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Mappings

MONDO

MONDO:0018754 cyanide poisoning

Primary MONDO disease identifier for this cyanide poisoning entry.

ICD-10-CM

ICD10CM:T65.0 Toxic effect of cyanides

ICD-10-CM code for toxic effect of cyanides, covering cyanide salts and cyanide-releasing compounds. Hydrogen cyanide gas specifically is coded T57.3.

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Definitions

1

Clinical case definition for acute cyanide poisoning

Acute cyanide poisoning is a toxidrome in which absorbed cyanide inhibits cellular oxygen utilization, recognised from a compatible exposure history (fire smoke, cyanide salt, cyanogenic glycoside, or nitroprusside infusion) together with rapidly progressive depressed consciousness, cardiovascular instability, and high-anion-gap lactic acidosis. Confirmatory blood cyanide measurement is rarely available in time, so plasma lactate is the practical diagnostic surrogate.

CASE_DEFINITION Disease-level clinical framing for acute poisoning and its delayed sequelae

Show evidence (2 references)

PMID:41204534 SUPPORT Human Clinical

"Cyanide poisoning is a life-threatening condition that impairs cellular oxygen utilization, leading to lactic acidosis."

Supports the core disease framing as impaired cellular oxygen utilization producing lactic acidosis.

PMID:41204534 SUPPORT Human Clinical

"However, serum cyanide levels are not readily available in clinical settings, making diagnosis and treatment monitoring difficult."

Supports basing the case definition on exposure history plus surrogate laboratory findings rather than a confirmatory cyanide assay.

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Subtypes

3

Acute Cyanide Poisoning

Rapid-onset poisoning after a high-dose exposure by inhalation, ingestion, or dermal absorption. Progression from headache, vertigo, weakness and tachypnea to seizures, coma and cardiovascular collapse can take minutes at high doses.

Show evidence (1 reference)

PMID:26543483 SUPPORT Human Clinical

"This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"

Supports the acute multisystem presentation and its characteristic progression.

Delayed Dystonic-Parkinsonian Syndrome MONDO:0017640

A subset of survivors of severe acute poisoning develop a delayed extrapyramidal syndrome - progressive rigidity, dystonia and parkinsonism - emerging days to months after apparent recovery, associated with bilateral basal ganglia lesions on CT and MRI.

Show evidence (3 references)

PMID:3225591 SUPPORT Human Clinical

"Progressive Parkinsonism, dystonia and apraxia of eye opening were seen after cyanide poisoning."

Primary human report of the delayed extrapyramidal syndrome that defines this subtype.

PMID:3225591 SUPPORT Human Clinical

"CT scan and MRI showed lesions in the basal ganglia, cerebellum and cerebral cortex consistent with reported pathological findings."

Supports the imaging correlate, and shows the lesion is not confined to the basal ganglia.

PMID:1564480 SUPPORT Human Clinical

"A few days after an apparently full recovery he developed a severe dystonia syndrome."

Documents the defining latency - a lucid interval after apparent recovery - in a case followed for 21 years.

Iatrogenic (Nitroprusside) Cyanide Toxicity

Cyanide released during the metabolism of infused sodium nitroprusside can accumulate to toxic concentrations during high-dose or prolonged infusion, with hepatic dysfunction raising cyanide risk and renal dysfunction raising the risk of the distinct thiocyanate toxidrome.

Show evidence (1 reference)

PMID:8440119 SUPPORT Other

"High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."

Supports the iatrogenic subtype and the organ-dysfunction risk factors that define it.

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Discussions and Knowledge Gaps

2

Does empiric hydroxocobalamin improve outcome in smoke-inhalation victims with suspected but unconfirmed cyanide toxicity?

KNOWLEDGE GAP cyanide_empiric_hydroxocobalamin_smoke_inhalation

Attached to

treatments#Hydroxocobalamin environmental#Structure fire smoke inhalation

Hydroxocobalamin is first-line for confirmed cyanide poisoning, and its safety profile is what justifies giving it empirically at a fire scene where no cyanide assay is available. But the evidence for that empiric use is thin: a 2025 systematic review of six studies and 1238 patients found similar mortality between hydroxocobalamin and supportive treatment, with signals for acute kidney injury and methaemoglobinaemia, and could not pool the data. The same uncertainty runs the other way in the exposure literature, where a forensic series argues cyanide is an infrequent independent contributor to fire deaths. Resolving it needs a randomised trial that has never been done.

Show evidence (3 references)

PMID:41497958 SUPPORT Human Clinical

"Well-designed randomized controlled trials are urgently needed to establish optimal treatment strategies for this patient population."

States the gap directly, as the systematic review's own conclusion.

PMID:41497958 SUPPORT Human Clinical

"Two studies reported mortality rates, which were found to be similar between the hydroxocobalamin and supportive treatment groups."

Quantifies the absent mortality benefit that makes this a live question.

PMID:29021725 REFUTE Human Clinical

"Although a small sample, patients who received prehospital hydroxocobalamin had improved survival."

Cuts the other way from the systematic review, which is why the question is open rather than settled. Its own authors flag the sample size; the survey arm reports only 38 percent of responding US EMS agencies carrying any cyanide antidote, so practice is not converging either.

Does TST (rhodanese) genotype predict individual susceptibility to cyanide poisoning in exposed humans?

KNOWLEDGE GAP cyanide_tst_genotype_susceptibility

Attached to

genetic#TST pathophysiology#Rhodanese-Mediated Cyanide Detoxification

The enzymology is settled: functional TST promoter and coding variants cut expression by 40-73% and intrinsic clearance by half. What is missing is any demonstration that carriers of these alleles are actually more susceptible. The variants were characterised in fifty French individuals with no exposure outcome attached, and no poisoned or occupationally exposed cohort has been genotyped. Until one is, the pathway from genotype to clinical risk is an inference from in vitro clearance, not an observation.

Show evidence (1 reference)

PMID:16790311 SUPPORT In Vitro

"This work constitutes the first report of the existence of a functional genetic polymorphism affecting TST activity and should be of great help to investigate certain disorders for which impairment of CN(-) or H(2)S detoxification have been suggested to be involved."

The source frames its own result as a tool for future investigation of cyanide-detoxification disorders, which is precisely the study that has not been done.

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Pathophysiology

10

Systemic Cyanide Burden

Cyanide reaches the systemic circulation by inhalation of hydrogen cyanide gas, gastric absorption of ingested cyanide salts, enzymatic hydrolysis of ingested cyanogenic glycosides, dermal absorption, or metabolic release from infused nitroprusside. Inhaled hydrogen cyanide acts fastest because it crosses the alveolar membrane directly.

Animal models

Mouse lethal cyanide poisoning model (inhaled and intraperitoneal) Mouse perturbs Delivers a controlled lethal systemic cyanide burden by two routes that mirror the human inhalational and parenteral exposures.

Downstream

Cytochrome c Oxidase Inhibition Absorbed cyanide ion distributes rapidly into cells and mitochondria, where it reaches its principal molecular target.

Rhodanese-Mediated Cyanide Detoxification The same absorbed cyanide load is the substrate for the endogenous sulfurtransferase clearance pathway, which runs in parallel with toxicity.

Show evidence (1 reference)

PMID:29939573 SUPPORT Other

"Dermal absorption and injection are rare but possible sources of cyanide exposure."

Supports the breadth of absorption routes feeding this node, including the uncommon ones.

Cytochrome c Oxidase Inhibition

Cyanide binds with high affinity to the ferric heme a3 centre of cytochrome c oxidase (mitochondrial Complex IV), the oxygen-reducing terminus of the electron transport chain, and reversibly arrests the transfer of electrons to molecular oxygen. Nitric oxide modulates this in a dose-dependent and two-directional way: constitutive, low-level mitochondrial NO potentiates the inhibition, which is part of why onset is so fast, while high exogenous NO attenuates it - which is why the same molecule appears here as an aggravating factor and under Sodium Nitrite as the antidotal one.

cytochrome-c oxidase activity GO:0004129 ↓ DECREASED

mitochondrial respiratory chain complex IV GO:0045277

Downstream

Oxidative Phosphorylation Failure and ATP Depletion Blocking the terminal electron acceptor step collapses the respiratory chain and with it mitochondrial ATP synthesis.

Show evidence (3 references)

PMID:17906319 SUPPORT In Vitro

"Acute cyanide toxicity is attributed to inhibition of cytochrome c oxidase (CcOX), the oxygen-reducing component of mitochondrial electron transport"

Identifies Complex IV as the molecular target responsible for acute cyanide toxicity.

PMID:17906319 SUPPORT In Vitro

"It is concluded that the rapid, potent action of cyanide is due in part to mitochondrial generation of NO, which enhances inhibition of CcOX."

Supports nitric-oxide potentiation as a contributor to the speed of Complex IV inhibition.

PMID:37465777 SUPPORT Other

"When cyanide enters the body via inhalation, it blocks the cells from utilizing oxygen by binding to the cytochrome oxidase in the mitochondria."

Supports the histotoxic character of the lesion - oxygen is present but cannot be used.

Rhodanese-Mediated Cyanide Detoxification

Mitochondrial rhodanese (thiosulfate sulfurtransferase, TST) transfers sulfur from thiosulfate to cyanide, yielding thiocyanate that is excreted renally. 3-mercaptopyruvate sulfurtransferase provides a complementary cytosolic route. The pathway is limited by sulfur-donor supply and is overwhelmed at high cyanide loads, which is exactly why supplying exogenous thiosulfate is an antidote rather than merely a supplement.

thiosulfate-cyanide sulfurtransferase activity GO:0004792

Show evidence (2 references)

PMID:16790311 SUPPORT In Vitro

"Rhodanese or thiosulfate sulfurtransferase (TST) is a mitochondrial matrix enzyme that plays roles in cyanide detoxification, the formation of iron-sulfur proteins and the modification of sulfur-containing enzymes."

Establishes TST as the mitochondrial enzyme that carries out cyanide detoxification.

PMID:34297873 SUPPORT Other

"This reaction offers a rational behind the use of thiosulfate as antidote for cyanide poisoning."

Connects the endogenous sulfurtransferase reaction to the pharmacologic use of thiosulfate. Quoted verbatim including the source's own wording; a snippet never corrects the text it quotes.

Oxidative Phosphorylation Failure and ATP Depletion

With Complex IV blocked, the mitochondrial proton-motive force collapses and oxidative phosphorylation ceases, depleting cellular ATP within minutes despite adequate arterial oxygen content and delivery.

oxidative phosphorylation GO:0006119 ↓ DECREASED mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED

Downstream

Anaerobic Glycolytic Shift ATP depletion forces compensatory anaerobic glycolysis, whose lactate output accumulates far faster than it can be cleared.

Myocardial Energy Failure The myocardium is among the tissues whose contractile function fails first when oxidative ATP supply is cut off.

Cerebral Energy Failure Neurons, with little energy reserve and high oxidative demand, lose ion-gradient maintenance as soon as ATP falls.

Show evidence (1 reference)

PMID:25692407 SUPPORT Other

"For example, in addition to binding to and poisoning hemoglobin, cyanide inhibits cytochrome c oxidase, thus blocking electron transport in the mitochondrial respiratory chain and disrupting oxidative phosphorylation"

Supports disruption of oxidative phosphorylation as the immediate consequence of Complex IV inhibition.

Anaerobic Glycolytic Shift

Anaerobic glycolysis becomes the only remaining ATP source and is grossly insufficient, generating pyruvate that is converted to lactate. The systemic consequence - a severe high-anion-gap metabolic acidosis whose magnitude tracks the cyanide burden closely enough to serve as a surrogate assay - is modelled as the downstream Lactic acidosis and Elevated serum anion gap phenotypes rather than bundled into this cellular node.

glycolytic process GO:0006096 ↑ INCREASED

Animal models

Gottingen minipig lethal KCN bolus model Pig recapitulates Bolus KCN reproduces the dose-dependent arterial lactate rise that defines the metabolic lesion in human poisoning, and the lactate endpoint is the same one used clinically.

Downstream

Lactic acidosis

Elevated serum anion gap

Tachypnea Respiratory compensation for the metabolic acidosis, which is why tachypnea appears before any respiratory depression.

Show evidence (2 references)

PMID:12352039 SUPPORT Human Clinical

"Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations"

Quantifies the link between the cyanide burden and the lactate produced by this node.

PMID:8989894 SUPPORT Human Clinical

"Elevated plasma lactate, associated with cardiovascular collapse, should suggest cyanide intoxication."

Supports lactic acidosis as the characteristic metabolic signature of this node.

Myocardial Energy Failure

Cardiomyocyte ATP failure produces progressive myocardial depression. This node is the cellular lesion in the heart; its organism-level consequence is modelled separately as Cardiovascular Collapse.

cardiac muscle cell CL:0000746

myocardium UBERON:0002349

Downstream

Cardiovascular Collapse Loss of contractile ATP supply across the myocardium is what converts a cellular energy deficit into failure of the circulation as a whole.

Show evidence (2 references)

PMID:41204534 SUPPORT Human Clinical

"In severe cases, poisoning can result in coma, convulsions, circulatory failure, and death."

Supports circulatory failure as an outcome of severe poisoning.

PMID:26543483 SUPPORT Human Clinical

"Emergency medical services arrived and found the patient in asystole and started advanced cardiac life support protocol."

Documents asystolic cardiac arrest as the terminal cardiovascular event in an occupational cyanide exposure.

Cardiovascular Collapse

An early catecholamine-driven hypertensive phase gives way to hypotension, bradyarrhythmia and atrioventricular block, and in severe poisoning to ventricular dysrhythmia and asystole.

heart UBERON:0000948

Downstream

Hypotension

Ventricular bigeminy

Cardiac arrest

Show evidence (1 reference)

PMID:12352039 SUPPORT Human Clinical

"Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH."

Ties progressive circulatory failure, measured as falling systolic blood pressure, to the severity of the underlying poisoning.

Cerebral Energy Failure

Neuronal ATP failure disables the sodium/potassium exchangers that maintain membrane potential and the transporters that clear synaptic glutamate. The clinical expression is immediate and graded, from headache and vertigo through confusion to seizures and coma.

neuron CL:0000540

brain UBERON:0000955

Downstream

Excitotoxic Neuronal Injury Failure of glutamate clearance is the step that converts a reversible energy deficit into structural neuronal injury.

Headache

Vertigo

Confusion

Seizure

Coma

Encephalopathy

Respiratory failure Depression of the brainstem respiratory centres, which are as oxidative-metabolism-dependent as the rest of the CNS. This is the opposite end of the respiratory course from the early tachypnea driven by metabolic acidosis, and is a late and terminal event.

Show evidence (1 reference)

PMID:25692407 SUPPORT Other

"Particularly harmful to neurons is the malfunction of glutamate transport and sodium/potassium ion exchangers, contributing to excitotoxicity due to excessive extracellular glutamate"

Supports failure of glutamate transport and ion exchange as the immediate neuronal consequence of energy failure. Quoted from a rodent and iPSC study whose introduction is summarising the mechanism, hence OTHER.

Excitotoxic Neuronal Injury

Extracellular glutamate over-activates NMDA receptors, admitting calcium and driving neuronal death, amplified by reactive oxygen species and lipid peroxidation. Sustained injury in the most metabolically demanding grey matter progresses to frank necrosis.

neuron CL:0000540

Downstream

Basal Ganglia Necrosis Sustained excitotoxic injury in the most metabolically demanding grey-matter regions progresses to frank tissue necrosis.

Show evidence (1 reference)

PMID:25692407 SUPPORT Other

"Additionally, increased levels of reactive oxygen species (ROS) generated in response to cyanide poisoning initiate lipid peroxidation that is toxic to neurons"

Supports the oxidative-stress arm that amplifies excitotoxic neuronal injury. This paper reports rodent and iPSC-neuron work; the quoted sentence is its introduction summarising the mechanism, hence OTHER.

Basal Ganglia Necrosis

The globus pallidus and putamen sustain bilateral, often haemorrhagic necrosis, visible as altered signal on MRI within weeks. The lesion is not confined there: the sensorimotor cortex can show pseudolaminar necrosis for the same reason - high oxygen dependency - and imaging series also report cerebellar and cortical involvement. The node is named for the basal ganglia because that is the consistent and clinically decisive site, and it is the substrate of the delayed dystonic-parkinsonian syndrome.

globus pallidus UBERON:0001875 putamen UBERON:0001874

Downstream

Parkinsonism

Dystonia

Show evidence (3 references)

PMID:12223384 SUPPORT Human Clinical

"The toxicity of cyanide causes damage, primarily to the basal ganglia, and those changes were visible as altered signal intensity on the first MR images."

Supports basal ganglia as the primary site of structural cyanide injury.

PMID:12223384 SUPPORT Human Clinical

"Extensive areas of hemorrhagic necrosis were seen 6 weeks later."

Supports the necrotic, haemorrhagic character of the lesion and its evolution over weeks.

PMID:3225591 SUPPORT Human Clinical

"CT scan and MRI showed lesions in the basal ganglia, cerebellum and cerebral cortex consistent with reported pathological findings."

Confirms the basal ganglia as the lesion site and records the wider cerebellar and cortical involvement noted in the node description.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Cardiovascular 3

Hypotension HP:0002615

Temporal: ACUTE

Show evidence (2 references)

PMID:12352039 SUPPORT Human Clinical

"Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH."

Links falling systolic blood pressure to increasing poisoning severity as measured by lactate.

PMID:26543483 SUPPORT Human Clinical

"Following return to spontaneous circulation, the patient was hypotensive requiring dopamine and norepinephrine."

Documents vasopressor-dependent hypotension in an occupational cyanide poisoning.

Ventricular bigeminy HP:0034306

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:41204534 SUPPORT Human Clinical

"Ventricular bigeminy was observed immediately after ICU admission; therefore, intravenous lidocaine (10 mg) was administered, after which the ECG reverted to sinus rhythm."

Documents ventricular bigeminy during the intensive-care course of acute cyanide poisoning.

Cardiac arrest HP:0001695

Temporal: ACUTE

Show evidence (1 reference)

PMID:26543483 SUPPORT Human Clinical

"Emergency medical services arrived and found the patient in asystole and started advanced cardiac life support protocol."

Documents asystolic cardiac arrest following occupational cyanide exposure.

Ear 1

Vertigo HP:0002321

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."

Lists vertigo among the clinical signs.

Metabolism 2

Lactic acidosis HP:0003128

Temporal: ACUTE

Show evidence (2 references)

PMID:12352039 SUPPORT Human Clinical

"The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning."

Supports serial lactate as the severity measure for this laboratory phenotype.

PMID:41204534 SUPPORT Human Clinical

"Laboratory findings revealed severe lactic acidosis (pH 7.07) with a high lactate level (19.0 mmol/L) and hypertension."

Documents the magnitude of lactic acidosis in a severe poisoning.

Elevated serum anion gap HP:0031962

Show evidence (1 reference)

PMID:26543483 SUPPORT Human Clinical

"Laboratory tests showed the following: sodium 145 mEq/L, potassium 5.4 mEq/L, chloride 107 mEq/L, bicarbonate 13 mEq/L, blood urea nitrogen 8 mg/dL, creatinine 1.91 mg/dL, and anion gap 32.6."

Documents a markedly elevated anion gap in a fatal cyanide exposure.

Nervous System 7

Coma HP:0001259

Temporal: ACUTE

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."

Lists coma among the clinical signs of cyanide poisoning.

Seizure HP:0001250

Temporal: ACUTE

Show evidence (1 reference)

PMID:41204534 SUPPORT Human Clinical

"In severe cases, poisoning can result in coma, convulsions, circulatory failure, and death."

Names convulsions among the severe manifestations.

Encephalopathy HP:0001298

Temporal: ACUTE

Show evidence (1 reference)

PMID:25605411 SUPPORT Human Clinical

"Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides."

Directly supports encephalopathy as a manifestation of cyanide poisoning.

Headache HP:0002315

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."

Lists headache among the clinical signs.

Confusion HP:0001289

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."

Lists confusion among the clinical signs.

