting: most exposures occur at home; disasters and power outages (generators). - Sex: male death rate ~0.22/100,000 vs female ~0.07/100,000 (>3× higher in males, 1999–2010 CDC data) — partly reflecting occupational exposure and intentional poisoning. - Age: highest death rates in adults ≥65 years (males 0.42, females 0.18 per 100,000). - Occupation: firefighters, garage/toll workers, welders, mechanics, foundry/blast-furnace workers, propane forklift operators. - Pregnancy: enhanced fetal vulnerability (see §9, §12). - Comorbidity: pre-existing coronary artery disease, anemia, chronic respiratory disease, and cerebrovascular disease increase susceptibility to a given COHb level. - Absent CO detectors in the home is a strong, modifiable risk factor for fatal poisoning (Yoon, JAMA 1998, PMID 9496987).

Genetic / host-susceptibility modifiers (not causal). True Mendelian causation is N/A. Reported modifiers of susceptibility or of delayed neurological sequelae (DNS) are limited and largely candidate-gene/observational: haptoglobin phenotype, HMOX1 (heme oxygenase-1) promoter (GT)n repeat polymorphisms, apolipoprotein E (APOE) genotype, and inflammatory-cytokine polymorphisms have been proposed to modulate outcome, but none are established. Individuals with higher baseline COHb (smokers), anemia (lower total O₂-carrying reserve), or cardiac/cerebrovascular disease tolerate less CO.

Protective factors. - CO detectors/alarms (primary environmental protection; legislative mandates reduce deaths). - Appliance maintenance, adequate ventilation, and never running engines/generators indoors. - No established genetic protective variant.

Gene–environment interaction. The dose–response to a fixed CO exposure is modulated by host oxygen-carrying reserve and antioxidant/inflammatory genotype (e.g., HMOX1, antioxidant enzymes), but this remains hypothesis-level (CTD lists CO–gene interactions primarily from toxicogenomic models, not clinical GxE). Treat as an open knowledge gap (KNOWLEDGE_GAP).

Sources: CDC QuickStats 1999–2010; Yoon 1998 PMID 9496987; CDC disaster clinical guidance.

3. Phenotypes

CO poisoning is a multisystem syndrome with nonspecific early symptoms (often misdiagnosed as viral illness or food poisoning). Manifestations correlate imperfectly with COHb level; clinical severity, duration of exposure, and host factors matter more than a single COHb number.

Neurologic / neuropsychiatric (dominant and prognostically important). - Headache — the most common early symptom (often "dull, frontal"). HPO: Headache HP:0002315. Frequency: very frequent/most common. - Dizziness / lightheadedness — HPO: Vertigo HP:0002321 / Dizziness. Frequent. - Confusion, impaired cognition, difficulty concentrating — HPO: Confusion HP:0001289; Cognitive impairment HP:0100543. Frequent-to-severe cases. - Syncope / loss of consciousness — HPO: Syncope HP:0001279; Loss of consciousness HP:0007185. A key severity marker and HBO indication. - Seizures — HPO: Seizure HP:0001250. Severe poisoning. - Coma — HPO: Reduced consciousness/confusion → Coma HP:0001259. Severe. - Delayed neurological/neuropsychiatric sequelae (DNS / DEACMP) — a hallmark: after apparent recovery, a lucid interval of days–weeks precedes cognitive decline, memory loss, parkinsonism, gait/movement disorders, personality/affective change, incontinence, and akinetic mutism. HPO overlaps: Parkinsonism HP:0001300, Memory impairment HP:0002354, Gait disturbance HP:0001288, Personality changes HP:0000751, Dystonia HP:0001332. Onset typically 2–40 days post-recovery; occurs in ~3–40% depending on severity/definition. - Peripheral neuropathy, hearing loss, vestibular dysfunction (less common).

Cardiovascular. - Myocardial ischemia / injury — chest pain, ECG ischemia, troponin rise, arrhythmia; myocardial infarction with angiographically normal coronaries possible. HPO: Myocardial infarction HP:0001658; Angina pectoris HP:0001681; Arrhythmia HP:0011675. Common in moderate–severe poisoning; associated with increased long-term mortality. - Hypotension, tachycardia.

Respiratory. - Dyspnea (HPO: Dyspnea HP:0002094), tachypnea; noncardiogenic pulmonary edema in severe cases.

General / constitutional. - Nausea and vomiting — HPO: Nausea and vomiting HP:0002017 (or Nausea HP:0002018 / Vomiting HP:0002013). Frequent; often mistaken for gastroenteritis. - Fatigue / weakness / malaise — HPO: Fatigue HP:0012378; Muscle weakness HP:0001324. - Visual disturbance / blurred vision — HPO: Blurred vision HP:0000622; rarely retinal hemorrhages, cortical blindness.

Dermatologic. - The classically taught "cherry-red" skin/lips is rare and unreliable (usually a postmortem finding); cyanosis or normal color is more typical. Bullous skin lesions/pressure necrosis can occur in comatose patients.

Laboratory abnormalities (phenotype: laboratory). - Elevated carboxyhemoglobin (COHb) — the defining lab abnormality. Normal <3% (nonsmokers), up to ~10–15% in heavy smokers. Symptomatic poisoning usually >10–20%. LOINC: COHb/Hb.total — LOINC 20563-3 (Carboxyhemoglobin/Hemoglobin.total in Blood). - Metabolic acidosis with elevated lactate (anaerobic metabolism) — LOINC: Lactate 2524-7; a severity marker. - Elevated cardiac troponin / CK-MB (myocardial injury). - Elevated creatine kinase ± rhabdomyolysis/AKI in immobilized/comatose patients. - Falsely normal SpO₂ on standard pulse oximetry — conventional oximeters cannot distinguish COHb from oxyhemoglobin ("saturation gap"); requires CO-oximetry (multi-wavelength). A critical diagnostic pitfall.

Quality-of-life impact. Survivors of moderate–severe poisoning, especially those developing DNS, may have persistent cognitive deficits, mood/anxiety disorders, chronic headache, and impaired executive function, with measurable declines on neuropsychological batteries and quality-of-life instruments; some do not fully recover by 12 months (Weaver, NEJM 2002). Chronic low-level exposure produces persistent headache, fatigue, and cognitive complaints.

Onset/severity/progression summary. Onset acute (minutes–hours of exposure); severity mild → severe/fatal and variable; a distinct biphasic course is possible (acute illness → apparent recovery → DNS). Symptom–COHb correlation is weak.

Sources: Merck Manual; MedLink Neurology; Weaver NEJM 2002 PMID 12362006.

4. Genetic / Molecular Information

Causal genes: None — Not Applicable. CO poisoning is a toxic exposure, not a Mendelian disorder. There are no causal genes, pathogenic variants (ACMG/AMP classes), allele frequencies, somatic/germline distinctions, or chromosomal abnormalities to report.

Molecular target of the toxicant (the meaningful "molecular" content). The pathogenic ligand is CO gas (CHEBI:17245), which binds ferrous (Fe²⁺) heme iron in multiple hemoproteins: - Hemoglobin (HBB/HBA) → carboxyhemoglobin. CO affinity ~200–250× that of O₂ (StatPearls cites ~240×). - Myoglobin (MB, HGNC gene MB) → carboxymyoglobin, impairing cardiac and skeletal muscle O₂ storage/utilization; contributes to myocardial dysfunction. - Cytochrome c oxidase (Complex IV, MT-CO1/2/3 + nuclear COX subunits) → inhibition of mitochondrial electron transport and oxidative phosphorylation (direct histotoxic hypoxia). - NADPH oxidase, cytochrome P450, guanylate cyclase, and NOS-associated hemes are additional CO targets influencing signaling and reactive-species production.

Modifier genes / epigenetics / chromosomal: No established modifiers (see §2 for candidate host modifiers such as HMOX1, APOE). Epigenetic and chromosomal sections are N/A for causation. (Note that CO is itself an endogenous signaling molecule generated by heme oxygenase-1, HMOX1, HGNC:5013 — biologically relevant context, not a disease gene.)

Sources: StatPearls NBK557888; ROS/oxidative-stress review PMID 24773392.

5. Environmental Information

  • Environmental factors: ambient CO from incomplete combustion (see §2 source list). Poorly ventilated enclosed spaces concentrate CO; concentration (ppm) × exposure duration determines dose. Regulatory context: OSHA PEL 50 ppm (8-h TWA); NIOSH IDLH 1,200 ppm; ambient CO tracked by EPA.
  • Lifestyle factors: tobacco smoking (chronic endogenous/exogenous CO load, baseline COHb elevation); indoor charcoal/generator use; occupational exposure.
  • Infectious agents: None — Not Applicable.