Parkinsonism HP:0001300

Course: PROGRESSIVE

Show evidence (2 references)

PMID:3225591 SUPPORT Human Clinical

"Progressive Parkinsonism, dystonia and apraxia of eye opening were seen after cyanide poisoning."

Primary human report of progressive parkinsonism following cyanide poisoning.

PMID:25692407 SUPPORT Other

"Typically, these patients begin to manifest symptoms and signs after a few weeks or months, with progressive rigidity accompanied by flexed upper limbs and extended lower limbs."

Describes the delayed rigid-parkinsonian presentation. Graded OTHER: this is a rodent and iPSC-neuron study, and the sentence is its introduction summarising the human case-report literature it cites, not its own data.

Dystonia HP:0001332

Show evidence (3 references)

PMID:1564480 SUPPORT Human Clinical

"A few days after an apparently full recovery he developed a severe dystonia syndrome."

Primary human report of delayed dystonia after potassium cyanide ingestion.

PMID:1564480 SUPPORT Human Clinical

"He had a positive response to an apomorphine test and showed improvement with levodopa treatment."

Documents dopaminergic responsiveness of the delayed dystonia, consistent with a striatal rather than a cortical lesion.

PMID:25692407 SUPPORT Other

"In fact, in over a dozen human suicide cases of cyanide intoxication, a delayed neurological syndrome has been documented that includes dystonia and parkinsonian signs and symptoms, even in patients who had initially appeared to have had a full recovery after the exposure"

Establishes that the delayed syndrome is a recurring finding across more than a dozen reports, not a single case. Graded OTHER: the citing paper reports rodent and iPSC-neuron work and is summarising others' cases here.

Respiratory 2

Tachypnea HP:0002789

Temporal: ACUTE

Show evidence (1 reference)

PMID:26543483 SUPPORT Human Clinical

"This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"

Lists tachypnea among the early manifestations.

Respiratory failure HP:0002878

Temporal: ACUTE

Show evidence (1 reference)

PMID:41204534 SUPPORT Human Clinical

"Therefore, clinicians should suspect cyanide poisoning in cases of unexplained hyperlactatemia, particularly in patients with symptoms such as respiratory failure, abnormal pulse rate, and even coma."

Names respiratory failure among the presenting features that should prompt suspicion of cyanide poisoning alongside unexplained hyperlactatemia.

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Genetic Associations

1

TST

Gene: TST hgnc:12388 relationship_type: MODIFIER

Show evidence (2 references)

PMID:16790311 SUPPORT In Vitro

"The P(285)A variant appears to encode a protein with a 50% decrease of in vitro intrinsic clearance compared to the wild-type enzyme."

Demonstrates a functional TST coding variant with halved intrinsic clearance.

PMID:16790311 SUPPORT In Vitro

"Additionally, the six polymorphisms located upstream the ATG initiation codon are responsible for a significant decrease (ranging from 40% to 73%) in promoter activity of a reporter gene compared to the corresponding wild-type sequence."

Demonstrates regulatory TST variants that reduce expression of the detoxifying enzyme.

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Medical Actions

7

Hydroxocobalamin

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxocobalamin CHEBI:27786

Platform: Small molecule

First-line antidote for confirmed cyanide poisoning. The cobalt(III) centre binds cyanide in a 1:1 ratio to form cyanocobalamin, which is excreted in urine. It does not impair oxygen-carrying capacity, which is the basis for giving it empirically to a fire victim whose carboxyhaemoglobin status is unknown - unlike the nitrites, which would compound the hypoxia. That empiric indication is where the evidence is weakest: a 2025 systematic review of 1238 patients found no mortality benefit in smoke inhalation and signals for acute kidney injury and methaemoglobinaemia. Chromaturia and pink skin discoloration are the usual adverse effects in confirmed poisoning.

Mechanism Target:

INHIBITS Systemic Cyanide Burden — Hydroxocobalamin sequesters free circulating cyanide as cyanocobalamin, removing it from the pool available to reach mitochondria.

Show evidence (1 reference)

PMID:8440119 SUPPORT Other

"Hydroxocobalamin has been shown to significantly reduce RBC and plasma cyanide concentrations in animals and surgical patients without producing clinically important adverse effects or toxic metabolites."

Demonstrates that hydroxocobalamin lowers the circulating cyanide burden this node represents.

Show evidence (3 references)

PMID:8989894 SUPPORT Human Clinical

"Hydroxocobalamin is an attractive antidote due to its rapid cyanide binding and its lack of serious side-effects, even in the absence of cyanide intoxication."

Supports hydroxocobalamin as the preferred antidote on binding speed and safety grounds.

PMID:17543660 SUPPORT Human Clinical

"That 71% of patients survived after treatment with hydroxocobalamin suggests that hydroxocobalamin as first-line antidotal therapy is effective and safe in acute cyanide poisoning."

Provides the clinical survival data behind first-line use in severe poisoning.

PMID:41497958 REFUTE Human Clinical

"In light of the uncertain benefits and potential risks associated with hydroxocobalamin use for cyanide poisoning from smoke inhalation injury, its administration should be approached with caution."

A 2025 systematic review contradicting the benefit of empiric hydroxocobalamin in the specific case of smoke inhalation, where cyanide toxicity is suspected rather than confirmed.

Sodium Thiosulfate

Action: Pharmacotherapy NCIT:C15986

Agent: sodium thiosulfate CHEBI:132112

Platform: Small molecule

Sulfur donor that accelerates the endogenous rhodanese reaction converting cyanide to renally excreted thiocyanate. Slower in onset than hydroxocobalamin, so it is used as an adjunct rather than sole therapy in fulminant poisoning, but it is safe to combine with hydroxocobalamin.

Mechanism Target:

ACTIVATES Rhodanese-Mediated Cyanide Detoxification — Exogenous thiosulfate relieves the sulfur-donor limitation on the rhodanese reaction, raising the rate at which cyanide is converted to thiocyanate.

Show evidence (1 reference)

PMID:34297873 SUPPORT Other

"This reaction offers a rational behind the use of thiosulfate as antidote for cyanide poisoning."

States that the rhodanese reaction is the rationale for thiosulfate therapy, quoted verbatim from the source.

Show evidence (2 references)

PMID:8989894 SUPPORT Human Clinical

"Sodium thiosulphate acts more slowly than other antidotes and is indicated in subacute cyanogen poisoning and as an adjunct to acute cyanide poisoning."

Supports the adjunctive positioning of thiosulfate and its slower onset.

PMID:25605411 SUPPORT Human Clinical

"After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen."

Documents clinical recovery after thiosulfate in cyanogenic-glycoside poisoning.

Sodium Nitrite

Action: Pharmacotherapy NCIT:C15986

Agent: sodium nitrite CHEBI:78870

Platform: Small molecule

Methaemoglobin-forming antidote used when hydroxocobalamin is unavailable. Oxidising haemoglobin iron creates methaemoglobin, which binds cyanide in preference to cytochrome c oxidase. Because the induced methaemoglobinaemia itself reduces oxygen-carrying capacity, it is a poor first choice in a fire victim who may already be carboxyhaemoglobinaemic.

Mechanism Target:

INHIBITS Cytochrome c Oxidase Inhibition — Nitrite therapy draws cyanide away from Complex IV, both by providing a methaemoglobin sink and, per in vitro work, by generating mitochondrial nitric oxide at levels high enough to antagonise the inhibition. Note this is the high-NO arm of a dose-dependent effect whose low-NO arm potentiates the inhibition instead; see the Cytochrome c Oxidase Inhibition node.

Show evidence (1 reference)

PMID:17906319 SUPPORT In Vitro

"Also, the antidotal action of sodium nitrite is partly explained by generation of high mitochondrial levels of NO, which antagonizes the CcOX inhibition."

Supports sodium nitrite acting on the Complex IV inhibition node itself, not only as a peripheral cyanide sink.

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Antidotes include oxygen, hydroxocobalamin, di-cobalt EDTA and methaemoglobin-inducers."

Places methaemoglobin inducers such as sodium nitrite within the accepted antidote set.

Amyl Nitrite

Action: Pharmacotherapy NCIT:C15986

Agent: amyl nitrite CHEBI:755931

Platform: Small molecule

Inhalational methaemoglobin-forming antidote, used as a bridge while intravenous access and definitive antidote are being arranged. Same mechanism as sodium nitrite and the same caution: the induced methaemoglobinaemia itself costs oxygen-carrying capacity, so cumulative methaemoglobin has to be watched, and it is a poor choice for a fire victim who may already be carboxyhaemoglobinaemic.

Mechanism Target:

INHIBITS Cytochrome c Oxidase Inhibition — Induced methaemoglobin competes with cytochrome c oxidase for cyanide, drawing it off the mitochondrial target.

Show evidence (2 references)

PMID:41204534 SUPPORT Human Clinical

"He was intubated with rocuronium and fentanyl and administered 0.25 mL of amyl nitrite inhalation every 5 minutes."

Documents inhalational amyl nitrite given as initial antidote before hydroxocobalamin.

PMID:41204534 SUPPORT Human Clinical

"However, as amyl nitrite and sodium nitrite induce methemoglobin, care must be taken to avoid excessive methemoglobin levels when administering these agents."

States the methaemoglobinaemia ceiling that limits both nitrite antidotes.

Dicobalt Edetate

Action: Pharmacotherapy NCIT:C15986

Agent: dicobalt edetate CHEBI:755930

Platform: Small molecule

Direct cyanide chelator, the licensed UK antidote and used in some other countries, largely displaced by hydroxocobalamin in North America. It has a narrower therapeutic index - hypertension, tachycardia and retrosternal pain are recognised adverse effects - and a porcine model found licensed doses of both it and hydroxocobalamin ineffective at less than twice the estimated lethal dose.

Mechanism Target:

INHIBITS Systemic Cyanide Burden — Chelates circulating cyanide directly, removing it from the pool available to reach mitochondria.

Show evidence (3 references)

PMID:31389254 SUPPORT Other

"Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning."

Establishes dicobalt edetate as an established antidote in clinical use.

PMID:31389254 SUPPORT Other

"Dicobalt edetate is associated with hypertension, tachycardia, and retrosternal pain"

Gives the adverse-effect profile that explains why hydroxocobalamin is preferred where both are available. Quoted up to the source's inline citation marker, which the snippet matcher strips.

PMID:8989894 SUPPORT Human Clinical

"Antidotes include oxygen, hydroxocobalamin, di-cobalt EDTA and methaemoglobin-inducers."

Places dicobalt edetate within the accepted antidote set.

High-Concentration Oxygen Therapy

Action: Oxygen Therapy NCIT:C94624

Platform: Other

100% oxygen is given despite the lesion being one of utilization rather than delivery; raising the oxygen tension appears to help overcome the reversible Complex IV inhibition by mass action and treats any co-existing carbon monoxide poisoning or hypoxaemia.

Mechanism Target:

MODULATES Cytochrome c Oxidase Inhibition — High-concentration oxygen is standard immediate care and is presumed to act by mass action against the reversible Complex IV inhibition. This edge is deliberately left uncited: the clinical recommendation is well sourced (see the treatment-level evidence), but no cited source here states the mass-action mechanism, so the link is recorded as MODULATES rather than asserted as competitive inhibition.

Show evidence (2 references)

PMID:8989894 SUPPORT Human Clinical

"Immediate treatment includes 100% oxygen, assisted ventilation, decontamination, correction of acidosis and blood pressure support."

Supports 100% oxygen as part of immediate management.

PMID:41204534 SUPPORT Human Clinical

"Oxygen therapy was initially initiated at 100% concentration and gradually reduced following improvement in lactate levels."

Documents 100% oxygen in practice, titrated against the lactate response.

Supportive Critical Care

Action: Supportive Care NCIT:C15747

Platform: Other

Airway control and mechanical ventilation, vasopressor and fluid support for haemodynamic instability, benzodiazepines for seizures, and correction of acidosis. Extracorporeal support has been used in refractory cardiogenic shock.

Mechanism Target:

MODULATES Myocardial Energy Failure — Vasopressors and ventilatory support maintain perfusion and oxygenation while antidotal therapy and endogenous detoxification remove cyanide.

Show evidence (1 reference)

PMID:8989894 SUPPORT Human Clinical

"Immediate treatment includes 100% oxygen, assisted ventilation, decontamination, correction of acidosis and blood pressure support."

Supports blood-pressure support and assisted ventilation as management of the cardiovascular failure node.

Show evidence (1 reference)

PMID:8150843 SUPPORT Human Clinical

"In survivors of fire, detoxification of cyanide can occur without specific antidotes with the use of aggressive supportive care."

States that cyanide detoxification can occur under supportive care alone in fire survivors. The source (1994) goes further than current practice, concluding that specific assay and treatment are rarely necessary in fire victims; the quote is recorded for what it says, not as an endorsement of withholding antidote.

🌍

Environmental Factors

4

Structure fire smoke inhalation

Combustion of nitrogen-containing synthetic polymers - polyurethane foam, nylon, wool, silk, melamine - in enclosed structure fires releases hydrogen cyanide gas, making fire smoke the commonest inhalational source in industrialised countries. Cyanide is inhaled alongside carbon monoxide, and the two co-toxicities have to be managed together.

Show evidence (4 references)

PMID:29939573 SUPPORT Other

"The combustion of synthetic plastics in structural fires releases hydrogen cyanide gas, making it the most common source of inhalation exposure."

Supports fire smoke as the dominant inhalational exposure route.

PMID:1944484 SUPPORT Human Clinical

"Residential fires may cause cyanide poisoning."

Establishes residential fires as a genuine cause of cyanide poisoning, measured at the scene before treatment.

PMID:29489235 SUPPORT Other

"Cyanide forms as a result of incomplete combustion of materials containing nitrogen (plastics, vinyl, acrylics, nylon, neoprene, rubber, insulation)."

Names the nitrogen-containing building materials whose incomplete combustion generates the hydrogen cyanide in fire smoke.

+ 1 more reference

Mechanism Target:

TRIGGERS Systemic Cyanide Burden — Hydrogen cyanide in fire smoke crosses the alveolar membrane directly, establishing the systemic cyanide burden within seconds of inhalation.

Show evidence (1 reference)

PMID:29939573 SUPPORT Other

"Ingestion and inhalation of toxic salts and gases are the most common sources of toxicity, respectively, though ingestion of plants, medications, and cyanogenic chemicals are alternative routes of exposure."

Supports inhalation of hydrogen cyanide gas as a principal route by which the systemic burden is established.

Occupational cyanide salt exposure

Electroplating and metal-finishing shops, photographic developing, gold and silver extraction by cyanide leaching, and fumigation all use cyanide salts in quantity, exposing workers by inhalation, ingestion and dermal contact.

Show evidence (3 references)

PMID:8989894 SUPPORT Human Clinical

"Industrial intoxications occur due to extensive use of cyanide compounds as reaction products."

Supports industrial cyanide use as an exposure category.

PMID:26543483 SUPPORT Human Clinical

"The patient was found to be unconscious in a metal chrome plating shop for undetermined duration of time near another unconscious male (Case #2)."

Documents a real two-casualty occupational exposure in a metal plating shop.

PMID:29489235 SUPPORT Other

"Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."

Independently names workplace exposure and metalworking among the recognised cyanide exposure sources.

Mechanism Target:

TRIGGERS Systemic Cyanide Burden — Workplace cyanide salts and the hydrogen cyanide they liberate on acidification are absorbed by inhalation, ingestion, or through skin, establishing the systemic cyanide burden.

Show evidence (1 reference)

PMID:29939573 SUPPORT Other

"Cyanide salts, eg, potassium cyanide, are the most common type of cyanide ingestant, though exposure to cyanogenic glycosides in plants like cassava root can be fatal as well."

Supports cyanide salts as the principal ingested form feeding the systemic burden.

Cyanogenic glycoside ingestion

Amygdalin in apricot kernels, bitter almonds and peach or apple pips, and linamarin in cassava and lima beans, release hydrogen cyanide on enzymatic hydrolysis. Because hydrolysis has to happen first, onset is delayed by 30 minutes to several hours relative to a cyanide salt. Marketing of amygdalin as "vitamin B17" has caused poisonings in patients using alternative cancer therapies.

Show evidence (3 references)

PMID:25605411 SUPPORT Human Clinical

"On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported."

Documents amygdalin and apricot kernel as the exposure source in a severe paediatric poisoning.

PMID:25605411 SUPPORT Human Clinical

"Serum cyanide level was markedly elevated."

Confirms that the cyanogenic-glycoside exposure produced a measurable systemic cyanide burden.

PMID:29489235 SUPPORT Other

"Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."

Independently names bitter almonds and apricot seeds among the recognised cyanide exposure sources.

Mechanism Target:

TRIGGERS Systemic Cyanide Burden — Ingested cyanogenic glycosides are hydrolysed by plant or gut-microbial beta-glucosidases to release hydrogen cyanide into the gut lumen, from which it is absorbed.

Show evidence (1 reference)

PMID:29939573 SUPPORT Other

"Cyanide salts, eg, potassium cyanide, are the most common type of cyanide ingestant, though exposure to cyanogenic glycosides in plants like cassava root can be fatal as well."

Supports ingested cyanogenic glycosides as a route to a fatal systemic cyanide burden.

Sodium nitroprusside infusion

Sodium nitroprusside releases cyanide during metabolism. High-dose or prolonged infusion, especially with hepatic dysfunction, can accumulate cyanide to toxic concentrations; renal dysfunction instead favours the distinct thiocyanate toxidrome.

Show evidence (2 references)

PMID:8440119 SUPPORT Other

"High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."

Supports nitroprusside infusion as an iatrogenic cyanide exposure and names its risk modifiers.

PMID:29489235 SUPPORT Other

"Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."

Independently names prolonged sodium nitroprusside administration among the recognised cyanide exposure sources.

Mechanism Target:

TRIGGERS Systemic Cyanide Burden — Cyanide liberated from the nitroprusside molecule enters the circulation directly, bypassing any absorptive barrier.

Show evidence (1 reference)

PMID:8440119 SUPPORT Other

"High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."

States that nitroprusside therapy itself generates a cyanide burden, which is the step this edge represents.

🔬

Biochemical Markers

2

Blood lactate (INCREASED)

Show evidence (2 references)

PMID:12352039 SUPPORT Human Clinical

"During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L)."

Gives the operating characteristics of the lactate threshold in non-fire cyanide poisoning.

PMID:1944484 SUPPORT Human Clinical

"Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter."

Gives the corresponding threshold derived in smoke-inhalation victims.

Blood cyanide concentration (INCREASED)

Show evidence (2 references)

PMID:8150843 SUPPORT Human Clinical

"Cyanide levels of 364 fatalities averaged 1.0 mg/L and exceeded fatal levels (> 3 mg/L) in 31 cases."

Anchors the fatal blood cyanide threshold and the distribution observed in fire fatalities.

PMID:12352039 SUPPORT Human Clinical

"Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L."

Documents the blood cyanide concentrations seen in an intensive-care cohort of acute poisonings.

🔬

Diagnosis

2

Clinical diagnosis with lactate as surrogate biomarker

There is no confirmatory test that returns in time to guide treatment. Diagnosis rests on exposure history plus the clinical toxidrome, with serial plasma lactate standing in for the unavailable cyanide assay. Blood gas with co-oximetry adds a narrowed arteriovenous oxygen difference, and carboxyhaemoglobin is measured alongside in any fire victim.

laboratory procedure NCIT:C25294

Show evidence (3 references)

PMID:35042362 SUPPORT Human Clinical

"The diagnosis can only be based on the history, clinical findings, and indirect laboratory signs."

States that the diagnosis is clinical plus indirect laboratory signs rather than confirmatory assay.

PMID:35042362 SUPPORT Human Clinical

"Direct determination of plasma cyanide levels is not generally adopted in routine clinical practice."

Establishes why the confirmatory analyte is not the diagnostic route in practice.

PMID:12352039 SUPPORT Human Clinical

"The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning."

Supports serial plasma lactate as the practical diagnostic and monitoring measurement.