Sources: CDC CO topic; Merck Manual.

6. Mechanism / Pathophysiology

CO injures tissue through two integrated arms — impaired oxygen delivery/utilization (hypoxic-ischemic) and direct cellular toxicity with oxidative/nitrosative stress and delayed immune-mediated neuroinflammation. The brain and heart, with the highest oxygen demand, are most vulnerable.

Causal chain (upstream → downstream)

A. Hypoxic-ischemic arm. 1. Inhaled CO diffuses across the alveolar–capillary membrane and binds hemoglobin Fe²⁺ → carboxyhemoglobin, reducing O₂-carrying capacity. 2. CO binding to one heme shifts the oxyhemoglobin dissociation curve leftward, further impairing O₂ release to tissue (functional anemia worse than simple loss of capacity). 3. → Tissue hypoxia, anaerobic metabolism, lactic acidosis (GO: cellular response to hypoxia GO:0071456; anaerobic respiration).

B. Direct cytotoxic / histotoxic arm (COHb-independent). 4. CO binds cytochrome c oxidase (Complex IV), inhibiting mitochondrial electron transport and ATP synthesis → histotoxic hypoxia even where O₂ is available (GO: mitochondrial electron transport, cytochrome c to oxygen GO:0006123; oxidative phosphorylation GO:0006119). CO also binds myoglobin → impaired cardiac oxygen utilization → myocardial depression, hypotension, and secondary global ischemia/reperfusion.

C. Oxidative/nitrosative stress and vascular arm. 5. CO displaces nitric oxide (NO) from platelets and hemoproteins → excess NO → peroxynitrite formation; NO/peroxynitrite drive leukocyte (neutrophil) adhesion to injured cerebral microvascular endothelium (β2-integrin–mediated). 6. Adherent neutrophils release myeloperoxidase, generating reactive oxygen species (ROS). ROS are produced from three temporally distinct sources: mitochondria (first minutes of exposure), xanthine oxidase (~20 min, from energy deprivation/purine catabolism), and NADPH oxidase during the post-exposure reoxygenation period — i.e., an ischemia–reperfusion–like injury (Chang et al., ROS review PMID 24773392; PMC9852609). GO: reactive oxygen species metabolic process GO:0072593; response to oxidative stress GO:0006979. 7. → Lipid peroxidation of membrane and myelin lipids; glutathione depletion (GO: lipid oxidation; lipid peroxidation).

D. Delayed immune-mediated demyelination (the DNS engine). 8. Lipid peroxidation generates malondialdehyde (MDA), which forms adducts with myelin basic protein (MBP) in the CNS. Modified MBP loses its normal cationic charge and antibody-recognition profile. 9. Chemically altered MBP is immunogenic: over days, degraded MBP appears in brain with influx of macrophages and CD4⁺ T-lymphocytes, and autoreactive lymphocyte proliferation to MBP develops, with microglial activation → adaptive autoimmune demyelination and delayed neuropathology. Rats made immunologically tolerant to MBP before CO poisoning show the acute biochemical MBP change but no lymphocyte response and no learning deficit, establishing causation (Thom SR et al., PNAS 2004;101(37):13660–13665, PMID 15342916). GO: adaptive immune response GO:0002250; inflammatory response GO:0006954; demyelination. 10. → Delayed neuronal apoptosis (hippocampus, basal ganglia), white-matter demyelination, and DNS.

Cell types involved (CL terms). Neurons (CL:0000540), especially hippocampal neurons and basal-ganglia/globus-pallidus neurons; oligodendrocytes (CL:0000128, myelin) as demyelination targets; microglial cells (CL:0000129); cardiac myocytes (CL:0000746); vascular endothelial cells (CL:0000115); neutrophils (CL:0000775); CD4⁺ T cells (CL:0000624); macrophages (CL:0000235); erythrocytes (CL:0000232, the COHb site).

Subcellular compartments (GO Cellular Component). Mitochondrion (GO:0005739), specifically the mitochondrial respiratory chain complex IV (GO:0005751); myelin sheath (GO:0043209); plasma membrane / cytosol.

Metabolic changes. Shift to anaerobic glycolysis; lactic acidosis; ATP depletion; glutathione depletion; disrupted heme-protein oxygen handling.

Immune involvement. Innate (neutrophil/microglia/macrophage, ROS) acutely; adaptive autoimmune (anti-MBP CD4⁺ T-cell) response driving delayed demyelination — a rare example of a toxic exposure triggering an autoimmune neurologic sequela.

Tissue-damage mechanisms. Oxidative stress, ischemia–reperfusion injury, lipid peroxidation, apoptosis/necrosis, and immune-mediated demyelination converge on the globus pallidus (watershed, high metabolic demand, vulnerable) and deep white matter.

Molecular profiling / advanced tech. Transcriptomic and proteomic studies in rodent DEACMP models show upregulated inflammatory and apoptotic pathways and MBP degradation; candidate serum biomarkers (S100B, NSE, GFAP, myelin-related autoantibodies) have been studied for DNS prediction. Human single-cell/spatial and CRISPR-screen data are not established for this exposure — an open knowledge gap.

Sources: ROS review PMID 24773392; Thom PNAS 2004 PMID 15342916; Mechanism of delayed encephalopathy PMID 32594050; MBP degradation rat PMID 20633582.

7. Anatomical Structures Affected

Organ level. - Primary: Brain (UBERON:0000955) and heart (UBERON:0000948) — highest O₂ demand. - Secondary / systemic: skeletal muscle (rhabdomyolysis), kidney (UBERON:0002113; AKI from rhabdomyolysis/hypoperfusion), lungs (UBERON:0002048; pulmonary edema), skin, retina/eye, peripheral nerves. - Body systems: nervous, cardiovascular, respiratory, musculoskeletal, and (fetal) reproductive/placental.

Tissue and cell level. - Basal ganglia — especially globus pallidus (UBERON:0001875), the signature CO lesion — and substantia nigra; deep cerebral white matter (UBERON:0002316); hippocampus (UBERON:0002421); cerebral cortex; occasionally putamen, caudate, thalamus (imaging: bilateral, symmetric). - Cell populations: pallidal neurons, hippocampal neurons, oligodendrocytes/myelin, cardiac myocytes, microvascular endothelium.

Subcellular level. Mitochondria (Complex IV) and myelin sheath are the principal molecular battlegrounds.

Localization / laterality. CNS lesions are characteristically bilateral and symmetric (globus pallidus > white matter). On MRI: globus pallidus shows T1 hypo-/T2-FLAIR hyperintensity with restricted diffusion (DWI) acutely; late subacute period shows diffuse white-matter demyelination.

Sources: AJNR Pallidoreticular DWI; Advanced neuroimaging of CO poisoning PMC5602327.

8. Temporal Development

  • Onset: acute — minutes to hours of exposure; any age (congenital exposure via maternal poisoning to geriatric).
  • Acute course: symptoms during/after exposure; severity tracks cumulative dose (concentration × time) more than a single COHb.
  • Biphasic pattern / DNS: after treatment and apparent recovery, a lucid interval of ~2–40 days may precede delayed neuropsychiatric sequelae (cognitive decline, parkinsonism, affective/behavioral change). This is the defining temporal feature.
  • Progression / recovery: many mild cases resolve fully within hours–days on oxygen. Moderate–severe cases risk persistent or delayed deficits; DNS may partially recover over 6–12 months, but a subset has permanent impairment.
  • Critical intervention window: benefit of hyperbaric oxygen (HBO) is greatest when started within 6 hours and not later than ~24 hours (UHMS).

Sources: Weaver NEJM 2002; Predictors of delayed encephalopathy PMC11979149.

9. Inheritance and Population (Epidemiology)

Inheritance: Not Applicable (non-genetic exposure). Penetrance, expressivity, anticipation, mosaicism, founder effects, consanguinity, and carrier frequency are all N/A.

Epidemiology (aggregate). - US unintentional mortality: ~430 deaths/year average (1999–2010, total 5,149; CDC); ~2,244 deaths over 2010–2015. In 2022, CDC provisional data recorded 1,244 total CO deaths (624 accidental + 579 suicides). - Morbidity: >100,000 US emergency-department visits/year for accidental CO poisoning, with >14,000 hospitalizations/year (CDC/USAFacts). - Sex ratio: male death rate ~0.22/100,000 vs female ~0.07/100,000 (males >3× higher, 1999–2010). - Age: highest death rates in adults ≥65 years (males 0.42, females 0.18 per 100,000). - Seasonality: strong winter predominance (heating season, power outages). - Global: CO poisoning is a leading cause of poisoning death worldwide; incidence and trends analyzed via GBD 1990–2021 (joinpoint/ARIMA; PMC12373207). Rates are higher where unvented biomass/coal heating and gas water heaters are common.