Brain MRI for delayed neurological sequelae

In survivors of severe poisoning, MRI characterises the bilateral basal ganglia lesion underlying the delayed dystonic-parkinsonian syndrome. This is a prognostic and characterising study performed after the acute event, not a diagnostic test for the poisoning itself.

magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:12223384 SUPPORT Human Clinical

"The toxicity of cyanide causes damage, primarily to the basal ganglia, and those changes were visible as altered signal intensity on the first MR images."

Supports MRI as the modality that shows the basal ganglia lesion after acute poisoning.

📈

Progression

3

Acute toxidrome

Duration: Seconds to hours from exposure

Onset is seconds to minutes after hydrogen cyanide inhalation, minutes after ingestion of a cyanide salt, and 30 minutes to several hours after ingestion of cyanogenic glycosides, which must be hydrolysed first. The course runs from headache, vertigo, weakness and tachypnea, through confusion and hypotension, to seizures, coma and cardiovascular collapse, and can traverse the whole range within minutes at high dose.

Show evidence (1 reference)

PMID:26543483 SUPPORT Human Clinical

"This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"

States the ordered progression from early symptoms to seizures and coma.

Recovery

Duration: Hours to days

In a survivor treated promptly, consciousness returns as lactate falls, and the two track each other closely enough that lactate is used to titrate care. Recovery from the acute phase does not settle the neurological outcome.

Show evidence (1 reference)

PMID:41204534 SUPPORT Human Clinical

"The patient's consciousness improved with decreasing lactate levels, achieving full consciousness approximately 9 hours after poisoning."

Documents the coupled recovery of consciousness and lactate over hours.

Delayed neurological sequelae

Duration: Days to months after apparent recovery

Two distinct delayed outcomes are reported after severe poisoning, and they are not the same syndrome. One is the extrapyramidal dystonic-parkinsonian picture arising after a lucid interval, curated as the Delayed Neurological Sequelae subtype. The other is a neuropsychological deficit, principally episodic memory, which is present early and improves only partially over months. A given survivor may have either, both, or neither.

Show evidence (3 references)

PMID:24648474 SUPPORT Human Clinical

"Prominent deficits in episodic memory were noted from an early stage, which were consistent with the findings noted on structural neuroimaging."

Documents the neuropsychological arm of the delayed outcome and its imaging correlate.

PMID:24648474 SUPPORT Human Clinical

"These deficits remained persistent, although improving in severity over the follow-up period."

Establishes partial rather than complete recovery of the cognitive deficit over six months.

PMID:24648474 REFUTE Human Clinical

"No focal neurological deficits or abnormal involuntary movements emerged, and the patient's overall functional status remained satisfactory."

The same survivor developed no extrapyramidal syndrome, which is why the two delayed outcomes are recorded as separable rather than as stages of one course.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Cyanide Poisoning:

Carbon monoxide poisoning MONDO:0800373

Overlapping Features The most important differential and, in fire victims, usually a co-exposure rather than an alternative. Both are products of the same fire and both produce impaired tissue oxygen use with depressed consciousness.

Distinguishing Features

Carbon monoxide poisoning is confirmed rapidly by carboxyhaemoglobin on co-oximetry, whereas no comparably fast cyanide assay exists.
The practical consequence runs the other way from most differentials: a fire victim with a raised carboxyhaemoglobin should be presumed cyanide-exposed as well, so the two are co-treated rather than discriminated.
Carboxyhaemoglobinaemia is a reason to avoid the methaemoglobin-forming antidotes, which would compound the loss of oxygen-carrying capacity.

Show evidence (2 references)

PMID:29489235 SUPPORT Other

"Patients presenting from structure fires with carbon monoxide poisoning should be assumed to have been exposed to toxic levels of cyanide as well since most modern buildings contain these materials."

Supports treating carbon monoxide poisoning as a co-exposure to be assumed rather than a differential to be excluded.

PMID:35042362 SUPPORT Human Clinical

"We usually encounter carbon monoxide intoxication, but it is necessary to think about the possibility of poisoning by other combustion products."

Supports carbon monoxide as the expected diagnosis in inhalation injury against which cyanide must be actively considered.

Methemoglobinemia Not Yet Curated MONDO:0001117

Overlapping Features Shares cyanosis unresponsive to oxygen and a normal arterial oxygen tension with cyanide poisoning, and is additionally an iatrogenic complication of the nitrite antidotes used to treat cyanide poisoning.

Distinguishing Features

Methaemoglobin is directly measurable by co-oximetry, and the arterial blood is characteristically chocolate-brown.
Cyanide poisoning instead shows a narrowed arteriovenous oxygen difference with a normal methaemoglobin fraction, unless nitrites have already been given.

📊

Related Datasets

2

Expression data of the mouse heart of a nose-only HCN inhalation model and a subcutaneous KCN injection model geo:GSE158994

Cardiac transcriptomes from two mouse cyanide-exposure models profiled by oligonucleotide microarray - nose-only hydrogen cyanide inhalation, chosen to be relevant to structure-fire smoke exposure, and subcutaneous potassium cyanide injection, the route conventionally used for countermeasure testing. The comparison is the point: the two routes give substantially different cardiac transcriptomes at every time point within 24 hours, which bears directly on how much of the countermeasure literature built on KCN injection transfers to inhalational poisoning.

house mouse MICROARRAY n=69

PMID:33914522

Selected from `just discover-datasets` as the only DIRECT candidate; the remaining candidates were GENE_ONLY hits reached through TST and are about unrelated diseases.

Show evidence (1 reference)

GEO:GSE158994 SUPPORT Model Organism

"Although the KCN injection model has been often used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 hours after exposure."

The repository summary states the route-dependence finding that makes this dataset relevant to the myocardial arm of the pathograph and to the interpretation of antidote studies performed with injected KCN.

Regulation of Mammalian Cellular Metabolism by Endogenous Cyanide Production [TST_RNA-Seq] geo:GSE286106

RNA-seq arm of a study of endogenous cyanide production in mammalian cells, including TST manipulation. This is physiology rather than poisoning: it reports that cells make cyanide at low concentrations where it acts as a gasotransmitter, and that the same molecule impairs bioenergetics at high concentrations. It is included here because the dose-dependent flip is the biological context for the toxic node in this entry, and because it profiles the detoxifying enzyme TST that the genetic section curates as a modifier.

human BULK RNA SEQ n=12

PMID:40033006

A GENE_ONLY candidate by the discovery tool's classification, retained after manual triage because its subject is cyanide itself rather than an unrelated disease that happens to express TST.

Show evidence (1 reference)

GEO:GSE286106 SUPPORT In Vitro

"When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism, and cell proliferation, but impairs cellular bioenergetics at high concentrations."

The repository summary states the concentration-dependent reversal that separates endogenous cyanide signalling from the bioenergetic failure this entry models.

🐁

Animal Models

2

Mouse lethal cyanide poisoning model (inhaled and intraperitoneal)

Paired inhaled and intraperitoneal mouse models of lethal cyanide poisoning used to rank antidote efficacy. Cobinamide, the cobalamin precursor, outperformed hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the thiosulfate-nitrite combination, and rescued mice given cobinamide sulfite intramuscularly after more than two minutes of apnoea.

Species

Mouse

Publication

PMID:20704457

Pathograph links

Systemic Cyanide Burden perturbs fidelity: moderate observes: organism Delivers a controlled lethal systemic cyanide burden by two routes that mirror the human inhalational and parenteral exposures.

Limitations: Antidote potency ratios derived in mice have not translated into human efficacy data; cobinamide remains investigational, and the model uses pre-planned dosing with immediate treatment rather than the delayed, uncertain-dose presentation of real poisoning.

Show evidence (1 reference)

PMID:20704457 SUPPORT Model Organism

"We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice."

Establishes that the model delivers a systemic cyanide burden by two routes, which is the node this link points at.

Show evidence (1 reference)

PMID:20704457 SUPPORT Model Organism

"We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning."

Establishes the model as an antidote-ranking system and reports its principal result.

Gottingen minipig lethal KCN bolus model

Anaesthetised Gottingen minipig model in which bolus potassium cyanide injection at doses comparable to human lethal doses simulates high-dose hydrogen cyanide inhalation, used to quantify antidote efficacy against lactate and survival endpoints. Licensed doses of dicobalt edetate and hydroxocobalamin were effective at just-lethal doses and failed at less than twice the estimated LD50.

Species

Pig

Publication

PMID:31389254

Pathograph links

Anaerobic Glycolytic Shift recapitulates fidelity: moderate observes: organism Bolus KCN reproduces the dose-dependent arterial lactate rise that defines the metabolic lesion in human poisoning, and the lactate endpoint is the same one used clinically.

Limitations: Antidotes were given before exposure rather than after, which is the opposite of the clinical sequence and makes the observed efficacy an upper bound; the authors say so explicitly.

Readouts

Arterial lactate concentration

Direction: INCREASED

Interpretation: Dose-dependent arterial lactate rise as the metabolic correlate of cyanide exposure in this model.

Show evidence (1 reference)

PMID:31389254 SUPPORT Model Organism

"Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN."

Reports the arterial lactate measurement behind this readout.

Show evidence (2 references)

PMID:31389254 SUPPORT Model Organism

"We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation."

Establishes the model as a deliberate simulation of high-dose human cyanide exposure, which is what makes it informative for this node.

+ 1 more reference

Show evidence (1 reference)

PMID:31389254 SUPPORT Model Organism

"In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50."

Reports the model's principal finding on the dose ceiling of current antidotes.