Prevalence framing for the KB (PrevalenceMeasureEnum): best modeled as ANNUAL_INCIDENCE (ED visits ~30/100,000/year in the US; deaths ~0.1–0.4/100,000/year), not a chronic point prevalence. prevalence_class qualitatively COMMON among acute poisonings.

Population demographics. Higher burden in lower-income households (older/unmaintained appliances), disaster-affected populations (generators), and in regions with indoor combustion heating/cooking. Intentional CO poisoning (suicide) skews male and adult.

Sources: CDC QuickStats 1999–2010; CDC NVSS 2010–2015; USAFacts 2022; GBD 1990–2021 PMC12373207.

10. Diagnostics

Core principle: diagnosis requires clinical suspicion (nonspecific symptoms + compatible exposure history, often multiple household members or a pet affected) plus direct COHb measurement. Standard pulse oximetry is falsely reassuring.

Laboratory / functional tests. - Carboxyhemoglobin (COHb) by CO-oximetry on arterial or venous blood (venous adequate for the level) — the confirmatory test. LOINC 20563-3. Interpret against baseline: nonsmoker <3%; smoker up to ~10–15%. Elevation confirms exposure; magnitude does not reliably grade severity. - Non-invasive pulse CO-oximetry (multi-wavelength, e.g., SpCO) — screening/triage; correlates imperfectly with blood COHb (PMC10890311). - ABG/VBG with lactate: metabolic acidosis, elevated lactate = severity markers. Measured (not calculated) SaO₂ needed. - Cardiac troponin, ECG — screen all moderate–severe poisonings for myocardial injury/ischemia (prognostic). - CK, renal function, urinalysis — rhabdomyolysis/AKI. - Pregnancy test in women of childbearing age (alters HBO threshold).

Imaging. - CT/MRI brain: bilateral symmetric globus-pallidus lesions; DWI restricted diffusion acutely; diffuse white-matter demyelination subacutely — supports diagnosis and prognosticates DNS risk. Advanced MRI (DTI, MRS, CEST-glutamate) is research-grade.

Biomarkers (investigational for DNS prediction). S100B, neuron-specific enolase (NSE), GFAP, and myelin-related autoantibodies have been studied as predictors of delayed encephalopathy but are not standard of care.

Genetic/omics testing: Not Applicable for diagnosis.

Clinical criteria / differential diagnosis. No formal DSM/ICD diagnostic criteria set beyond exposure + elevated COHb + compatible illness. Differential: viral illness/influenza, gastroenteritis/food poisoning, migraine, acute coronary syndrome, stroke, other toxic gas/cyanide exposure (concurrent in fires — consider cyanide co-toxicity), and psychiatric/functional disorders. Clues favoring CO: multiple people/pets ill in the same environment, symptoms improving away from home, winter/heating context.

Screening. Not a population lab-screening target; home CO alarms are the practical "screening" tool for asymptomatic detection of dangerous ambient levels.

Sources: StatPearls NBK557888; The Diagnosis and Treatment of CO Poisoning PMC6381775; CO-oximetry correlation PMC10890311.

11. Outcome / Prognosis

  • Acute mortality: most treated symptomatic patients survive; case fatality is driven by severe exposure, coma, cardiac arrest, and delayed presentation. Severe poisoning with coma or myocardial injury carries substantially higher mortality.
  • Cardiac injury as a prognostic marker: myocardial injury (elevated troponin) during acute poisoning is associated with increased long-term mortality independent of acute severity.
  • Delayed neurological sequelae (DNS/DEACMP): the principal morbidity — reported in roughly 3–40% of moderate–severe cases depending on definition and follow-up; risk factors include older age, loss of consciousness, longer exposure, severe acidosis, and abnormal early neuroimaging. In Weaver's RCT, cognitive sequelae at 6 weeks occurred in 25% (HBO group) vs 46% (normobaric group).
  • Recovery: many with DNS improve over 6–12 months; a subset has permanent cognitive, extrapyramidal (parkinsonism/dystonia), or affective deficits.
  • Morbidity/QoL: persistent neurocognitive impairment, mood disorders, chronic headache, functional disability; measured with neuropsychological batteries and QoL tools.
  • Fetal outcome: maternal poisoning can cause fetal death, CNS malformation, or neurodevelopmental injury; fetal COHb runs higher and clears more slowly than maternal (see §12).

Sources: Weaver NEJM 2002 PMID 12362006; Predictors of delayed encephalopathy PMC11979149.

12. Treatment

Immediate / supportive (MAXO: supportive care MAXO:0000950). - Remove from exposure; secure airway, breathing, circulation; treat seizures, hypotension, arrhythmia; cardiac monitoring; correct acidosis by restoring oxygenation/perfusion.

Normobaric oxygen — first-line (MAXO: oxygen therapy MAXO:0035013; therapeutic agent dioxygen CHEBI:15379). - High-flow 100% O₂ via non-rebreather mask (or ETT) for all suspected/confirmed cases. Rationale: accelerates COHb elimination. CO half-life ~300 min (4–5 h) on room air → ~60–90 min on 100% normobaric O₂ → ~20–30 min on hyperbaric O₂. Continue until asymptomatic and COHb near-normal (typically <3–5%).

Hyperbaric oxygen (HBO) therapy (MAXO: hyperbaric oxygen therapy MAXO:0000257). - Mechanism/rationale: 100% O₂ at 2.5–3.0 ATA dramatically shortens COHb half-life, rapidly dissociates CO from cytochrome c oxidase and myoglobin, and is proposed to reduce lipid peroxidation, leukocyte–endothelial adhesion, and the immune-mediated demyelination cascade — potentially preventing delayed neurological sequelae, not just clearing COHb. - Indications (UHMS 2020 / clinical consensus): consider HBO — ideally within 6 h, no later than ~24 h — for patients with loss of consciousness (any duration), neurologic deficits/abnormal cognition, cardiac ischemia/arrhythmia, severe metabolic acidosis, COHb >25% (adults), and pregnancy (lower threshold, generally symptomatic exposure or COHb >15–20%, because fetal COHb is higher and clears slowly). Prolonged HBO/oxygen may be warranted after methylene-chloride exposure (ongoing endogenous CO production). - Evidence base (conflicting): - Thom et al., 1995 — prospective RCT: HBO reduced incidence of DNS in mild–moderate CO poisoning presenting within 6 h (PMID 7710151). - Weaver et al., NEJM 2002 — quadruple-blinded RCT: three HBO sessions within 24 h reduced cognitive sequelae at 6 weeks (25% vs 46%) and at 12 months (PMID 12362006). - Scheinkestel et al., MJA 1999 — RCT found no benefit (methodological differences; delayed/varied protocols) (PMID 10092916). - Cochrane review (Buckley et al., 2011, CD002041) concluded evidence is insufficient/conflicting to define which patients benefit — HBO remains standard practice for severe poisoning at many centers despite equipoise.

Pharmacogenomics / targeted / gene / cell / RNA therapies: Not Applicable (no molecular-target drug therapy). Experimental adjuncts studied mainly in models: erythropoietin (neuroprotection; rat serum-biomarker study PMC3586885), N-acetylcysteine, hypothermia, and — as an experimental antidote concept — engineered high-affinity CO-scavenger molecules (e.g., recombinant neuroglobin/"CO-scavenger" therapeutics in preclinical development to accelerate CO removal). None are approved.

Treatment strategy summary. All symptomatic patients → immediate high-flow 100% O₂ + supportive care; risk-stratify (LOC, neuro deficit, cardiac ischemia, acidosis, COHb, pregnancy) → refer for HBO if indicated and available within the therapeutic window. Arrange neuropsychological follow-up to detect DNS.

Adverse events. HBO risks: barotrauma (middle ear/sinus, rare pulmonary), oxygen toxicity seizures, confinement anxiety, transient myopia. Normobaric high-FiO₂ is generally safe over the short treatment course.

Sources: UHMS HBO indications 2020; Weaver NEJM 2002; Thom 1995 PMID 7710151; Scheinkestel 1999 PMID 10092916; Cochrane CD002041.

13. Prevention

Primary prevention (the highest-yield domain). - CO alarms/detectors in homes near sleeping areas and on every level (MAXO/behavioral: environmental intervention). Legislative mandates for residential CO alarms reduce fatalities; battery replacement and testing emphasized. - Appliance safety: annual professional inspection/maintenance of furnaces, water heaters, and vents; never use ovens/ranges for heating. - Generator safety: operate portable generators outdoors, ≥20 ft from windows/doors/vents, never indoors/garages (key message during storms/outages). - Vehicle/engine safety: never run engines in attached/closed garages; check exhaust systems. - No indoor charcoal grills / camp stoves. - Public health education, especially before winter and after disasters; CDC/EPA campaigns.