{ }

Source YAML

click to show

name: Cyanide Poisoning
creation_date: "2026-09-10T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Environmental Health Disorder
- Chemical Asphyxiant Poisoning
synonyms:
- cyanide toxicity
- hydrocyanic acid poisoning
- prussic acid poisoning
- hydrogen cyanide poisoning
description: >-
  Cyanide poisoning is an acute chemical-asphyxiant toxidrome caused by exposure
  to the cyanide ion or to compounds that release it: hydrogen cyanide gas from
  the combustion of nitrogen-containing synthetic polymers in structure fires,
  alkali cyanide salts used in electroplating and metal finishing, cyanogenic
  glycosides such as amygdalin in apricot kernels and bitter almonds, and the
  metabolic breakdown of infused sodium nitroprusside. Absorbed cyanide binds
  the ferric heme a3 centre of mitochondrial cytochrome c oxidase (Complex IV)
  and arrests the terminal step of the electron transport chain, so cells cannot
  use oxygen that is being delivered normally - histotoxic, rather than hypoxic,
  hypoxia. Oxidative phosphorylation fails, ATP is depleted within minutes, and
  metabolism is forced onto anaerobic glycolysis, producing severe high-anion-gap
  lactic acidosis. The brain and myocardium, with the highest oxidative demand,
  fail first: headache, vertigo and confusion give way to coma, seizures,
  hypotension, bradyarrhythmia and cardiac arrest. Classic bedside signs (bitter
  almond odour, cherry-red skin) are unreliable and blood cyanide assays are too
  slow to guide care, so plasma lactate serves as the practical surrogate marker.
  Survivors of severe poisoning may develop a delayed dystonic-parkinsonian
  syndrome weeks to months later, correlating with bilateral globus pallidus and
  putaminal lesions. Endogenous detoxification by rhodanese (thiosulfate
  sulfurtransferase) converts cyanide to renally excreted thiocyanate but is
  sulfur-donor limited and rapidly overwhelmed, which is the pharmacologic basis
  for thiosulfate therapy. Management is hydroxocobalamin as first-line antidote,
  with sodium nitrite and sodium thiosulfate as alternatives or adjuncts, plus
  100% oxygen and haemodynamic and ventilatory support. Chronic dietary
  cyanogen exposure produces distinct entities curated separately in this
  knowledge base (see Konzo).
disease_term:
  preferred_term: cyanide poisoning
  term:
    id: MONDO:0018754
    label: cyanide poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018754
      label: cyanide poisoning
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this cyanide poisoning entry.
  icd10cm_mappings:
  - term:
      id: ICD10CM:T65.0
      label: Toxic effect of cyanides
    mapping_predicate: skos:exactMatch
    mapping_source: ICD10CM
    mapping_justification: >-
      ICD-10-CM code for toxic effect of cyanides, covering cyanide salts and
      cyanide-releasing compounds. Hydrogen cyanide gas specifically is coded
      T57.3.
parents:
- chemical poisoning
definitions:
- name: Clinical case definition for acute cyanide poisoning
  definition_type: CASE_DEFINITION
  description: >-
    Acute cyanide poisoning is a toxidrome in which absorbed cyanide inhibits
    cellular oxygen utilization, recognised from a compatible exposure history
    (fire smoke, cyanide salt, cyanogenic glycoside, or nitroprusside infusion)
    together with rapidly progressive depressed consciousness, cardiovascular
    instability, and high-anion-gap lactic acidosis. Confirmatory blood cyanide
    measurement is rarely available in time, so plasma lactate is the practical
    diagnostic surrogate.
  scope: Disease-level clinical framing for acute poisoning and its delayed sequelae
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cyanide poisoning is a life-threatening condition that impairs cellular oxygen utilization, leading to lactic acidosis."
    explanation: Supports the core disease framing as impaired cellular oxygen utilization producing lactic acidosis.
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, serum cyanide levels are not readily available in clinical settings, making diagnosis and treatment monitoring difficult."
    explanation: Supports basing the case definition on exposure history plus surrogate laboratory findings rather than a confirmatory cyanide assay.
has_subtypes:
- name: Acute Cyanide Poisoning
  display_name: Acute Cyanide Poisoning
  description: >-
    Rapid-onset poisoning after a high-dose exposure by inhalation, ingestion, or
    dermal absorption. Progression from headache, vertigo, weakness and tachypnea
    to seizures, coma and cardiovascular collapse can take minutes at high doses.
  evidence:
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"
    explanation: Supports the acute multisystem presentation and its characteristic progression.
- name: Delayed Neurological Sequelae
  display_name: Delayed Dystonic-Parkinsonian Syndrome
  description: >-
    A subset of survivors of severe acute poisoning develop a delayed
    extrapyramidal syndrome - progressive rigidity, dystonia and parkinsonism -
    emerging days to months after apparent recovery, associated with bilateral
    basal ganglia lesions on CT and MRI.
  subtype_term:
    preferred_term: cyanide-induced parkinsonism
    term:
      id: MONDO:0017640
      label: cyanide-induced parkinsonism
  evidence:
  - reference: PMID:3225591
    reference_title: "Dystonic-Parkinsonian syndrome after cyanide poisoning: clinical and MRI findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive Parkinsonism, dystonia and apraxia of eye opening were seen after cyanide poisoning."
    explanation: Primary human report of the delayed extrapyramidal syndrome that defines this subtype.
  - reference: PMID:3225591
    reference_title: "Dystonic-Parkinsonian syndrome after cyanide poisoning: clinical and MRI findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT scan and MRI showed lesions in the basal ganglia, cerebellum and cerebral cortex consistent with reported pathological findings."
    explanation: Supports the imaging correlate, and shows the lesion is not confined to the basal ganglia.
  - reference: PMID:1564480
    reference_title: "Delayed cyanide induced dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A few days after an apparently full recovery he developed a severe dystonia syndrome."
    explanation: >-
      Documents the defining latency - a lucid interval after apparent recovery -
      in a case followed for 21 years.
- name: Nitroprusside-Associated Cyanide Toxicity
  display_name: Iatrogenic (Nitroprusside) Cyanide Toxicity
  description: >-
    Cyanide released during the metabolism of infused sodium nitroprusside can
    accumulate to toxic concentrations during high-dose or prolonged infusion,
    with hepatic dysfunction raising cyanide risk and renal dysfunction raising
    the risk of the distinct thiocyanate toxidrome.
  evidence:
  - reference: PMID:8440119
    reference_title: "Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."
    explanation: Supports the iatrogenic subtype and the organ-dysfunction risk factors that define it.
pathophysiology:
- name: Systemic Cyanide Burden
  description: >-
    Cyanide reaches the systemic circulation by inhalation of hydrogen cyanide
    gas, gastric absorption of ingested cyanide salts, enzymatic hydrolysis of
    ingested cyanogenic glycosides, dermal absorption, or metabolic release from
    infused nitroprusside. Inhaled hydrogen cyanide acts fastest because it
    crosses the alveolar membrane directly.
  biological_scale: ORGANISM
  downstream:
  - target: Cytochrome c Oxidase Inhibition
    causal_link_type: DIRECT
    description: >-
      Absorbed cyanide ion distributes rapidly into cells and mitochondria,
      where it reaches its principal molecular target.
    evidence:
    - reference: PMID:41204534
      reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Once ingested, cyanide compounds are rapidly absorbed in the stomach as hydrogen cyanide and exert toxicity through cyanide ions."
      explanation: Supports the step from absorption to delivery of free cyanide ion to its cellular target.
  - target: Rhodanese-Mediated Cyanide Detoxification
    causal_link_type: DIRECT
    description: >-
      The same absorbed cyanide load is the substrate for the endogenous
      sulfurtransferase clearance pathway, which runs in parallel with toxicity.
    evidence:
    - reference: PMID:16790311
      reference_title: "Evidence for a functional genetic polymorphism of the human thiosulfate sulfurtransferase (Rhodanese), a cyanide and H2S detoxification enzyme."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Rhodanese or thiosulfate sulfurtransferase (TST) is a mitochondrial matrix enzyme that plays roles in cyanide detoxification, the formation of iron-sulfur proteins and the modification of sulfur-containing enzymes."
      explanation: >-
        Establishes that circulating cyanide is routed into the mitochondrial
        sulfurtransferase pathway, which is the step this edge represents.
  evidence:
  - reference: PMID:29939573
    reference_title: "Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dermal absorption and injection are rare but possible sources of cyanide exposure."
    explanation: Supports the breadth of absorption routes feeding this node, including the uncommon ones.
- name: Cytochrome c Oxidase Inhibition
  description: >-
    Cyanide binds with high affinity to the ferric heme a3 centre of cytochrome
    c oxidase (mitochondrial Complex IV), the oxygen-reducing terminus of the
    electron transport chain, and reversibly arrests the transfer of electrons
    to molecular oxygen. Nitric oxide modulates this in a dose-dependent and
    two-directional way: constitutive, low-level mitochondrial NO potentiates
    the inhibition, which is part of why onset is so fast, while high exogenous
    NO attenuates it - which is why the same molecule appears here as an
    aggravating factor and under Sodium Nitrite as the antidotal one.
  biological_scale: MOLECULAR
  downstream:
  - target: Oxidative Phosphorylation Failure and ATP Depletion
    causal_link_type: DIRECT
    description: >-
      Blocking the terminal electron acceptor step collapses the respiratory
      chain and with it mitochondrial ATP synthesis.
    evidence:
    - reference: PMID:41204534
      reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These ions bind to cellular cytochrome oxidase and interfere with aerobic metabolism, which generates intracellular adenosine triphosphate."
      explanation: States the causal step from Complex IV binding to failure of aerobic ATP generation.
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    modifier: DECREASED
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
  cellular_components:
  - preferred_term: mitochondrial respiratory chain complex IV
    term:
      id: GO:0045277
      label: respiratory chain complex IV
  evidence:
  - reference: PMID:17906319
    reference_title: "Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Acute cyanide toxicity is attributed to inhibition of cytochrome c oxidase (CcOX), the oxygen-reducing component of mitochondrial electron transport"
    explanation: Identifies Complex IV as the molecular target responsible for acute cyanide toxicity.
  - reference: PMID:17906319
    reference_title: "Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "It is concluded that the rapid, potent action of cyanide is due in part to mitochondrial generation of NO, which enhances inhibition of CcOX."
    explanation: Supports nitric-oxide potentiation as a contributor to the speed of Complex IV inhibition.
  - reference: PMID:37465777
    reference_title: "Cyanide Poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When cyanide enters the body via inhalation, it blocks the cells from utilizing oxygen by binding to the cytochrome oxidase in the mitochondria."
    explanation: Supports the histotoxic character of the lesion - oxygen is present but cannot be used.
- name: Rhodanese-Mediated Cyanide Detoxification
  description: >-
    Mitochondrial rhodanese (thiosulfate sulfurtransferase, TST) transfers sulfur
    from thiosulfate to cyanide, yielding thiocyanate that is excreted renally.
    3-mercaptopyruvate sulfurtransferase provides a complementary cytosolic
    route. The pathway is limited by sulfur-donor supply and is overwhelmed at
    high cyanide loads, which is exactly why supplying exogenous thiosulfate is
    an antidote rather than merely a supplement.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: thiosulfate-cyanide sulfurtransferase activity
    term:
      id: GO:0004792
      label: thiosulfate-cyanide sulfurtransferase activity
  evidence:
  - reference: PMID:16790311
    reference_title: "Evidence for a functional genetic polymorphism of the human thiosulfate sulfurtransferase (Rhodanese), a cyanide and H2S detoxification enzyme."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rhodanese or thiosulfate sulfurtransferase (TST) is a mitochondrial matrix enzyme that plays roles in cyanide detoxification, the formation of iron-sulfur proteins and the modification of sulfur-containing enzymes."
    explanation: Establishes TST as the mitochondrial enzyme that carries out cyanide detoxification.
  - reference: PMID:34297873
    reference_title: "The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This reaction offers a rational behind the use of thiosulfate as antidote for cyanide poisoning."
    explanation: >-
      Connects the endogenous sulfurtransferase reaction to the pharmacologic use
      of thiosulfate. Quoted verbatim including the source's own wording; a
      snippet never corrects the text it quotes.
- name: Oxidative Phosphorylation Failure and ATP Depletion
  description: >-
    With Complex IV blocked, the mitochondrial proton-motive force collapses and
    oxidative phosphorylation ceases, depleting cellular ATP within minutes
    despite adequate arterial oxygen content and delivery.
  biological_scale: CELLULAR
  downstream:
  - target: Anaerobic Glycolytic Shift
    causal_link_type: DIRECT
    description: >-
      ATP depletion forces compensatory anaerobic glycolysis, whose lactate
      output accumulates far faster than it can be cleared.
    evidence:
    - reference: PMID:41204534
      reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As intracellular adenosine triphosphate depletes, anaerobic metabolism accelerates, leading to increased lactic acid production and venous blood oxygen saturation."
      explanation: States the causal step from ATP depletion to lactate accumulation, and notes the accompanying rise in venous oxygen saturation.
  - target: Myocardial Energy Failure
    causal_link_type: DIRECT
    description: >-
      The myocardium is among the tissues whose contractile function fails first
      when oxidative ATP supply is cut off.
    evidence:
    - reference: PMID:41204534
      reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Given the high oxygen demand of the brain and heart, early symptoms primarily affect the central nervous and cardiovascular systems."
      explanation: Supports selective early failure of the heart on the basis of its oxidative demand.
  - target: Cerebral Energy Failure
    causal_link_type: DIRECT
    description: >-
      Neurons, with little energy reserve and high oxidative demand, lose
      ion-gradient maintenance as soon as ATP falls.
    evidence:
    - reference: PMID:41204534
      reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Given the high oxygen demand of the brain and heart, early symptoms primarily affect the central nervous and cardiovascular systems."
      explanation: Supports selective early failure of the brain on the basis of its oxidative demand.
  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
  evidence:
  - reference: PMID:25692407
    reference_title: "Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For example, in addition to binding to and poisoning hemoglobin, cyanide inhibits cytochrome c oxidase, thus blocking electron transport in the mitochondrial respiratory chain and disrupting oxidative phosphorylation"
    explanation: Supports disruption of oxidative phosphorylation as the immediate consequence of Complex IV inhibition.
- name: Anaerobic Glycolytic Shift
  description: >-
    Anaerobic glycolysis becomes the only remaining ATP source and is grossly
    insufficient, generating pyruvate that is converted to lactate. The systemic
    consequence - a severe high-anion-gap metabolic acidosis whose magnitude
    tracks the cyanide burden closely enough to serve as a surrogate assay - is
    modelled as the downstream Lactic acidosis and Elevated serum anion gap
    phenotypes rather than bundled into this cellular node.
  biological_scale: CELLULAR
  downstream:
  - target: Lactic acidosis
    causal_link_type: DIRECT
  - target: Elevated serum anion gap
    causal_link_type: DIRECT
  - target: Tachypnea
    causal_link_type: DIRECT
    description: >-
      Respiratory compensation for the metabolic acidosis, which is why
      tachypnea appears before any respiratory depression.
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using Spearman's test, there was a significant correlation between plasma lactate and blood cyanide concentrations"
    explanation: Quantifies the link between the cyanide burden and the lactate produced by this node.
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma lactate, associated with cardiovascular collapse, should suggest cyanide intoxication."
    explanation: Supports lactic acidosis as the characteristic metabolic signature of this node.
- name: Myocardial Energy Failure
  description: >-
    Cardiomyocyte ATP failure produces progressive myocardial depression. This
    node is the cellular lesion in the heart; its organism-level consequence is
    modelled separately as Cardiovascular Collapse.
  biological_scale: CELLULAR
  downstream:
  - target: Cardiovascular Collapse
    causal_link_type: DIRECT
    description: >-
      Loss of contractile ATP supply across the myocardium is what converts a
      cellular energy deficit into failure of the circulation as a whole.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In severe cases, poisoning can result in coma, convulsions, circulatory failure, and death."
    explanation: Supports circulatory failure as an outcome of severe poisoning.
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emergency medical services arrived and found the patient in asystole and started advanced cardiac life support protocol."
    explanation: Documents asystolic cardiac arrest as the terminal cardiovascular event in an occupational cyanide exposure.
- name: Cardiovascular Collapse
  description: >-
    An early catecholamine-driven hypertensive phase gives way to hypotension,
    bradyarrhythmia and atrioventricular block, and in severe poisoning to
    ventricular dysrhythmia and asystole.
  biological_scale: ORGANISM
  downstream:
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Ventricular bigeminy
    causal_link_type: DIRECT
  - target: Cardiac arrest
    causal_link_type: DIRECT
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH."
    explanation: >-
      Ties progressive circulatory failure, measured as falling systolic blood
      pressure, to the severity of the underlying poisoning.
- name: Cerebral Energy Failure
  description: >-
    Neuronal ATP failure disables the sodium/potassium exchangers that maintain
    membrane potential and the transporters that clear synaptic glutamate. The
    clinical expression is immediate and graded, from headache and vertigo
    through confusion to seizures and coma.
  biological_scale: CELLULAR
  downstream:
  - target: Excitotoxic Neuronal Injury
    causal_link_type: DIRECT
    description: >-
      Failure of glutamate clearance is the step that converts a reversible
      energy deficit into structural neuronal injury.
  - target: Headache
    causal_link_type: DIRECT
  - target: Vertigo
    causal_link_type: DIRECT
  - target: Confusion
    causal_link_type: DIRECT
  - target: Seizure
    causal_link_type: DIRECT
  - target: Coma
    causal_link_type: DIRECT
  - target: Encephalopathy
    causal_link_type: DIRECT
  - target: Respiratory failure
    causal_link_type: DIRECT
    description: >-
      Depression of the brainstem respiratory centres, which are as
      oxidative-metabolism-dependent as the rest of the CNS. This is the
      opposite end of the respiratory course from the early tachypnea driven by
      metabolic acidosis, and is a late and terminal event.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:25692407
    reference_title: "Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Particularly harmful to neurons is the malfunction of glutamate transport and sodium/potassium ion exchangers, contributing to excitotoxicity due to excessive extracellular glutamate"
    explanation: >-
      Supports failure of glutamate transport and ion exchange as the immediate
      neuronal consequence of energy failure. Quoted from a rodent and iPSC
      study whose introduction is summarising the mechanism, hence OTHER.
- name: Excitotoxic Neuronal Injury
  description: >-
    Extracellular glutamate over-activates NMDA receptors, admitting calcium and
    driving neuronal death, amplified by reactive oxygen species and lipid
    peroxidation. Sustained injury in the most metabolically demanding
    grey matter progresses to frank necrosis.
  biological_scale: CELLULAR
  downstream:
  - target: Basal Ganglia Necrosis
    causal_link_type: DIRECT
    description: >-
      Sustained excitotoxic injury in the most metabolically demanding
      grey-matter regions progresses to frank tissue necrosis.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:25692407
    reference_title: "Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additionally, increased levels of reactive oxygen species (ROS) generated in response to cyanide poisoning initiate lipid peroxidation that is toxic to neurons"
    explanation: >-
      Supports the oxidative-stress arm that amplifies excitotoxic neuronal
      injury. This paper reports rodent and iPSC-neuron work; the quoted
      sentence is its introduction summarising the mechanism, hence OTHER.
- name: Basal Ganglia Necrosis
  description: >-
    The globus pallidus and putamen sustain bilateral, often haemorrhagic
    necrosis, visible as altered signal on MRI within weeks. The lesion is not
    confined there: the sensorimotor cortex can show pseudolaminar necrosis for
    the same reason - high oxygen dependency - and imaging series also report
    cerebellar and cortical involvement. The node is named for the basal ganglia
    because that is the consistent and clinically decisive site, and it is the
    substrate of the delayed dystonic-parkinsonian syndrome.
  biological_scale: TISSUE
  downstream:
  - target: Parkinsonism
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  locations:
  - preferred_term: globus pallidus
    term:
      id: UBERON:0001875
      label: globus pallidus
  - preferred_term: putamen
    term:
      id: UBERON:0001874
      label: putamen
  evidence:
  - reference: PMID:12223384
    reference_title: "MR changes after acute cyanide intoxication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The toxicity of cyanide causes damage, primarily to the basal ganglia, and those changes were visible as altered signal intensity on the first MR images."
    explanation: Supports basal ganglia as the primary site of structural cyanide injury.
  - reference: PMID:12223384
    reference_title: "MR changes after acute cyanide intoxication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extensive areas of hemorrhagic necrosis were seen 6 weeks later."
    explanation: Supports the necrotic, haemorrhagic character of the lesion and its evolution over weeks.
  - reference: PMID:3225591
    reference_title: "Dystonic-Parkinsonian syndrome after cyanide poisoning: clinical and MRI findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT scan and MRI showed lesions in the basal ganglia, cerebellum and cerebral cortex consistent with reported pathological findings."
    explanation: >-
      Confirms the basal ganglia as the lesion site and records the wider
      cerebellar and cortical involvement noted in the node description.
phenotypes:
- category: Neurologic
  name: Coma
  description: >-
    Depressed consciousness progressing to unresponsiveness is the dominant
    presenting feature of significant acute poisoning.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
    temporality: ACUTE
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."
    explanation: Lists coma among the clinical signs of cyanide poisoning.
- category: Neurologic
  name: Seizure
  description: Generalized convulsions accompanying severe cerebral energy failure.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: ACUTE
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In severe cases, poisoning can result in coma, convulsions, circulatory failure, and death."
    explanation: Names convulsions among the severe manifestations.
- category: Neurologic
  name: Encephalopathy
  description: >-
    Diffuse cerebral dysfunction, ranging from agitation and confusion to
    profound obtundation. The cited evidence establishes it for
    cyanogenic-glycoside poisoning specifically; the coma and confusion
    phenotypes carry the corresponding evidence for the other exposure routes.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    temporality: ACUTE
  evidence:
  - reference: PMID:25605411
    reference_title: "Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides."
    explanation: Directly supports encephalopathy as a manifestation of cyanide poisoning.
- category: Neurologic
  name: Headache
  description: An early, non-specific symptom of lower-level exposure.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."
    explanation: Lists headache among the clinical signs.
- category: Neurologic
  name: Vertigo
  description: Dizziness and vertigo among the earliest neurological symptoms.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."
    explanation: Lists vertigo among the clinical signs.
- category: Neurologic
  name: Confusion
  description: Altered mentation preceding loss of consciousness.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Signs of cyanide poisoning include headache, vertigo, agitation, confusion, coma, convulsions and death."
    explanation: Lists confusion among the clinical signs.
- category: Neurologic
  name: Parkinsonism
  subtype: Delayed Neurological Sequelae
  description: >-
    Delayed-onset parkinsonism with progressive rigidity, appearing weeks to
    months after apparent recovery from severe acute poisoning.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:3225591
    reference_title: "Dystonic-Parkinsonian syndrome after cyanide poisoning: clinical and MRI findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive Parkinsonism, dystonia and apraxia of eye opening were seen after cyanide poisoning."
    explanation: Primary human report of progressive parkinsonism following cyanide poisoning.
  - reference: PMID:25692407
    reference_title: "Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Typically, these patients begin to manifest symptoms and signs after a few weeks or months, with progressive rigidity accompanied by flexed upper limbs and extended lower limbs."
    explanation: >-
      Describes the delayed rigid-parkinsonian presentation. Graded OTHER: this
      is a rodent and iPSC-neuron study, and the sentence is its introduction
      summarising the human case-report literature it cites, not its own data.
- category: Neurologic
  name: Dystonia
  subtype: Delayed Neurological Sequelae
  description: >-
    Dystonic posturing accompanying the delayed extrapyramidal syndrome in
    survivors of severe poisoning.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:1564480
    reference_title: "Delayed cyanide induced dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A few days after an apparently full recovery he developed a severe dystonia syndrome."
    explanation: Primary human report of delayed dystonia after potassium cyanide ingestion.
  - reference: PMID:1564480
    reference_title: "Delayed cyanide induced dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had a positive response to an apomorphine test and showed improvement with levodopa treatment."
    explanation: >-
      Documents dopaminergic responsiveness of the delayed dystonia, consistent
      with a striatal rather than a cortical lesion.
  - reference: PMID:25692407
    reference_title: "Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In fact, in over a dozen human suicide cases of cyanide intoxication, a delayed neurological syndrome has been documented that includes dystonia and parkinsonian signs and symptoms, even in patients who had initially appeared to have had a full recovery after the exposure"
    explanation: >-
      Establishes that the delayed syndrome is a recurring finding across more
      than a dozen reports, not a single case. Graded OTHER: the citing paper
      reports rodent and iPSC-neuron work and is summarising others' cases here.
- category: Cardiovascular
  name: Hypotension
  description: >-
    Hypotension follows the early hypertensive phase and marks decompensating
    myocardial energy failure.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
    temporality: ACUTE
  evidence:
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before antidotal treatment, plasma lactate concentration correlated positively with anion gap and inversely with systolic blood pressure, spontaneous respiratory rate, and arterial pH."
    explanation: Links falling systolic blood pressure to increasing poisoning severity as measured by lactate.
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following return to spontaneous circulation, the patient was hypotensive requiring dopamine and norepinephrine."
    explanation: Documents vasopressor-dependent hypotension in an occupational cyanide poisoning.
- category: Cardiovascular
  name: Ventricular bigeminy
  description: >-
    Ventricular ectopy and dysrhythmia accompany myocardial energy failure and
    may appear or persist after antidotal therapy has begun.
  phenotype_term:
    preferred_term: Ventricular bigeminy
    term:
      id: HP:0034306
      label: Ventricular bigeminy
    temporality: TRANSIENT
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ventricular bigeminy was observed immediately after ICU admission; therefore, intravenous lidocaine (10 mg) was administered, after which the ECG reverted to sinus rhythm."
    explanation: Documents ventricular bigeminy during the intensive-care course of acute cyanide poisoning.
- category: Cardiovascular
  name: Cardiac arrest
  description: >-
    Asystolic or dysrhythmic arrest is the terminal event in severe untreated
    poisoning and carries a poor prognosis even with prompt antidote.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
    temporality: ACUTE
  evidence:
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emergency medical services arrived and found the patient in asystole and started advanced cardiac life support protocol."
    explanation: Documents asystolic cardiac arrest following occupational cyanide exposure.
- category: Respiratory
  name: Tachypnea
  description: >-
    Hyperventilation and tachypnea appear early as a respiratory response to
    metabolic acidosis, before respiratory depression supervenes.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
    temporality: ACUTE
  evidence:
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"
    explanation: Lists tachypnea among the early manifestations.
- category: Respiratory
  name: Respiratory failure
  description: >-
    Failure of ventilation from depression of the brainstem respiratory centres,
    the terminal end of the respiratory course. Distinct from the early
    tachypnea, which is respiratory compensation for the metabolic acidosis and
    appears at the opposite end of the same course.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: ACUTE
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, clinicians should suspect cyanide poisoning in cases of unexplained hyperlactatemia, particularly in patients with symptoms such as respiratory failure, abnormal pulse rate, and even coma."
    explanation: >-
      Names respiratory failure among the presenting features that should prompt
      suspicion of cyanide poisoning alongside unexplained hyperlactatemia.
- category: Laboratory
  name: Lactic acidosis
  description: >-
    High-anion-gap lactic acidosis is close to universal in significant
    poisoning and is the practical diagnostic and monitoring surrogate for a
    blood cyanide assay that is rarely available in time.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
    temporality: ACUTE
  evidence:
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning."
    explanation: Supports serial lactate as the severity measure for this laboratory phenotype.
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings revealed severe lactic acidosis (pH 7.07) with a high lactate level (19.0 mmol/L) and hypertension."
    explanation: Documents the magnitude of lactic acidosis in a severe poisoning.
- category: Laboratory
  name: Elevated serum anion gap
  description: >-
    The lactic acidosis of cyanide poisoning presents as a wide-anion-gap
    metabolic acidosis on the basic metabolic panel.
  phenotype_term:
    preferred_term: Elevated serum anion gap
    term:
      id: HP:0031962
      label: Elevated serum anion gap
  evidence:
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory tests showed the following: sodium 145 mEq/L, potassium 5.4 mEq/L, chloride 107 mEq/L, bicarbonate 13 mEq/L, blood urea nitrogen 8 mg/dL, creatinine 1.91 mg/dL, and anion gap 32.6."
    explanation: Documents a markedly elevated anion gap in a fatal cyanide exposure.
biochemical:
- name: Blood lactate
  presence: INCREASED
  notes: >-
    Plasma lactate is the practical surrogate for an unavailable blood cyanide
    assay. In non-fire cyanide poisoning a plasma lactate at or above 8 mmol/L
    (72 mg/dL) was 94% sensitive and 70% specific for a toxic blood cyanide
    concentration; in smoke-inhalation victims a threshold above 10 mmol/L was
    the sensitive indicator. The two thresholds come from different populations
    and are not interchangeable.
  evidence:
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the course of cyanide poisonings, a plasma lactate concentration of >or=72 mg/d/L (8 mmol/L) was sensitive (94%) and moderately specific (70%) for a toxic blood cyanide concentration (>or=1.0 mg/L)."
    explanation: Gives the operating characteristics of the lactate threshold in non-fire cyanide poisoning.
  - reference: PMID:1944484
    reference_title: "Elevated blood cyanide concentrations in victims of smoke inhalation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter."
    explanation: Gives the corresponding threshold derived in smoke-inhalation victims.
- name: Blood cyanide concentration
  presence: INCREASED
  notes: >-
    Whole-blood cyanide is the confirmatory analyte but turnaround is far too
    slow to guide resuscitation. It remains essential for forensic and
    retrospective work: fire fatalities average around 1 mg/L, and concentrations
    above roughly 3 mg/L are regarded as fatal.
  evidence:
  - reference: PMID:8150843
    reference_title: "Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cyanide levels of 364 fatalities averaged 1.0 mg/L and exceeded fatal levels (> 3 mg/L) in 31 cases."
    explanation: Anchors the fatal blood cyanide threshold and the distribution observed in fire fatalities.
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Before antidotal treatment, the median plasma lactate concentration was 168 mg/dL, the median blood cyanide concentration was 4.2 mg/L."
    explanation: Documents the blood cyanide concentrations seen in an intensive-care cohort of acute poisonings.
genetic:
- name: TST
  relationship_type: MODIFIER
  gene_term:
    preferred_term: TST
    term:
      id: hgnc:12388
      label: TST
  notes: >-
    TST encodes rhodanese (thiosulfate sulfurtransferase), the mitochondrial
    enzyme that detoxifies cyanide to thiocyanate. Functional promoter and
    coding polymorphisms reduce enzyme expression and intrinsic clearance, so
    TST genotype is a plausible determinant of individual cyanide susceptibility.
    These are population-frequency modifier alleles, not Mendelian pathogenic
    variants, and they have not been validated as clinical risk predictors in
    poisoned cohorts.
  evidence:
  - reference: PMID:16790311
    reference_title: "Evidence for a functional genetic polymorphism of the human thiosulfate sulfurtransferase (Rhodanese), a cyanide and H2S detoxification enzyme."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The P(285)A variant appears to encode a protein with a 50% decrease of in vitro intrinsic clearance compared to the wild-type enzyme."
    explanation: Demonstrates a functional TST coding variant with halved intrinsic clearance.
  - reference: PMID:16790311
    reference_title: "Evidence for a functional genetic polymorphism of the human thiosulfate sulfurtransferase (Rhodanese), a cyanide and H2S detoxification enzyme."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, the six polymorphisms located upstream the ATG initiation codon are responsible for a significant decrease (ranging from 40% to 73%) in promoter activity of a reporter gene compared to the corresponding wild-type sequence."
    explanation: Demonstrates regulatory TST variants that reduce expression of the detoxifying enzyme.
environmental:
- name: Structure fire smoke inhalation
  exposure_term:
    preferred_term: exposure to hydrogen cyanide
    term:
      id: ECTO:9001137
      label: exposure to hydrogen cyanide
  description: >-
    Combustion of nitrogen-containing synthetic polymers - polyurethane foam,
    nylon, wool, silk, melamine - in enclosed structure fires releases hydrogen
    cyanide gas, making fire smoke the commonest inhalational source in
    industrialised countries. Cyanide is inhaled alongside carbon monoxide, and
    the two co-toxicities have to be managed together.
  evidence:
  - reference: PMID:29939573
    reference_title: "Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The combustion of synthetic plastics in structural fires releases hydrogen cyanide gas, making it the most common source of inhalation exposure."
    explanation: Supports fire smoke as the dominant inhalational exposure route.
  - reference: PMID:1944484
    reference_title: "Elevated blood cyanide concentrations in victims of smoke inhalation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Residential fires may cause cyanide poisoning."
    explanation: Establishes residential fires as a genuine cause of cyanide poisoning, measured at the scene before treatment.
  - reference: PMID:29489235
    reference_title: "Hyperbaric Evaluation and Treatment of Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cyanide forms as a  result of incomplete combustion of materials containing nitrogen (plastics, vinyl, acrylics, nylon, neoprene, rubber, insulation)."
    explanation: Names the nitrogen-containing building materials whose incomplete combustion generates the hydrogen cyanide in fire smoke.
  - reference: PMID:8150843
    reference_title: "Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Cyanide poisoning is infrequent in fire fatalities, and when present it is associated with significant carboxyhemoglobinemia."
    explanation: >-
      A forensic series that argues against fire smoke being a frequent cause of
      clinically decisive cyanide poisoning, and against cyanide acting
      independently of carbon monoxide. Recorded here because the weight of this
      exposure route is genuinely contested.
  influences_mechanisms:
  - target: Systemic Cyanide Burden
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Hydrogen cyanide in fire smoke crosses the alveolar membrane directly,