Secondary prevention (early detection). - CO alarms detecting dangerous ambient levels before symptoms; prompt evaluation of clustered household symptoms; consider CO in nonspecific winter illness ("influenza-like" clusters).

Tertiary prevention (limiting sequelae in the poisoned). - Prompt high-flow/hyperbaric oxygen within the therapeutic window; neuropsychological follow-up to identify and rehabilitate DNS; removal/remediation of the CO source before discharge to prevent re-exposure.

Prophylaxis / immunization / genetic screening / counseling: vaccination and genetic counseling are Not Applicable. "Prophylaxis" = engineering/behavioral source control + alarms.

Sources: CDC clinical/disaster guidance; Yoon 1998 PMID 9496987.

14. Other Species / Natural Disease

  • Taxonomy / cross-species susceptibility: CO is toxic to all aerobic, hemoglobin-bearing animals — mechanism (heme binding) is evolutionarily conserved. Species commonly poisoned alongside humans include domestic dog (Canis lupus familiaris, NCBITaxon:9615) and cat (Felis catus, NCBITaxon:9685) — pets are a classic "sentinel" for household CO exposure. Also documented in birds (historically the "canary in the coal mine," Serinus canaria), which are especially sensitive due to high metabolic/respiratory rates.
  • Natural/veterinary disease: accidental CO poisoning occurs in companion animals (house fires, faulty heaters, vehicle transport) and livestock in poorly ventilated heated barns; veterinary toxicology recognizes it with a pathophysiology mirroring humans. Not a Mendelian OMIA entry (it is a toxic exposure).
  • Comparative biology: rodents show the same globus-pallidus/hippocampal vulnerability, MBP-adduct autoimmunity, and DNS-like learning deficits, validating cross-species conservation of both the hypoxic and immune arms.
  • Zoonotic potential: None — Not Applicable (non-infectious).

Sources: Thom PNAS 2004 (rat); veterinary toxicology consensus (background).

15. Model Organisms

  • Rat (Rattus norvegicus, NCBITaxon:10116) — the dominant model. Standard induced-exposure protocols (e.g., 1,000 ppm 40 min then 3,000 ppm 20 min) reproduce: transient hippocampal MBP degradation (Hara et al., PMID 20633582), immune-mediated delayed neuropathology and learning deficits (Thom et al., PMID 15342916), decreased hippocampal neural precursor cells in DEACMP models (Nat Sci Rep, s41598-021-85860-9), altered nicotinic cholinergic signaling (PMID 24704181), and neuroprotection studies (erythropoietin, PMC3586885). Model type: induced (inhalational exposure), not genetic.
  • Mouse (Mus musculus, NCBITaxon:10090) — used for oxidative-stress/ROS-source dissection (mitochondria/xanthine oxidase/NADPH oxidase) and inflammatory-pathway studies; transgenic/knockout mice (e.g., NOS, NADPH oxidase subunits) dissect specific mechanistic arms.
  • In vitro / cellular: neuronal and oligodendrocyte cultures, endothelial–neutrophil adhesion assays, and mitochondrial respiration assays (Complex IV inhibition).

Phenotype recapitulation. Rodent models reproduce the biphasic course (acute exposure → delayed neuropathology), the globus-pallidus/hippocampal vulnerability, demyelination, and the autoimmune anti-MBP mechanism — strong construct/face validity, including the pivotal MBP-tolerance experiment establishing causation.

Limitations. Species differences in CO tolerance and COHb kinetics; some protocols produce MBP degradation without measurable cognitive deficit (dose-dependence), highlighting a human–model translational caveat (HUMAN_MODEL_MISMATCH): the immune-mediated DNS mechanism is best characterized in rodents, and its quantitative fidelity to human DNS remains an open translational question.

Resources: MGI/RGD for mouse/rat strains; primary literature via PubMed. No dedicated CO-poisoning model repository (it is an induced-exposure paradigm, not a genetic line).

Sources: Thom PNAS 2004 PMID 15342916; MBP degradation PMID 20633582; Neural precursor cells Sci Rep; Nicotinic cholinergic PMID 24704181.