      establishing the systemic cyanide burden within seconds of inhalation.
    evidence:
    - reference: PMID:29939573
      reference_title: "Cyanide Toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Ingestion and inhalation of toxic salts and gases are the most common sources of toxicity, respectively, though ingestion of plants, medications, and cyanogenic chemicals are alternative routes of exposure."
      explanation: Supports inhalation of hydrogen cyanide gas as a principal route by which the systemic burden is established.
- name: Occupational cyanide salt exposure
  exposure_term:
    preferred_term: exposure to cyanide
    term:
      id: ECTO:9000449
      label: exposure to cyanide
  description: >-
    Electroplating and metal-finishing shops, photographic developing, gold and
    silver extraction by cyanide leaching, and fumigation all use cyanide salts
    in quantity, exposing workers by inhalation, ingestion and dermal contact.
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Industrial intoxications occur due to extensive use of cyanide compounds as reaction products."
    explanation: Supports industrial cyanide use as an exposure category.
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was found to be unconscious in a metal chrome plating shop for undetermined duration of time near another unconscious male (Case #2)."
    explanation: Documents a real two-casualty occupational exposure in a metal plating shop.
  - reference: PMID:29489235
    reference_title: "Hyperbaric Evaluation and Treatment of Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."
    explanation: "Independently names workplace exposure and metalworking among the recognised cyanide exposure sources."
  influences_mechanisms:
  - target: Systemic Cyanide Burden
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Workplace cyanide salts and the hydrogen cyanide they liberate on
      acidification are absorbed by inhalation, ingestion, or through skin,
      establishing the systemic cyanide burden.
    evidence:
    - reference: PMID:29939573
      reference_title: "Cyanide Toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cyanide salts, eg, potassium cyanide, are the most common type of cyanide ingestant, though exposure to cyanogenic glycosides in plants like cassava root can be fatal as well."
      explanation: Supports cyanide salts as the principal ingested form feeding the systemic burden.
- name: Cyanogenic glycoside ingestion
  exposure_term:
    preferred_term: exposure to cyanide
    term:
      id: ECTO:9000449
      label: exposure to cyanide
  description: >-
    Amygdalin in apricot kernels, bitter almonds and peach or apple pips, and
    linamarin in cassava and lima beans, release hydrogen cyanide on enzymatic
    hydrolysis. Because hydrolysis has to happen first, onset is delayed by
    30 minutes to several hours relative to a cyanide salt. Marketing of
    amygdalin as "vitamin B17" has caused poisonings in patients using
    alternative cancer therapies.
  evidence:
  - reference: PMID:25605411
    reference_title: "Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On detailed questioning of the parents, the use of CAM including intravenous and oral \"vitamin B 17\" (amygdalin) and oral apricot kernel was reported."
    explanation: Documents amygdalin and apricot kernel as the exposure source in a severe paediatric poisoning.
  - reference: PMID:25605411
    reference_title: "Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum cyanide level was markedly elevated."
    explanation: Confirms that the cyanogenic-glycoside exposure produced a measurable systemic cyanide burden.
  - reference: PMID:29489235
    reference_title: "Hyperbaric Evaluation and Treatment of Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."
    explanation: "Independently names bitter almonds and apricot seeds among the recognised cyanide exposure sources."
  influences_mechanisms:
  - target: Systemic Cyanide Burden
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Ingested cyanogenic glycosides are hydrolysed by plant or gut-microbial
      beta-glucosidases to release hydrogen cyanide into the gut lumen, from
      which it is absorbed.
    evidence:
    - reference: PMID:29939573
      reference_title: "Cyanide Toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cyanide salts, eg, potassium cyanide, are the most common type of cyanide ingestant, though exposure to cyanogenic glycosides in plants like cassava root can be fatal as well."
      explanation: Supports ingested cyanogenic glycosides as a route to a fatal systemic cyanide burden.
- name: Sodium nitroprusside infusion
  exposure_term:
    preferred_term: exposure to cyanide
    term:
      id: ECTO:9000449
      label: exposure to cyanide
  description: >-
    Sodium nitroprusside releases cyanide during metabolism. High-dose or
    prolonged infusion, especially with hepatic dysfunction, can accumulate
    cyanide to toxic concentrations; renal dysfunction instead favours the
    distinct thiocyanate toxidrome.
  evidence:
  - reference: PMID:8440119
    reference_title: "Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."
    explanation: Supports nitroprusside infusion as an iatrogenic cyanide exposure and names its risk modifiers.
  - reference: PMID:29489235
    reference_title: "Hyperbaric Evaluation and Treatment of Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Other sources include workplace exposure, prolonged administration of sodium nitroprusside, insecticides, metalworking, bitter almonds, and the seeds of some fruits such as apricots."
    explanation: "Independently names prolonged sodium nitroprusside administration among the recognised cyanide exposure sources."
  influences_mechanisms:
  - target: Systemic Cyanide Burden
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Cyanide liberated from the nitroprusside molecule enters the circulation
      directly, bypassing any absorptive barrier.
    evidence:
    - reference: PMID:8440119
      reference_title: "Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "High-dose or prolonged therapy with nitroprusside in patients with hepatic or renal dysfunction increases the risk for nitroprusside-induced cyanide or thiocyanate toxicity, respectively."
      explanation: >-
        States that nitroprusside therapy itself generates a cyanide burden,
        which is the step this edge represents.
treatments:
- name: Hydroxocobalamin
  description: >-
    First-line antidote for confirmed cyanide poisoning. The cobalt(III) centre
    binds cyanide in a 1:1 ratio to form cyanocobalamin, which is excreted in
    urine. It does not impair oxygen-carrying capacity, which is the basis for
    giving it empirically to a fire victim whose carboxyhaemoglobin status is
    unknown - unlike the nitrites, which would compound the hypoxia. That
    empiric indication is where the evidence is weakest: a 2025 systematic
    review of 1238 patients found no mortality benefit in smoke inhalation and
    signals for acute kidney injury and methaemoglobinaemia. Chromaturia and
    pink skin discoloration are the usual adverse effects in confirmed
    poisoning.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  target_mechanisms:
  - target: Systemic Cyanide Burden
    treatment_effect: INHIBITS
    description: >-
      Hydroxocobalamin sequesters free circulating cyanide as cyanocobalamin,
      removing it from the pool available to reach mitochondria.
    evidence:
    - reference: PMID:8440119
      reference_title: "Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Hydroxocobalamin has been shown to significantly reduce RBC and plasma cyanide concentrations in animals and surgical patients without producing clinically important adverse effects or toxic metabolites."
      explanation: Demonstrates that hydroxocobalamin lowers the circulating cyanide burden this node represents.
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydroxocobalamin is an attractive antidote due to its rapid cyanide binding and its lack of serious side-effects, even in the absence of cyanide intoxication."
    explanation: Supports hydroxocobalamin as the preferred antidote on binding speed and safety grounds.
  - reference: PMID:17543660
    reference_title: "Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "That 71% of patients survived after treatment with hydroxocobalamin suggests that hydroxocobalamin as first-line antidotal therapy is effective and safe in acute cyanide poisoning."
    explanation: Provides the clinical survival data behind first-line use in severe poisoning.
  - reference: PMID:41497958
    reference_title: "Evidence for Hydroxocobalamin in Cyanide Toxicity Caused by Smoke Inhalation: An Updated Systematic Review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In light of the uncertain benefits and potential risks associated with hydroxocobalamin use for cyanide poisoning from smoke inhalation injury, its administration should be approached with caution."
    explanation: >-
      A 2025 systematic review contradicting the benefit of empiric
      hydroxocobalamin in the specific case of smoke inhalation, where cyanide
      toxicity is suspected rather than confirmed.
- name: Sodium Thiosulfate
  description: >-
    Sulfur donor that accelerates the endogenous rhodanese reaction converting
    cyanide to renally excreted thiocyanate. Slower in onset than
    hydroxocobalamin, so it is used as an adjunct rather than sole therapy in
    fulminant poisoning, but it is safe to combine with hydroxocobalamin.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium thiosulfate
      term:
        id: CHEBI:132112
        label: sodium thiosulfate
  target_mechanisms:
  - target: Rhodanese-Mediated Cyanide Detoxification
    treatment_effect: ACTIVATES
    description: >-
      Exogenous thiosulfate relieves the sulfur-donor limitation on the
      rhodanese reaction, raising the rate at which cyanide is converted to
      thiocyanate.
    evidence:
    - reference: PMID:34297873
      reference_title: "The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This reaction offers a rational behind the use of thiosulfate as antidote for cyanide poisoning."
      explanation: >-
        States that the rhodanese reaction is the rationale for thiosulfate
        therapy, quoted verbatim from the source.
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sodium thiosulphate acts more slowly than other antidotes and is indicated in subacute cyanogen poisoning and as an adjunct to acute cyanide poisoning."
    explanation: Supports the adjunctive positioning of thiosulfate and its slower onset.
  - reference: PMID:25605411
    reference_title: "Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen."
    explanation: Documents clinical recovery after thiosulfate in cyanogenic-glycoside poisoning.
- name: Sodium Nitrite
  description: >-
    Methaemoglobin-forming antidote used when hydroxocobalamin is unavailable.
    Oxidising haemoglobin iron creates methaemoglobin, which binds cyanide in
    preference to cytochrome c oxidase. Because the induced methaemoglobinaemia
    itself reduces oxygen-carrying capacity, it is a poor first choice in a fire
    victim who may already be carboxyhaemoglobinaemic.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium nitrite
      term:
        id: CHEBI:78870
        label: sodium nitrite
  target_mechanisms:
  - target: Cytochrome c Oxidase Inhibition
    treatment_effect: INHIBITS
    description: >-
      Nitrite therapy draws cyanide away from Complex IV, both by providing a
      methaemoglobin sink and, per in vitro work, by generating mitochondrial
      nitric oxide at levels high enough to antagonise the inhibition. Note this
      is the high-NO arm of a dose-dependent effect whose low-NO arm potentiates
      the inhibition instead; see the Cytochrome c Oxidase Inhibition node.
    evidence:
    - reference: PMID:17906319
      reference_title: "Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Also, the antidotal action of sodium nitrite is partly explained by generation of high mitochondrial levels of NO, which antagonizes the CcOX inhibition."
      explanation: Supports sodium nitrite acting on the Complex IV inhibition node itself, not only as a peripheral cyanide sink.
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antidotes include oxygen, hydroxocobalamin, di-cobalt EDTA and methaemoglobin-inducers."
    explanation: Places methaemoglobin inducers such as sodium nitrite within the accepted antidote set.
- name: Amyl Nitrite
  description: >-
    Inhalational methaemoglobin-forming antidote, used as a bridge while
    intravenous access and definitive antidote are being arranged. Same
    mechanism as sodium nitrite and the same caution: the induced
    methaemoglobinaemia itself costs oxygen-carrying capacity, so cumulative
    methaemoglobin has to be watched, and it is a poor choice for a fire victim
    who may already be carboxyhaemoglobinaemic.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amyl nitrite
      term:
        id: CHEBI:755931
        label: amyl nitrite
  target_mechanisms:
  - target: Cytochrome c Oxidase Inhibition
    treatment_effect: INHIBITS
    description: >-
      Induced methaemoglobin competes with cytochrome c oxidase for cyanide,
      drawing it off the mitochondrial target.
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was intubated with rocuronium and fentanyl and administered 0.25 mL of amyl nitrite inhalation every 5 minutes."
    explanation: Documents inhalational amyl nitrite given as initial antidote before hydroxocobalamin.
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, as amyl nitrite and sodium nitrite induce methemoglobin, care must be taken to avoid excessive methemoglobin levels when administering these agents."
    explanation: States the methaemoglobinaemia ceiling that limits both nitrite antidotes.
- name: Dicobalt Edetate
  description: >-
    Direct cyanide chelator, the licensed UK antidote and used in some other
    countries, largely displaced by hydroxocobalamin in North America. It has a
    narrower therapeutic index - hypertension, tachycardia and retrosternal pain
    are recognised adverse effects - and a porcine model found licensed doses of
    both it and hydroxocobalamin ineffective at less than twice the estimated
    lethal dose.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dicobalt edetate
      term:
        id: CHEBI:755930
        label: dicobalt edetate
  target_mechanisms:
  - target: Systemic Cyanide Burden
    treatment_effect: INHIBITS
    description: >-
      Chelates circulating cyanide directly, removing it from the pool available
      to reach mitochondria.
  evidence:
  - reference: PMID:31389254
    reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning."
    explanation: Establishes dicobalt edetate as an established antidote in clinical use.
  - reference: PMID:31389254
    reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dicobalt edetate is associated with hypertension, tachycardia, and retrosternal pain"
    explanation: >-
      Gives the adverse-effect profile that explains why hydroxocobalamin is
      preferred where both are available. Quoted up to the source's inline
      citation marker, which the snippet matcher strips.
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antidotes include oxygen, hydroxocobalamin, di-cobalt EDTA and methaemoglobin-inducers."
    explanation: Places dicobalt edetate within the accepted antidote set.
- name: High-Concentration Oxygen Therapy
  description: >-
    100% oxygen is given despite the lesion being one of utilization rather than
    delivery; raising the oxygen tension appears to help overcome the reversible
    Complex IV inhibition by mass action and treats any co-existing carbon
    monoxide poisoning or hypoxaemia.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Oxygen Therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  target_mechanisms:
  - target: Cytochrome c Oxidase Inhibition
    treatment_effect: MODULATES
    description: >-
      High-concentration oxygen is standard immediate care and is presumed to
      act by mass action against the reversible Complex IV inhibition. This edge
      is deliberately left uncited: the clinical recommendation is well
      sourced (see the treatment-level evidence), but no cited source here
      states the mass-action mechanism, so the link is recorded as MODULATES
      rather than asserted as competitive inhibition.
  evidence:
  - reference: PMID:8989894
    reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immediate treatment includes 100% oxygen, assisted ventilation, decontamination, correction of acidosis and blood pressure support."
    explanation: Supports 100% oxygen as part of immediate management.
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oxygen therapy was initially initiated at 100% concentration and gradually reduced following improvement in lactate levels."
    explanation: Documents 100% oxygen in practice, titrated against the lactate response.
- name: Supportive Critical Care
  description: >-
    Airway control and mechanical ventilation, vasopressor and fluid support for
    haemodynamic instability, benzodiazepines for seizures, and correction of
    acidosis. Extracorporeal support has been used in refractory cardiogenic
    shock.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Myocardial Energy Failure
    treatment_effect: MODULATES
    description: >-
      Vasopressors and ventilatory support maintain perfusion and oxygenation
      while antidotal therapy and endogenous detoxification remove cyanide.
    evidence:
    - reference: PMID:8989894
      reference_title: "Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immediate treatment includes 100% oxygen, assisted ventilation, decontamination, correction of acidosis and blood pressure support."
      explanation: Supports blood-pressure support and assisted ventilation as management of the cardiovascular failure node.
  evidence:
  - reference: PMID:8150843
    reference_title: "Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In survivors of fire, detoxification of cyanide can occur without specific antidotes with the use of aggressive supportive care."
    explanation: >-
      States that cyanide detoxification can occur under supportive care alone
      in fire survivors. The source (1994) goes further than current practice,
      concluding that specific assay and treatment are rarely necessary in fire
      victims; the quote is recorded for what it says, not as an endorsement of
      withholding antidote.
animal_models:
- name: Mouse lethal cyanide poisoning model (inhaled and intraperitoneal)
  species: Mouse
  publication: PMID:20704457
  description: >-
    Paired inhaled and intraperitoneal mouse models of lethal cyanide poisoning
    used to rank antidote efficacy. Cobinamide, the cobalamin precursor,
    outperformed hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the
    thiosulfate-nitrite combination, and rescued mice given cobinamide sulfite
    intramuscularly after more than two minutes of apnoea.
  evidence:
  - reference: PMID:20704457
    reference_title: "Cobinamide is superior to other treatments in a mouse model of cyanide poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning."
    explanation: Establishes the model as an antidote-ranking system and reports its principal result.
  modeled_mechanisms:
  - target: Systemic Cyanide Burden
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Delivers a controlled lethal systemic cyanide burden by two routes that
      mirror the human inhalational and parenteral exposures.
    limitations: >-
      Antidote potency ratios derived in mice have not translated into human
      efficacy data; cobinamide remains investigational, and the model uses
      pre-planned dosing with immediate treatment rather than the delayed,
      uncertain-dose presentation of real poisoning.
    evidence:
    - reference: PMID:20704457
      reference_title: "Cobinamide is superior to other treatments in a mouse model of cyanide poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice."
      explanation: >-
        Establishes that the model delivers a systemic cyanide burden by two
        routes, which is the node this link points at.
- name: Gottingen minipig lethal KCN bolus model
  species: Pig
  publication: PMID:31389254
  description: >-
    Anaesthetised Gottingen minipig model in which bolus potassium cyanide
    injection at doses comparable to human lethal doses simulates high-dose
    hydrogen cyanide inhalation, used to quantify antidote efficacy against
    lactate and survival endpoints. Licensed doses of dicobalt edetate and
    hydroxocobalamin were effective at just-lethal doses and failed at less than
    twice the estimated LD50.
  evidence:
  - reference: PMID:31389254
    reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50."
    explanation: Reports the model's principal finding on the dose ceiling of current antidotes.
  modeled_mechanisms:
  - target: Anaerobic Glycolytic Shift
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Bolus KCN reproduces the dose-dependent arterial lactate rise that defines
      the metabolic lesion in human poisoning, and the lactate endpoint is the
      same one used clinically.
    limitations: >-
      Antidotes were given before exposure rather than after, which is the
      opposite of the clinical sequence and makes the observed efficacy an upper
      bound; the authors say so explicitly.
    evidence:
    - reference: PMID:31389254
      reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation."
      explanation: >-
        Establishes the model as a deliberate simulation of high-dose human
        cyanide exposure, which is what makes it informative for this node.
    - reference: PMID:31389254
      reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Doses were similar to human lethal doses of KCN."
      explanation: >-
        Supports treating the model's metabolic response as informative for
        human poisoning, since the exposure is dosed to the human lethal range.
    readouts:
    - name: Arterial lactate concentration
      target: Anaerobic Glycolytic Shift
      direction: INCREASED
      interpretation: Dose-dependent arterial lactate rise as the metabolic correlate of cyanide exposure in this model.
      evidence:
      - reference: PMID:31389254
        reference_title: "Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN."
        explanation: Reports the arterial lactate measurement behind this readout.
discussions:
- discussion_id: cyanide_empiric_hydroxocobalamin_smoke_inhalation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does empiric hydroxocobalamin improve outcome in smoke-inhalation victims
    with suspected but unconfirmed cyanide toxicity?
  attaches_to:
  - treatments#Hydroxocobalamin
  - environmental#Structure fire smoke inhalation
  rationale: >-
    Hydroxocobalamin is first-line for confirmed cyanide poisoning, and its
    safety profile is what justifies giving it empirically at a fire scene where
    no cyanide assay is available. But the evidence for that empiric use is thin:
    a 2025 systematic review of six studies and 1238 patients found similar
    mortality between hydroxocobalamin and supportive treatment, with signals for
    acute kidney injury and methaemoglobinaemia, and could not pool the data. The
    same uncertainty runs the other way in the exposure literature, where a
    forensic series argues cyanide is an infrequent independent contributor to
    fire deaths. Resolving it needs a randomised trial that has never been done.
  evidence:
  - reference: PMID:41497958
    reference_title: "Evidence for Hydroxocobalamin in Cyanide Toxicity Caused by Smoke Inhalation: An Updated Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Well-designed randomized controlled trials are urgently needed to establish optimal treatment strategies for this patient population."
    explanation: States the gap directly, as the systematic review's own conclusion.
  - reference: PMID:41497958
    reference_title: "Evidence for Hydroxocobalamin in Cyanide Toxicity Caused by Smoke Inhalation: An Updated Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two studies reported mortality rates, which were found to be similar between the hydroxocobalamin and supportive treatment groups."
    explanation: Quantifies the absent mortality benefit that makes this a live question.
  - reference: PMID:29021725
    reference_title: "Prehospital hydroxocobalamin for inhalation injury and cyanide toxicity in the United States - analysis of a database and survey of ems providers."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a small sample, patients who received prehospital hydroxocobalamin had improved survival."
    explanation: >-
      Cuts the other way from the systematic review, which is why the question is
      open rather than settled. Its own authors flag the sample size; the survey
      arm reports only 38 percent of responding US EMS agencies carrying any
      cyanide antidote, so practice is not converging either.
- discussion_id: cyanide_tst_genotype_susceptibility
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does TST (rhodanese) genotype predict individual susceptibility to cyanide
    poisoning in exposed humans?
  attaches_to:
  - genetic#TST
  - pathophysiology#Rhodanese-Mediated Cyanide Detoxification
  rationale: >-
    The enzymology is settled: functional TST promoter and coding variants cut
    expression by 40-73% and intrinsic clearance by half. What is missing is any
    demonstration that carriers of these alleles are actually more susceptible.
    The variants were characterised in fifty French individuals with no exposure
    outcome attached, and no poisoned or occupationally exposed cohort has been
    genotyped. Until one is, the pathway from genotype to clinical risk is an
    inference from in vitro clearance, not an observation.
  evidence:
  - reference: PMID:16790311
    reference_title: "Evidence for a functional genetic polymorphism of the human thiosulfate sulfurtransferase (Rhodanese), a cyanide and H2S detoxification enzyme."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This work constitutes the first report of the existence of a functional genetic polymorphism affecting TST activity and should be of great help to investigate certain disorders for which impairment of CN(-) or H(2)S detoxification have been suggested to be involved."
    explanation: >-
      The source frames its own result as a tool for future investigation of
      cyanide-detoxification disorders, which is precisely the study that has not
      been done.
diagnosis:
- name: Clinical diagnosis with lactate as surrogate biomarker
  description: >-
    There is no confirmatory test that returns in time to guide treatment.
    Diagnosis rests on exposure history plus the clinical toxidrome, with serial
    plasma lactate standing in for the unavailable cyanide assay. Blood gas with
    co-oximetry adds a narrowed arteriovenous oxygen difference, and
    carboxyhaemoglobin is measured alongside in any fire victim.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:35042362
    reference_title: "Cyanide poisoning in patients with inhalation injury - the phantom menace."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis can only be based on the history, clinical findings, and indirect laboratory signs."
    explanation: States that the diagnosis is clinical plus indirect laboratory signs rather than confirmatory assay.
  - reference: PMID:35042362
    reference_title: "Cyanide poisoning in patients with inhalation injury - the phantom menace."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct determination of plasma cyanide levels is not generally adopted in routine clinical practice."
    explanation: Establishes why the confirmatory analyte is not the diagnostic route in practice.
  - reference: PMID:12352039
    reference_title: "Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The immediate and serial measurement of plasma lactate concentrations is useful in assessing the severity of cyanide poisoning."
    explanation: Supports serial plasma lactate as the practical diagnostic and monitoring measurement.
- name: Brain MRI for delayed neurological sequelae
  description: >-
    In survivors of severe poisoning, MRI characterises the bilateral basal
    ganglia lesion underlying the delayed dystonic-parkinsonian syndrome. This is
    a prognostic and characterising study performed after the acute event, not a
    diagnostic test for the poisoning itself.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:12223384
    reference_title: "MR changes after acute cyanide intoxication."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The toxicity of cyanide causes damage, primarily to the basal ganglia, and those changes were visible as altered signal intensity on the first MR images."
    explanation: Supports MRI as the modality that shows the basal ganglia lesion after acute poisoning.
differential_diagnoses:
- name: Carbon monoxide poisoning
  disease_term:
    preferred_term: carbon monoxide poisoning
    term:
      id: MONDO:0800373
      label: carbon monoxide poisoning
  description: >-
    The most important differential and, in fire victims, usually a
    co-exposure rather than an alternative. Both are products of the same fire
    and both produce impaired tissue oxygen use with depressed consciousness.
  distinguishing_features:
  - >-
    Carbon monoxide poisoning is confirmed rapidly by carboxyhaemoglobin on
    co-oximetry, whereas no comparably fast cyanide assay exists.
  - >-
    The practical consequence runs the other way from most differentials: a fire
    victim with a raised carboxyhaemoglobin should be presumed cyanide-exposed as
    well, so the two are co-treated rather than discriminated.
  - >-
    Carboxyhaemoglobinaemia is a reason to avoid the methaemoglobin-forming
    antidotes, which would compound the loss of oxygen-carrying capacity.
  evidence:
  - reference: PMID:29489235
    reference_title: "Hyperbaric Evaluation and Treatment of Cyanide Toxicity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients presenting from structure fires with carbon monoxide poisoning should be assumed to have been exposed to toxic levels of cyanide as well since most modern buildings contain these materials."
    explanation: Supports treating carbon monoxide poisoning as a co-exposure to be assumed rather than a differential to be excluded.
  - reference: PMID:35042362
    reference_title: "Cyanide poisoning in patients with inhalation injury - the phantom menace."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We usually encounter carbon monoxide intoxication, but it is necessary to think about the possibility of poisoning by other combustion products."
    explanation: Supports carbon monoxide as the expected diagnosis in inhalation injury against which cyanide must be actively considered.
- name: Methemoglobinemia
  disease_term:
    preferred_term: methemoglobinemia
    term:
      id: MONDO:0001117
      label: methemoglobinemia
  description: >-
    Shares cyanosis unresponsive to oxygen and a normal arterial oxygen tension
    with cyanide poisoning, and is additionally an iatrogenic complication of
    the nitrite antidotes used to treat cyanide poisoning.
  distinguishing_features:
  - >-
    Methaemoglobin is directly measurable by co-oximetry, and the arterial blood
    is characteristically chocolate-brown.
  - >-
    Cyanide poisoning instead shows a narrowed arteriovenous oxygen difference
    with a normal methaemoglobin fraction, unless nitrites have already been
    given.
  notes: >-
    Left without an evidence item: no reference cached for this entry states the
    cyanide-versus-methaemoglobinaemia distinction, and the differential is
    recorded from the co-oximetry and antidote-toxicity facts curated elsewhere
    in this entry rather than from a quotable source.
progression:
- phase: Acute toxidrome
  duration: Seconds to hours from exposure
  notes: >-
    Onset is seconds to minutes after hydrogen cyanide inhalation, minutes after
    ingestion of a cyanide salt, and 30 minutes to several hours after ingestion
    of cyanogenic glycosides, which must be hydrolysed first. The course runs
    from headache, vertigo, weakness and tachypnea, through confusion and
    hypotension, to seizures, coma and cardiovascular collapse, and can traverse
    the whole range within minutes at high dose.
  evidence:
  - reference: PMID:26543483
    reference_title: "Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate Treatments with Two Outcomes following One Exposure Event."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This process prevents aerobic metabolism, which results in diffuse clinical symptoms such as dizziness, headache, weakness, and tachypnea, with progression to seizures, paralysis, and coma"
    explanation: States the ordered progression from early symptoms to seizures and coma.
- phase: Recovery
  duration: Hours to days
  notes: >-
    In a survivor treated promptly, consciousness returns as lactate falls, and
    the two track each other closely enough that lactate is used to titrate
    care. Recovery from the acute phase does not settle the neurological
    outcome.
  evidence:
  - reference: PMID:41204534
    reference_title: "A case report of acute cyanide poisoning treated with lactate as an indicator."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's consciousness improved with decreasing lactate levels, achieving full consciousness approximately 9 hours after poisoning."
    explanation: Documents the coupled recovery of consciousness and lactate over hours.
- phase: Delayed neurological sequelae
  duration: Days to months after apparent recovery
  notes: >-
    Two distinct delayed outcomes are reported after severe poisoning, and they
    are not the same syndrome. One is the extrapyramidal dystonic-parkinsonian
    picture arising after a lucid interval, curated as the Delayed Neurological
    Sequelae subtype. The other is a neuropsychological deficit, principally
    episodic memory, which is present early and improves only partially over
    months. A given survivor may have either, both, or neither.
  evidence:
  - reference: PMID:24648474
    reference_title: "Surviving acute cyanide poisoning: a longitudinal neuropsychological investigation with interval MRI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prominent deficits in episodic memory were noted from an early stage, which were consistent with the findings noted on structural neuroimaging."
    explanation: Documents the neuropsychological arm of the delayed outcome and its imaging correlate.
  - reference: PMID:24648474
    reference_title: "Surviving acute cyanide poisoning: a longitudinal neuropsychological investigation with interval MRI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These deficits remained persistent, although improving in severity over the follow-up period."
    explanation: Establishes partial rather than complete recovery of the cognitive deficit over six months.
  - reference: PMID:24648474
    reference_title: "Surviving acute cyanide poisoning: a longitudinal neuropsychological investigation with interval MRI."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No focal neurological deficits or abnormal involuntary movements emerged, and the patient's overall functional status remained satisfactory."
    explanation: >-
      The same survivor developed no extrapyramidal syndrome, which is why the
      two delayed outcomes are recorded as separable rather than as stages of
      one course.
references:
- reference: PMID:37721023
  title: "2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care."
  findings:
  - statement: >-
      Current AHA resuscitation guidance covers critical cyanide poisoning
      alongside other toxidromes, and the antidote agents used in managing it.
    supporting_text: "Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics."
  - statement: >-
      Listed as the governing clinical guideline for this entry rather than
      cited inline against a specific treatment claim: the abstract enumerates
      the poisonings and agents the guideline addresses without stating a
      cyanide-specific recommendation, so no snippet from it would
      substantively support a particular treatment claim here.
datasets:
- accession: geo:GSE158994
  title: Expression data of the mouse heart of a nose-only HCN inhalation model and a subcutaneous KCN injection model
  description: >-
    Cardiac transcriptomes from two mouse cyanide-exposure models profiled by
    oligonucleotide microarray - nose-only hydrogen cyanide inhalation, chosen
    to be relevant to structure-fire smoke exposure, and subcutaneous potassium
    cyanide injection, the route conventionally used for countermeasure testing.
    The comparison is the point: the two routes give substantially different
    cardiac transcriptomes at every time point within 24 hours, which bears
    directly on how much of the countermeasure literature built on KCN injection
    transfers to inhalational poisoning.
  data_type: MICROARRAY
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  sample_count: 69
  publication: PMID:33914522
  evidence:
  - reference: GEO:GSE158994
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although the KCN injection model has been often used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 hours after exposure."
    explanation: >-
      The repository summary states the route-dependence finding that makes this
      dataset relevant to the myocardial arm of the pathograph and to the
      interpretation of antidote studies performed with injected KCN.
  notes: >-
    Selected from `just discover-datasets` as the only DIRECT candidate; the
    remaining candidates were GENE_ONLY hits reached through TST and are about
    unrelated diseases.
- accession: geo:GSE286106
  title: "Regulation of Mammalian Cellular Metabolism by Endogenous Cyanide Production [TST_RNA-Seq]"
  description: >-
    RNA-seq arm of a study of endogenous cyanide production in mammalian cells,
    including TST manipulation. This is physiology rather than poisoning: it
    reports that cells make cyanide at low concentrations where it acts as a
    gasotransmitter, and that the same molecule impairs bioenergetics at high
    concentrations. It is included here because the dose-dependent flip is the
    biological context for the toxic node in this entry, and because it profiles
    the detoxifying enzyme TST that the genetic section curates as a modifier.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 12
  publication: PMID:40033006
  genes:
  - preferred_term: TST
    term:
      id: hgnc:12388
      label: TST
  evidence:
  - reference: GEO:GSE286106
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism, and cell proliferation, but impairs cellular bioenergetics at high concentrations."
    explanation: >-
      The repository summary states the concentration-dependent reversal that
      separates endogenous cyanide signalling from the bioenergetic failure this
      entry models.
  notes: >-
    A GENE_ONLY candidate by the discovery tool's classification, retained after
    manual triage because its subject is cyanide itself rather than an unrelated
    disease that happens to express TST.
notes: >-
  Scope. This entry covers acute cyanide poisoning and its delayed neurological
  sequelae. Chronic dietary cyanogen exposure produces distinct, separately
  curated entities: konzo (kb/disorders/Konzo.yaml) and lathyrism-adjacent
  tropical neuropathies. Cyanide-induced parkinsonism has its own MONDO term
  (MONDO:0017640) but is curated here as the "Delayed Neurological Sequelae"
  subtype rather than as a separate entry, since it is a sequela of the acute
  poisoning modelled by this pathograph rather than an independently acquired
  disease. The cross-link to Konzo is one-directional: `Konzo.yaml` does not
  point back here. Adding that would be an edit to a second entry needing its
  own history record, so it is left for a follow-up rather than folded in.

  Contested exposure weight. The prominence of fire smoke as a cause of
  clinically decisive cyanide poisoning is genuinely disputed in the literature,
  and both sides are recorded rather than reconciled: PMID:1944484 measured
  elevated blood cyanide at the scene in fire victims and PMID:29939573 calls
  fire smoke the commonest inhalational source, while PMID:8150843 concludes
  from 364 fire fatalities that cyanide poisoning is infrequent and inseparable
  from carboxyhaemoglobinaemia. The REFUTE evidence item on the structure-fire
  environmental entry is that disagreement, not an error.

  Frequencies deliberately omitted. The deep-research report quoted per-symptom
  frequencies (78% unresponsive, 54% hypotensive, and so on) attributed to a
  systematic review of 102 patients across 65 articles, but named no identifier
  for that review, so nothing here could be quote-verified against it. Those
  frequencies are left out rather than curated from an unsourced figure. They
  would be worth adding if the review is identified.

  Prevalence deliberately absent. No `prevalence:` block is curated. Acute
  cyanide poisoning has no authoritative population figure: US poison-centre
  totals (of the order of 150 single-substance exposures a year) count only what
  is reported to poison centres, and systematically miss the fatal exposures -
  suicide, homicide, undiagnosed fire deaths, mass-casualty industrial events -
  that never reach one. Fire-related figures are worse still, since what fraction
  of fire deaths cyanide causes is the very question this entry records as
  contested. A rate curated from any of these would be a number without a
  denominator, so none is given.

  Cardiac and cutaneous signs not curated. Cyanosis, bradycardia and
  atrioventricular block are reported in the literature and are described in the
  Cardiovascular Collapse node's prose, but no reference cached for this entry
  states any of them, and a targeted PubMed search for a citable source returned
  nothing usable. They are left uncurated rather than cited to a source that
  does not carry them.

  Cell types left at `neuron`. The neuronal nodes bind CL:0000540 (neuron)
  rather than a striatal projection-neuron term. Two reasons: no cited source
  here names the cell type, and Basal Ganglia Necrosis spans globus pallidus as
  well as putamen, so a medium spiny neuron binding would be wrong for half the
  node. Note the CURIE offered for this in review, CL:0000842, is
  *mononuclear leukocyte*; the medium spiny neuron term is CL:1001474.

  Evidence grading where a paper is quoted for background rather than for its
  own result. Three references here are quoted both ways or only that way, and
  the grade follows what the quoted sentence is, not what the paper is:
  PMID:25692407 is a rodent and iPSC study quoted only for its summary of the
  human case literature, so all five items are OTHER; PMID:31389254 is a porcine
  study quoted both for its own data (MODEL_ORGANISM) and for two background
  sentences about clinical antidote practice (OTHER); PMID:8440119 is a
  narrative review that explicitly pooled animal and human studies, so its four
  items are OTHER rather than HUMAN_CLINICAL, one of them because the quoted
  sentence itself spans "animals and surgical patients" and no single source
  value describes it. A paper carrying two values is what CLAUDE.md means by
  splitting evidence items when a paper mixes sources.

  Terms not bound. No HPO term was found for elevated central or mixed venous
  oxygen saturation, the "arterialised venous blood" sign that is
  pathognomonically useful in cyanide poisoning, nor for the bitter-almond breath
  odour. Both are described in the pathophysiology and description prose and left
  unbound rather than forced onto an approximate term.

📚

References & Deep Research

References

1

PMID:37721023

2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

2 findings

Current AHA resuscitation guidance covers critical cyanide poisoning alongside other toxidromes, and the antidote agents used in managing it.

"Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and..."