Ontology Term Quick-Reference (for KB population)

Domain Term ID
Disease carbon monoxide poisoning MONDO:0021113 (verify)
Chemical (toxicant) carbon monoxide CHEBI:17245
Chemical (therapy) dioxygen CHEBI:15379
Chemical (source) dichloromethane CHEBI:15767
Phenotype Headache HP:0002315
Phenotype Syncope HP:0001279
Phenotype Seizure HP:0001250
Phenotype Confusion HP:0001289
Phenotype Parkinsonism HP:0001300
Phenotype Memory impairment HP:0002354
Phenotype Myocardial infarction HP:0001658
Phenotype Nausea and vomiting HP:0002017
Phenotype Dyspnea HP:0002094
Process oxidative phosphorylation GO:0006119
Process mito. electron transport, cyt c → O₂ GO:0006123
Process response to oxidative stress GO:0006979
Process ROS metabolic process GO:0072593
Process cellular response to hypoxia GO:0071456
Process inflammatory response GO:0006954
Process adaptive immune response GO:0002250
Cell neuron CL:0000540
Cell oligodendrocyte CL:0000128
Cell microglial cell CL:0000129
Cell CD4+ T cell CL:0000624
Cell erythrocyte CL:0000232
Cell cardiac myocyte CL:0000746
Anatomy brain UBERON:0000955
Anatomy globus pallidus UBERON:0001875
Anatomy cerebral white matter UBERON:0002316
Anatomy hippocampus UBERON:0002421
Anatomy heart UBERON:0000948
Subcellular mitochondrion GO:0005739
Subcellular respiratory chain complex IV GO:0005751
Subcellular myelin sheath GO:0043209
Treatment oxygen therapy MAXO:0035013 (verify)
Treatment hyperbaric oxygen therapy MAXO:0000257 (verify)
Treatment supportive care MAXO:0000950
Lab Carboxyhemoglobin/Hb.total LOINC 20563-3

Curation Caveats (dismech-specific)

  1. Verify every ontology ID before committing — MONDO:0021113 and the MAXO oxygen/HBO IDs are provisional in this report (OLS/OAK not confirmed in-session). Run just validate-terms-file and runoak … info per the anti-hallucination SOP.
  2. All snippets must be exact abstract quotes — this report paraphrases sources; before entering any evidence: snippet, run just fetch-reference PMID:XXXX and confirm the exact substring (e.g., PMIDs 12362006, 7710151, 15342916, 24773392, 20633582, 32594050, 24704181, 10092916, 9496987).
  3. evidence_source tagging: Weaver/Thom-1995/Scheinkestel = HUMAN_CLINICAL; Thom PNAS 2004, MBP-degradation, EPO, nicotinic-cholinergic studies = MODEL_ORGANISM; ROS-source dissection = mix of IN_VITRO/MODEL_ORGANISM (split items accordingly).
  4. Genetic/inheritance sections should be curated as explicitly N/A or omitted — this is an environmental exposure, not a Mendelian disease.
  5. Key KNOWLEDGE_GAP / HUMAN_MODEL_MISMATCH candidates: (a) whether the rodent anti-MBP autoimmune DNS mechanism quantitatively explains human delayed encephalopathy; (b) which patients benefit from HBO (unresolved per Cochrane); (c) validity of serum biomarkers (S100B/NSE/GFAP) for DNS prediction.

Primary sources cited

Bottom line: Carbon monoxide poisoning is an acute environmental toxic-inhalation syndrome (MONDO:0021113, ICD-10 T58, MeSH D002249) with no genetic etiology. Its pathophysiology is a dual insult — carboxyhemoglobin-mediated hypoxia plus direct mitochondrial/heme-protein toxicity, oxidative/ischemia-reperfusion injury, and a distinctive immune-mediated (anti-MBP) delayed demyelinating cascade that produces delayed neuropsychiatric sequelae. The brain (globus pallidus, white matter, hippocampus) and heart bear the injury. Management is 100% oxygen ± hyperbaric oxygen (benefit best-supported by Weaver 2002 but contested by Scheinkestel/Cochrane), and the disease is highly preventable through CO alarms and combustion-source safety. Curate the genetic/inheritance sections as Not Applicable, verify all ontology IDs and PMID snippets against the dismech validation stack before committing, and flag the HBO-benefit question and rodent-DNS translational fidelity as knowledge gaps.