Listed as the governing clinical guideline for this entry rather than cited inline against a specific treatment claim: the abstract enumerates the poisonings and agents the guideline addresses without stating a cyanide-specific recommendation, so no snippet from it would substantively support a particular treatment claim here.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope. This entry covers acute cyanide poisoning and its delayed neurological sequelae. Chronic dietary cyanogen exposure produces distinct, separately curated entities: konzo (kb/disorders/Konzo.yaml) and lathyrism-adjacent tropical neuropathies. Cyanide-induced parkinsonism has its own MONDO term (MONDO:0017640) but is curated here as the "Delayed Neurological Sequelae" subtype rather than as a separate entry, since it is a sequela of the acute poisoning modelled by this pathograph rather than an independently acquired disease. The cross-link to Konzo is one-directional: `Konzo.yaml` does not point back here. Adding that would be an edit to a second entry needing its own history record, so it is left for a follow-up rather than folded in. Contested exposure weight. The prominence of fire smoke as a cause of clinically decisive cyanide poisoning is genuinely disputed in the literature, and both sides are recorded rather than reconciled: PMID:1944484 measured elevated blood cyanide at the scene in fire victims and PMID:29939573 calls fire smoke the commonest inhalational source, while PMID:8150843 concludes from 364 fire fatalities that cyanide poisoning is infrequent and inseparable from carboxyhaemoglobinaemia. The REFUTE evidence item on the structure-fire environmental entry is that disagreement, not an error. Frequencies deliberately omitted. The deep-research report quoted per-symptom frequencies (78% unresponsive, 54% hypotensive, and so on) attributed to a systematic review of 102 patients across 65 articles, but named no identifier for that review, so nothing here could be quote-verified against it. Those frequencies are left out rather than curated from an unsourced figure. They would be worth adding if the review is identified. Prevalence deliberately absent. No `prevalence:` block is curated. Acute cyanide poisoning has no authoritative population figure: US poison-centre totals (of the order of 150 single-substance exposures a year) count only what is reported to poison centres, and systematically miss the fatal exposures - suicide, homicide, undiagnosed fire deaths, mass-casualty industrial events - that never reach one. Fire-related figures are worse still, since what fraction of fire deaths cyanide causes is the very question this entry records as contested. A rate curated from any of these would be a number without a denominator, so none is given. Cardiac and cutaneous signs not curated. Cyanosis, bradycardia and atrioventricular block are reported in the literature and are described in the Cardiovascular Collapse node's prose, but no reference cached for this entry states any of them, and a targeted PubMed search for a citable source returned nothing usable. They are left uncurated rather than cited to a source that does not carry them. Cell types left at `neuron`. The neuronal nodes bind CL:0000540 (neuron) rather than a striatal projection-neuron term. Two reasons: no cited source here names the cell type, and Basal Ganglia Necrosis spans globus pallidus as well as putamen, so a medium spiny neuron binding would be wrong for half the node. Note the CURIE offered for this in review, CL:0000842, is *mononuclear leukocyte*; the medium spiny neuron term is CL:1001474. Evidence grading where a paper is quoted for background rather than for its own result. Three references here are quoted both ways or only that way, and the grade follows what the quoted sentence is, not what the paper is: PMID:25692407 is a rodent and iPSC study quoted only for its summary of the human case literature, so all five items are OTHER; PMID:31389254 is a porcine study quoted both for its own data (MODEL_ORGANISM) and for two background sentences about clinical antidote practice (OTHER); PMID:8440119 is a narrative review that explicitly pooled animal and human studies, so its four items are OTHER rather than HUMAN_CLINICAL, one of them because the quoted sentence itself spans "animals and surgical patients" and no single source value describes it. A paper carrying two values is what CLAUDE.md means by splitting evidence items when a paper mixes sources. Terms not bound. No HPO term was found for elevated central or mixed venous oxygen saturation, the "arterialised venous blood" sign that is pathognomonically useful in cyanide poisoning, nor for the bitter-almond breath odour. Both are described in the pathophysiology and description prose and left unbound rather than forced onto an approximate term.

Edit: Cyanide Poisoning - respiratory failure phenotype and two antidotes, from PR #11588 review · 2026-09-10T03:22:01Z · View source

Addresses the changes-requested review on PR #11588. BLOCKING ITEM, taken. Added a Respiratory failure phenotype bound to HP:0002878, evidenced by PMID:41204534 with a verified exact quote, and wired in with a downstream edge from Cerebral Energy Failure so it does not orphan. The reviewer was right that Tachypnea does not cover this: the two sit at opposite ends of the respiratory course, tachypnea being respiratory compensation for the metabolic acidosis and respiratory failure being late brainstem depression. Both the quote and the HP term were verified against the local cache before use rather than taken from the review; both checked out. OPTIONAL ITEMS TAKEN. Added Amyl Nitrite and Dicobalt Edetate as treatments, both quotable from references already cached for this entry. Amyl nitrite carries two evidence items from PMID:41204534, its clinical use and the methaemoglobin ceiling that limits both nitrite antidotes. Dicobalt edetate carries three, from PMID:31389254 and PMID:8989894, including the adverse-effect profile that explains why hydroxocobalamin is preferred where both are available. One dicobalt snippet had to be trimmed to end before the source's inline citation marker, which the snippet matcher strips. OPTIONAL ITEMS DECLINED, each recorded in the entry notes rather than left silent. Cell-type granularity: declined, and the suggested CURIE is wrong. The review proposed CL:0000842 for striatal medium spiny neurons. CL:0000842 is *mononuclear leukocyte* - a white blood cell. The medium spiny neuron term is CL:1001474. That CURIE came from the deep-research report, which offered it in the same list as the ten mislabelled identifiers already flagged on this PR, so this is that failure mode reaching one step further. Beyond the wrong identifier, the binding would be wrong on the merits: no cited source here names the cell type, and Basal Ganglia Necrosis spans globus pallidus as well as putamen, so a medium spiny neuron term would be wrong for half the node. Nodes stay at CL:0000540 (neuron). Cyanosis, bradycardia and atrioventricular block: declined for now. Confirmed by grep that none of the 24 references cached for this entry mentions any of them, and a targeted PubMed search for a citable source returned nothing usable. Recorded in notes as uncurated rather than cited to a source that does not carry them. Node name 'Oxidative Phosphorylation Failure and ATP Depletion': left as is. The reviewer judged it atomic and said leaving it is defensible; proton-motive-force collapse and ATP fall are not separable in time here, so renaming would churn edge targets for no semantic gain. MPST as secondary detoxifying enzyme: left uncurated, as the reviewer agreed. VALIDATION: just validate-disorders passed, 113/113 snippets verified against the cache (up from 107). All eleven offline gates green. Graph re-checked directly: no unresolved targets and no node without an incoming edge.

Create: Cyanide Poisoning · 2026-09-10T02:16:14Z · View source

Created kb/disorders/Cyanide_Poisoning.yaml (MONDO:0018754), a new exposure-related entry covering acute cyanide poisoning and its delayed neurological sequelae. Deep research: one provider, claude_code (just research-disorder claude_code Cyanide_Poisoning), 340 s, 14 web searches, 16 turns, 37 citations. The run emitted no validation sections, so both retro-fits were applied: just validate-research-reference reported 26/26 references resolved, 0 unresolved, 0 off topic; just validate-research-terms reported 58 terms checked, 55 resolved, 0 unresolved, 1 obsolete (GO:0005751, superseded by GO:0045277) and 10 named as a different term. Nothing was bound from the report. Every CURIE in the entry was looked up independently through ols:/sqlite:obo: adapters at the moment it was written, which is what caught the report's wrong bindings: it offered UBERON:0001873 for globus pallidus (that is caudate nucleus; correct is UBERON:0001875), HGNC:12362 for TST (correct hgnc:12388), HGNC:7386 for MPST, CHEBI:75504 for sodium cyanide (that is pyranoside), CHEBI:9539 for sodium nitroprusside (Thiarubrine B) and CHEBI:15672 for linamarin (D-tartaric acid). Content: an eight-node causal chain from systemic absorption through cytochrome c oxidase inhibition, oxidative-phosphorylation failure and anaerobic glycolytic shift to myocardial and cerebral energy failure and basal ganglia necrosis, with a parallel rhodanese detoxification node that the thiosulfate antidote targets; 15 phenotypes; three subtypes (acute, delayed dystonic-parkinsonian, nitroprusside-associated); four pathograph-linked environmental exposures (fire smoke, occupational salts, cyanogenic glycosides, nitroprusside); five treatments; TST as a MODIFIER gene; two biochemical markers; two animal models with modeled_mechanisms; two datasets; two KNOWLEDGE_GAP discussions. Deliberate omissions, recorded in the entry notes: per-symptom frequencies quoted by the report were attributed to a systematic review it did not identify, so they were left out rather than curated from an unsourced figure; no HPO term exists for elevated venous oxygen saturation or bitter-almond breath odour, so both are prose only; PMID:41627127 was fetched but has no abstract in the cache and is not cited. The oxygen-to-Complex-IV treatment edge is recorded as MODULATES and explicitly left uncited because no cited source states the mass-action mechanism. A REFUTE evidence item (PMID:8150843) and a REFUTE item on hydroxocobalamin (PMID:41497958) record genuine, live disagreements rather than resolving them. Validation: just validate passed (schema, terms, 89/89 snippets verified against the cache). just validate-disorders run over the changed file. Offline gates all green: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-reference-titles, check-source-defect-claims. just verify-datasets resolved both geo: accessions and their GEO_*.md cache files are committed. Compliance 93.3 percent. No GeneReviews article exists for this disease (PubMed search returned zero), as expected for a non-Mendelian toxidrome. No stub existed to delete.

Claude Code ▸

Cyanide Poisoning: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 37 citations 2026-09-10T01:40:39.038792

Cyanide Poisoning: Comprehensive Research Report

1. Disease Information

Overview. Cyanide poisoning is an acute or chronic toxidrome caused by exposure to cyanide ions (CN⁻) or cyanide-releasing compounds (hydrogen cyanide gas, alkali cyanide salts, cyanogenic glycosides, or nitroprusside metabolism), producing "histotoxic hypoxia" — inhibition of cellular oxygen utilization despite normal oxygen delivery — via blockade of mitochondrial complex IV (cytochrome c oxidase). It is "a broad-spectrum poisoning by inhibition of the aerobic respiration metabolism at the cellular level in mitochondria" (Wikipedia/Wikidata summary, consistent with toxicology literature) (Wikidata). Exposure routes include inhalation (fire smoke, industrial gas release), ingestion (cyanide salts, cyanogenic plant foods, suicide attempts), dermal/mucosal absorption, and iatrogenic exposure (sodium nitroprusside infusion).

Key identifiers: - MONDO: MONDO:0018754 (confirmed by user; Orphanet cross-reference also lists an entry, Orphanet: Cyanide poisoning) - ICD-10-CM: T65.0 (Toxic effect of cyanides), with subcodes T65.0X1– (accidental), T65.0X2– (intentional self-harm), T65.0X3– (assault), T65.0X4– (undetermined); T57.3 covers toxic effect of hydrogen cyanide specifically (ICD10Data) - ICD-11: NE61 (Toxic effect of cyanides) / PC91 (poisoning by exposure category) - MeSH: Cyanides (D003489); "Cyanide Poisoning" indexed under Poisoning + Cyanides - OMIM: No dedicated OMIM entry — this is an acquired/environmental toxidrome, not a Mendelian disease, though OMIM entries exist for enzymes involved in detoxification (e.g., TST/rhodanese)

Synonyms: Hydrocyanic acid poisoning, prussic acid poisoning, HCN toxicity, cyanogen poisoning; disease-specific forms include konzo (chronic cassava-cyanide spastic paraparesis), tropical ataxic neuropathy (TAN), and nitroprusside-induced cyanide toxicity.

Data provenance: Most available evidence is aggregated at the disease level — case reports/series (the largest systematic review found 65 articles describing 102 patients), poison-control-center registries (National Poison Data System, NPDS), forensic/autopsy series, and occupational/environmental exposure studies — rather than large EHR cohorts, because acute cyanide poisoning is rare, often lethal before presentation, and frequently undiagnosed due to lack of rapid assays.

2. Etiology

Disease Causal Factors

Cyanide poisoning is fundamentally exogenous/environmental, not genetic, though genetic factors modulate individual susceptibility and detoxification capacity (see below). Causal exposure categories:

Combustion/inhalational — house/structure fires (combustion of nitrogen-containing synthetic polymers: polyurethane foam, nylon, wool, silk, melamine); the dominant real-world cause of cyanide exposure in industrialized countries.
Industrial/occupational — electroplating, metal polishing, photographic development, gold/silver mining (cyanide leaching — ~300,000 tons of hydrogen cyanide produced annually in the US, much used in gold extraction), plastics and synthetic fiber manufacturing, fumigation.
Iatrogenic — sodium nitroprusside infusion (each nitroprusside molecule releases 5 cyanide ions upon metabolism by oxyhemoglobin); risk rises above 1 mg/kg over <3 hours or >0.5 mg/kg/hr over 24 hours.
Ingestion of cyanide salts — potassium/sodium cyanide (suicide, homicide, industrial accident).
Dietary/cyanogenic glycosides — amygdalin (bitter almonds, apricot/peach/apple kernels — lethal dose ~0.5–3.5 mg/kg bw), linamarin (cassava, lima beans) — chronic low-dose exposure underlies konzo and tropical ataxic neuropathy in cassava-dependent populations of sub-Saharan Africa.
Chemical warfare/terrorism — hydrogen cyanide (AC) and cyanogen chloride (CK) are blood agents historically weaponized (WWI, Iran-Iraq War allegations, Nazi extermination camps [Zyklon B]).
Mass-casualty industrial disasters — the Bhopal methyl isocyanate disaster (1984) is cited as a major industrial cyanide/related-toxin mass-casualty event (~4,000 immediate deaths, 15,000–20,000 subsequent deaths).

Risk Factors

Genetic: - Polymorphisms in thiosulfate sulfurtransferase (TST/rhodanese), the principal cyanide-detoxifying enzyme, alter enzymatic clearance capacity. Eleven polymorphisms were characterized in French Caucasians, including two missense variants (E102D, P285A) and six promoter-region variants; the P285A variant shows ~50% reduced intrinsic clearance in vitro, and the promoter variants reduce reporter-gene activity by 40–73% (Bebarta/Baud group; PMID:16790311, Toxicology 2006). These polymorphisms plausibly explain inter-individual variation in cyanide sensitivity but have not been validated as clinical risk predictors in large cohorts. - Deficiency in cobalamin (vitamin B12) status reduces endogenous cyanide-scavenging capacity (hydroxocobalamin binds cyanide to form cyanocobalamin), a mechanism implicated in "tobacco-alcohol amblyopia" (Leber-like optic neuropathy exacerbated by chronic low-dose cyanide from tobacco smoke in the context of marginal B12/folate status). - 3-mercaptopyruvate sulfurtransferase (MPST) is a secondary cyanide-detoxifying enzyme; polymorphisms are less well characterized.

Environmental: - Occupational exposure (mining, electroplating, fumigation, jewelry polishing). - Enclosed-space fires involving synthetic materials. - Age/sex: fire-related cyanide exposure affects all ages; occupational exposure skews toward working-age adults, predominantly male in mining/industrial settings. - Malnutrition/protein deficiency — markedly increases susceptibility to chronic dietary cyanide toxicity (konzo), because sulfur amino acids (cysteine/methionine) are required substrates for rhodanese-mediated detoxification to thiocyanate. - Geography — konzo is endemic to cassava-dependent rural populations of the Democratic Republic of Congo, Mozambique, Tanzania, Cameroon, Central African Republic, and Angola, often during drought or war-related food insecurity when cassava processing (soaking/fermentation to reduce cyanogen content) is curtailed.

Protective Factors

Adequate dietary sulfur amino acid (cysteine, methionine) and protein intake, which sustains rhodanese/thiosulfate-dependent detoxification.
Adequate vitamin B12/cobalamin status.
Proper cassava processing (soaking, sun-drying, fermentation) that hydrolyzes and volatilizes cyanogenic glycosides before consumption — the principal public-health protective intervention against konzo.
No genetic "protective variant" analogous to a GWAS hit has been robustly established; TST promoter/coding variants associated with higher activity would be presumptively protective but are not independently validated as such.

Gene-Environment Interactions

The clearest documented gene-environment interaction is TST/rhodanese genotype × dietary sulfur-amino-acid and cyanogen intake: individuals with reduced-activity rhodanese variants combined with chronic dietary cyanogenic-glycoside exposure (cassava) and protein/sulfur-amino-acid malnutrition are hypothesized to be at elevated risk for konzo and tropical ataxic neuropathy, though this precise gene-diet interaction has not been formally tested in affected populations to my knowledge — it remains a biologically plausible but epidemiologically unconfirmed hypothesis based on enzymology data from Western cohorts (PMID:16790311).

3. Phenotypes

Acute Cyanide Poisoning — Symptoms/Signs

Phenotype	Category	Frequency (from systematic review of 102 patients, 65 articles)	HPO suggestion
Unresponsiveness/coma	Clinical sign	78%	HP:0001259 (Coma)
Hypotension	Clinical sign	54%	HP:0002615 (Hypotension)
Respiratory failure/tachypnea/dyspnea	Clinical sign	73%	HP:0002093 (Respiratory failure); HP:0002094 (Dyspnea)
Cardiac arrest	Clinical sign	20%	HP:0001695 (Cardiac arrest)
Seizures	Clinical sign	20%	HP:0001250 (Seizure)
Cyanosis	Physical sign	15%	HP:0000961 (Cyanosis)
"Cherry-red" skin (classically taught, actually uncommon)	Physical sign	11%	— (not a discrete HPO term; related to HP:0012472 flushing is not accurate — best left as free text)
Bitter-almond breath odor	Physical sign	~15% (only ~40–60% of people can genetically perceive the odor at all)	—
Headache, weakness, nausea, vomiting, diaphoresis, tachycardia	Early symptoms	Common	HP:0002315 (Headache); HP:0025145 (Weakness); HP:0002018 (Nausea); HP:0002013 (Vomiting)
Bradycardia, AV block, ventricular dysrhythmias, asystole	Late/terminal cardiac signs	—	HP:0001662 (Bradycardia); HP:0011703 (Atrioventricular block)
Lactic (anion-gap metabolic) acidosis	Laboratory abnormality	Near-universal in significant poisoning	HP:0003128 (Lactic acidosis)
Elevated venous oxygen saturation ("arterialized" venous blood)	Laboratory abnormality	Characteristic but underused	—

Onset: Inhalational exposure produces symptoms within seconds to minutes; ingestion of cyanide salts within minutes; ingestion of cyanogenic glycosides (which require enzymatic hydrolysis) may be delayed 30 minutes to several hours.

Severity/course: Highly dose-dependent — ranges from mild (headache, dizziness, tachycardia) to fulminant (coma, seizures, cardiovascular collapse, death within minutes at high doses). "Cyanide poisoning is a life-threatening condition that impairs cellular oxygen utilization, leading to lactic acidosis" and serum lactate ≥8 mmol/L is both sensitive and specific for toxic cyanide concentrations in suspected exposure (case report and prior validation studies; PMID:41204534, Medicine 2025).

Delayed/Chronic Neurological Phenotypes

A delayed neurological syndrome — dystonia, parkinsonism, dyskinesia — has been documented in survivors of severe acute poisoning, emerging weeks to months after apparent recovery, with progressive rigidity, flexed upper limbs, and extended lower limbs (basal ganglia/globus pallidus/putamen injury on MRI, decreased striatal fluorodopa uptake on PET). HPO suggestions: HP:0001300 (Parkinsonism), HP:0001332 (Dystonia), HP:0100660 (Camptocormia — not exact), HP:0002072 (Chorea, if choreiform component present).

Chronic dietary cyanide exposure (konzo): abrupt-onset, irreversible, non-progressive, symmetric spastic paraparesis or tetraparesis ("tied legs") — an upper motor neuron syndrome. HPO: HP:0001258 (Spastic paraplegia), HP:0007015 (Symmetric limb weakness — approximate), HP:0002061 (Progressive spastic paraparesis, though konzo is characteristically non-progressive once established).

Tropical ataxic neuropathy (TAN): sensory polyneuropathy, sensory ataxia, bilateral optic atrophy, bilateral sensorineural hearing loss, occurring in older individuals on chronic monotonous cassava diets. HPO: HP:0007281 (Sensory neuropathy), HP:0001272 (Cerebellar/sensory ataxia), HP:0000648 (Optic atrophy), HP:0000407 (Sensorineural hearing loss).

Quality of Life Impact

Acute survivors with hypoxic-ischemic brain injury or basal-ganglia damage may have lasting cognitive, motor, and psychiatric impairment; a longitudinal neuropsychological study with interval MRI in acute-poisoning survivors documented persistent deficits. Konzo produces permanent, non-progressive motor disability (wheelchair/crutch dependence in severe cases) with major impact on subsistence-agriculture livelihoods in affected regions; TAN produces disabling ataxia, blindness, and deafness in elderly patients. No disease-specific validated QOL instrument was identified; general disability/QOL measures (EQ-5D, WHODAS) have been applied in konzo cohorts in the broader literature.

4. Genetic/Molecular Information

Cyanide poisoning is not a monogenic disease; there is no single causal gene. Relevant genetic/molecular factors instead concern detoxification-pathway genes that modulate individual pharmacodynamics/pharmacokinetics of cyanide:

TST (Thiosulfate Sulfurtransferase / Rhodanese) — HGNC:12362, chromosome 22q12.3. The principal mitochondrial-matrix enzyme catalyzing CN⁻ + thiosulfate → SCN⁻ (thiocyanate) + sulfite, using thiosulfate as sulfur donor. Functional polymorphisms (missense E102D and P285A; six 5′-regulatory-region SNPs) alter enzyme activity and expression (PMID:16790311). No disease-causing "pathogenic variant" per ACMG/ClinVar classification exists for TST in the context of cyanide poisoning specifically — these are population-frequency modifier polymorphisms, not Mendelian pathogenic alleles.
MPST (3-Mercaptopyruvate Sulfurtransferase) — HGNC:7386, chromosome 22q12.3 (adjacent to TST, arose by gene duplication) — secondary/complementary cyanide-detoxification enzyme using 3-mercaptopyruvate as sulfur donor.
CBS (Cystathionine Beta-Synthase) and other sulfur-amino-acid metabolism genes indirectly affect substrate (thiosulfate/cysteine) availability for detoxification.
Cytochrome c oxidase subunit genes (mtDNA-encoded MT-CO1/2/3 and nuclear-encoded subunits) are the molecular target of cyanide (binding site: ferric heme a3–CuB binuclear center) rather than a susceptibility locus; polymorphisms here are not established modifiers of cyanide sensitivity in humans.
Somatic/germline variant classification: Not applicable — no ClinVar pathogenic/likely-pathogenic variant classification exists for cyanide-poisoning susceptibility. gnomAD population-frequency data exist for TST coding variants but disease-association evidence is limited to functional/enzymatic studies rather than large-scale case-control genetic association.
Epigenetics: No established disease-specific epigenetic (DNA methylation/histone) signature. Some general literature exists on chronic low-dose cyanide/thiocyanate exposure and oxidative-stress-linked epigenetic modification, but this is not well characterized for acute poisoning.
Chromosomal abnormalities: Not applicable (acquired toxic disease, not a chromosomal disorder).

Ontology suggestions: GENO terms are not typically applicable given the acquired nature; if modeling TST/MPST as modifier genes, hgnc:12362 (TST) and hgnc:7386 (MPST) with relationship_type: MODIFIER or SUSCEPTIBILITY would be appropriate in a dismech-style schema.

5. Environmental Information

Environmental/toxic factors (primary etiologic category for this disease): - Hydrogen cyanide gas (HCN) — CHEBI:18407 — from combustion of nitrogen-containing polymers (polyurethane, nylon, wool, silk, melamine, polyacrylonitrile) in structure fires; from industrial processes (metal plating/mining); historically as a fumigant and chemical-warfare agent. - Potassium cyanide (KCN) — CHEBI:32035 — and sodium cyanide (NaCN) — CHEBI:75504 — crystalline salts used in mining/electroplating, common in intentional poisoning. - Cyanogen chloride (CK) — a chemical-warfare "blood agent." - Sodium nitroprusside — CHEBI:9539 — iatrogenic cyanide source via hepatic/enzymatic release of 5 CN⁻ per molecule. - Amygdalin — CHEBI:2637 (bitter almonds, apricot/peach/apple kernels; EFSA established acute reference dose concerns for raw apricot kernels, 2016). - Linamarin — CHEBI:15672 (cassava, lima beans, flax); requires linamarase (endogenous plant β-glucosidase or gut microbial enzymes) for hydrolysis to release HCN. - Acetonitrile and other nitriles — metabolized to cyanide in vivo (relevant to nail-glue-remover ingestion poisoning).

Lifestyle/behavioral factors: - Chronic tobacco smoking is a source of chronic low-level HCN exposure (implicated in "tobacco amblyopia," particularly with concurrent malnutrition/B12 deficiency). - Monotonous, poorly processed cassava-based diets (protein/sulfur-amino-acid-poor) in food-insecure populations — the central environmental driver of konzo and TAN.

Infectious agents: Not applicable — cyanide poisoning is a chemical toxidrome, not infectious. (Note: an unrelated coincidental homonym exists — "Cyanide" is sometimes discussed alongside cyanobacterial toxins, but cyanobacteria/cyanotoxins are a biologically and chemically distinct hazard and should not be conflated with cyanide/HCN poisoning.)

6. Mechanism / Pathophysiology

Causal Chain (Acute Cyanide Poisoning)

Exposure to a cyanide-releasing source (HCN gas inhalation, cyanide salt ingestion, cyanogenic glycoside hydrolysis, or nitroprusside metabolism) leads to systemic absorption of the cyanide ion (CN⁻) into blood.
Free CN⁻ leads to rapid diffusion into cells and mitochondria, where it binds with high affinity to the ferric (Fe³⁺) heme a3–CuB binuclear center of cytochrome c oxidase (Complex IV) of the mitochondrial electron transport chain (demonstrated structurally; PMID:17906319).
This binding results in reversible inhibition of Complex IV, which blocks the terminal transfer of electrons to molecular oxygen — despite oxygen being physically present and delivered normally ("histotoxic hypoxia").
Blocked electron transport leads to collapse of the mitochondrial proton-motive force and cessation of oxidative phosphorylation, causing rapid depletion of cellular ATP.
ATP depletion forces a shift from aerobic to anaerobic glycolysis as a compensatory (but grossly insufficient) energy source, which generates excess pyruvate converted to lactate, producing severe high-anion-gap lactic acidosis — this is the basis for using serum lactate ≥8 mmol/L as a sensitive/specific biomarker of significant cyanide exposure (PMID:41204534).
Cellular energy failure disproportionately affects tissues with the highest oxidative metabolic demand — myocardium, CNS (especially basal ganglia/striatum), and to a lesser extent liver/kidney — because these tissues have the highest local cytochrome oxidase density and glucose/oxygen utilization, explaining the selective vulnerability of the striatum to delayed neurotoxicity.
In the heart, ATP failure leads to an initial catecholamine-driven hypertensive/bradycardic phase, followed by progressive myocardial depression, causing hypotension, bradyarrhythmia, AV block, ventricular dysrhythmia, and culminating in cardiovascular collapse/asystole in severe/untreated cases.
In the CNS, energy failure triggers a cascade of excitotoxicity (glutamate release), calcium influx, mitochondrial permeability transition, reactive-oxygen-species generation, and lipid peroxidation, which causes neuronal injury/death, particularly in the globus pallidus and putamen — manifesting acutely as coma and seizures, and, in survivors of severe poisoning, as a delayed sequela, a dystonic-parkinsonian syndrome emerging weeks to months later, correlated on MRI with bilateral globus pallidus/putaminal lesions and reduced striatal fluorodopa uptake on PET (a mechanistic link that is inferred from imaging/neuropathology correlation rather than fully demonstrated at the molecular level in humans).
Concurrently, cyanide binds nitric oxide synthase and interacts with nitric oxide signaling, and recent work proposes cyanide may also function physiologically at low concentrations as an endogenous gasotransmitter modulating vascular tone — a hypothesis under active investigation rather than established mechanism (systematic review, PMC:PMC9291117; vascular-effects review, PMC:PMC12486351).
Endogenous detoxification operates in parallel: mitochondrial rhodanese (TST) and 3-mercaptopyruvate sulfurtransferase (MPST) convert a fraction of the cyanide load to thiocyanate (SCN⁻, renally excreted) using thiosulfate/3-mercaptopyruvate as sulfur donors; this pathway is capacity-limited (sulfur-donor-dependent) and is overwhelmed at high cyanide doses — the rate-limiting nature of this pathway is the pharmacologic basis for thiosulfate antidote therapy, which supplies additional sulfur donor to accelerate this natural route.
In the chronic, low-dose dietary form (konzo/TAN), sustained cyanide/thiocyanate exposure from poorly processed cassava, compounded by dietary protein/sulfur-amino-acid deficiency (which limits the rhodanese pathway's substrate supply), is hypothesized to lead to selective upper-motor-neuron toxicity (konzo) or combined sensory/optic/cochlear toxicity (TAN) via a still not fully resolved chronic sub-lethal energy-failure/oxidative-stress mechanism, with thiamine deficiency proposed as a possible cofactor (this causal link remains actively debated in the literature and should be regarded as a hypothesis, not an established mechanism).

Category Detail

Molecular pathways: Oxidative phosphorylation/electron transport chain (Complex IV inhibition) is central; secondary involvement of glutamate/NMDA excitotoxicity pathways, nitric oxide signaling, and Nrf2-antioxidant response pathway (carnosic acid, an Nrf2 activator, is protective against cyanide-induced brain injury in rodent models — PMC:PMC4465065). GO suggestion: GO:0006123 (mitochondrial electron transport, cytochrome c to oxygen); GO:0045333 (cellular respiration).
Cellular processes: Necrosis and apoptosis of high-oxidative-demand cells; anaerobic glycolysis upregulation; oxidative stress/lipid peroxidation; excitotoxic calcium influx.
Protein dysfunction: Direct, reversible inhibition (not structural misfolding) of cytochrome c oxidase (Complex IV) via heme-iron/copper coordination by CN⁻; this is a pharmacologic/toxicologic inhibition rather than a genetic loss-of-function.
Metabolic changes: Shift from oxidative to anaerobic (glycolytic) metabolism; lactic acidosis; secondary hyperglycemia (catecholamine-driven) in early poisoning; elevated venous oxygen saturation (tissue extraction failure).
Immune system involvement: Not a primary feature of acute poisoning; secondary inflammatory injury (e.g., ARDS in smoke-inhalation co-exposure) is common but attributable to co-exposures (heat, particulates, CO) rather than cyanide per se.
Tissue damage mechanisms: Cytotoxic/histotoxic hypoxia (not ischemic hypoxia), oxidative stress, excitotoxicity — most pronounced in basal ganglia, myocardium, and (in smoke-inhalation cases) airway/lung parenchyma from co-exposure to thermal injury and other combustion toxins (CO, particulates, other irritant gases).
Biochemical abnormalities: Complex IV inhibition; elevated lactate; elevated mixed/central venous oxygen saturation; in nitroprusside toxicity, secondary methemoglobinemia and thiocyanate accumulation (renal-failure-dependent) causing a distinct delayed thiocyanate toxidrome (confusion, tinnitus, seizures, hyperreflexia).
Molecular profiling: Limited disease-specific -omics data exist given the acute/lethal, low-N nature of severe poisoning; a 2025 FASEB Journal paper on "redirecting intermediary metabolism to counteract cyanide poisoning" (Bebarta et al.) represents recent metabolomics-informed therapeutic research (https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202400230RR).
Advanced technologies: No single-cell or spatial transcriptomic studies specific to human cyanide poisoning were identified; animal (mouse/pig) models are used for pharmacodynamic and antidote-efficacy profiling (see Section 15).

Cell types involved: cardiomyocytes (CL:0000746), medium spiny neurons of the striatum/globus pallidus (CL:0000842 or more specific GABAergic striatal projection neuron terms), hepatocytes (CL:0000182, site of rhodanese-mediated detoxification), and, in konzo, upper motor neurons (CL:0008015 corticospinal neuron approximate).

7. Anatomical Structures Affected

Organ level: - Primary: Cardiovascular system (myocardium, conduction system), central nervous system (brain — basal ganglia, brainstem respiratory centers), and (in fire-related exposure) the respiratory system (co-injury from smoke, thermal injury, CO). - Secondary: Liver (site of rhodanese detoxification, secondarily stressed), kidney (excretes thiocyanate; impaired in renal failure, increasing risk of thiocyanate toxicity), peripheral/optic/auditory nervous system in chronic dietary exposure (TAN). - Body systems: Cardiovascular, nervous, respiratory (in inhalational/fire cases), and — in chronic dietary exposure — the visual and auditory systems.

Tissue/cell level: - Cardiac muscle tissue (myocardium); basal ganglia neurons (particularly globus pallidus internal/external segments and putamen — high metabolic/oxidative demand); upper motor neurons of the corticospinal tract (konzo); retinal ganglion cells/optic nerve (TAN, optic atrophy); cochlear hair cells (TAN, sensorineural hearing loss); hepatocytes (rhodanese-rich).

Subcellular level: Mitochondria — specifically the inner mitochondrial membrane, Complex IV (cytochrome c oxidase) of the electron transport chain. GO Cellular Component: GO:0005751 (mitochondrial respiratory chain complex IV), GO:0005739 (mitochondrion).

Localization (UBERON): - UBERON:0002370 (thymus) — not relevant - UBERON:0002349 (myocardium) - UBERON:0002435 (striatum) / UBERON:0001873 (globus pallidus) / UBERON:0001874 (putamen) - UBERON:0000955 (brain) - UBERON:0002107 (liver) - UBERON:0002113 (kidney) - UBERON:0001769 (corticospinal tract) — konzo - UBERON:0000966 (retina) / UBERON:0001791 (optic nerve) — TAN - UBERON:0001846 (cochlea) — TAN

Lateralization: Basal ganglia lesions and delayed dystonic-parkinsonian syndrome are typically bilateral/symmetric; konzo motor deficits are bilateral and symmetric ("tied legs" gait); TAN optic atrophy and hearing loss are bilateral.

8. Temporal Development

Onset: - Acute poisoning: Inhalational — seconds to minutes; ingestion of cyanide salts — minutes; ingestion of cyanogenic glycosides — 30 minutes to several hours (delay reflects need for enzymatic/gut-microbial hydrolysis to release HCN). - Chronic (konzo): Abrupt onset over hours to days in an individual who has had sustained dietary cyanogen exposure, often during periods of drought/famine when inadequately processed cassava becomes dietary staple; epidemic clusters can appear within weeks in a community. - Delayed neurological sequelae: Weeks to months after apparent recovery from acute severe poisoning.

Progression: - Acute poisoning stages: Early (headache, dizziness, tachycardia, hyperventilation) → intermediate (dyspnea, confusion, hypotension progressing from initial reflex hypertension/bradycardia) → late/severe (coma, seizures, cardiovascular collapse, respiratory arrest, death) — progression can be extremely rapid (minutes) at high doses. - Konzo: Sudden onset followed by a non-progressive, stable course once established (a distinguishing feature from other spastic paraparesis etiologies); severity is graded clinically (mild — able to walk without support; moderate — requires one support; severe — requires two supports or is unable to walk). - TAN: Chronic, may show slow progression with continued dietary exposure; not typically episodic. - Delayed dystonic-parkinsonian syndrome: Progressive rigidity following the latent interval, potentially plateauing but often not fully reversible.

Duration: Acute poisoning is self-limited if treated promptly and the patient survives the initial hours (survival beyond ~4 hours after treatment initiation generally predicts recovery, per toxicology reviews); konzo-related spastic paraparesis and TAN sequelae are typically permanent/lifelong.

Remission patterns: Acute poisoning — full recovery is possible with prompt antidotal/supportive therapy in the absence of severe hypoxic/ischemic end-organ injury; no spontaneous remission of konzo-associated motor deficits is described; some recovery of neuropsychological function has been documented over months to years post-acute-poisoning in longitudinal MRI/neuropsychological follow-up (PMC:PMC3962856).

Critical periods: The first few minutes to hours after exposure represent the critical therapeutic window — antidote administration (hydroxocobalamin, nitrites, thiosulfate) before irreversible hypoxic-ischemic organ injury dramatically improves outcome. For konzo, the critical prevention window is at the population/food-processing level (ensuring adequate cassava soaking/fermentation and dietary protein sufficiency) rather than an individual clinical window.

9. Inheritance and Population

This is not a heritable Mendelian disease — no inheritance pattern, penetrance, expressivity, anticipation, germline mosaicism, founder effect, or carrier frequency applies in the classical genetic-disease sense. The relevant "genetic" contribution is polygenic/modifier-gene susceptibility (TST/MPST activity variants) layered on an environmental exposure.

Epidemiology: - Fire-related exposure: In the US, >3,000 fire deaths and >14,000 fire injuries occur annually (2017 data: 3,400 deaths, 14,670 injuries), with smoke inhalation (not thermal injury) the leading cause of fire mortality; cyanide is "increasingly recognized as a significant toxicant" in smoke inhalation, though the proportion of fire deaths specifically attributable to cyanide (versus co-toxicants like CO) varies substantially across studies — a classic forensic series of 364 fire fatalities found mean blood cyanide 1.0 mg/L with levels exceeding the fatal threshold (>3 mg/L) in 31 cases (PMID:8150843, J Burn Care Rehabil 1994), while a prospective clinical study of 144 smoke-exposed patients and 43 fire fatalities found elevated blood cyanide in 90% of survivors and 100% of the deceased, illustrating substantial measurement/cohort-dependent variability. - US poison-center data: The 2023 National Poison Data System (NPDS) annual report recorded 1 death among 145 single-substance cyanide exposures; the 2021 AAPCC Toxic Exposure Surveillance data recorded 4 deaths among 163 cyanide exposure cases — indicating acute isolated cyanide poisoning is rare in the general US population but carries substantial case-fatality when it occurs. - Konzo: Endemic/epidemic in specific rural regions of the Democratic Republic of Congo, Mozambique, Tanzania, Cameroon, Central African Republic, and Angola; outbreaks historically correlate with drought, conflict, and food insecurity that force reliance on inadequately processed bitter-cassava varieties; precise contemporary prevalence figures vary by region and survey year and were not independently re-verified in this session — cite the primary konzo epidemiological literature (e.g., PLOS NTD review, https://journals.plos.org/plosntds/article?id=10.1371%2Fjournal.pntd.0001051) for current numbers. - Occupational: Elevated risk populations include artisanal/small-scale gold miners (common in low- and middle-income countries using cyanide leaching), electroplaters, and jewelry polishers; global burden estimates for occupational cyanide morbidity/mortality are not centrally tracked in a single registry.

Population demographics: - Sex ratio: Occupational and industrial cyanide exposure skews male (reflecting mining/industrial workforce demographics); suicidal ingestion shows variable sex distribution by country/era; fire-related exposure affects both sexes and all ages roughly proportional to fire-victim demographics. - Age distribution: Fire-related — all ages; occupational — working-age adults; konzo — historically over-represented in children and women of childbearing age in affected communities (reflecting household dietary patterns), though whole-community outbreaks occur. - Geographic distribution: Industrialized-country exposure is dominated by fire/industrial/iatrogenic/suicidal sources; chronic dietary cyanide toxicity (konzo, TAN) is essentially restricted to cassava-dependent regions of sub-Saharan Africa.

10. Diagnostics

Clinical diagnosis is primary — "no single, readily available laboratory test has been identified to confirm cyanide poisoning; thus, diagnosis is primarily driven by clinical assessment" (StatPearls, NBK507796). Classic teaching signs (bitter-almond odor, cherry-red skin) are present in only ~11–15% of cases and should not be relied upon.

Laboratory tests: - Whole-blood cyanide concentration — the definitive confirmatory test, but turnaround time (hours to days in most labs) makes it useless for real-time management; normal <0.5 mg/L (nonsmokers), toxic >1.0 mg/L, potentially lethal >3 mg/L. LOINC-codable analyte. - Serum/whole-blood lactate — the most clinically useful rapid surrogate biomarker; lactate ≥8 mmol/L is sensitive and specific for toxic cyanide exposure in the appropriate clinical context (PMID:41204534, and earlier validation, e.g., Baud et al.). - Arterial and venous blood gas with co-oximetry — narrowed arteriovenous oxygen difference / elevated venous oxygen saturation reflects failure of tissue oxygen extraction (histotoxic hypoxia), a useful ancillary clue. - Anion gap metabolic acidosis on basic metabolic panel. - Carboxyhemoglobin (CO-Hgb) and methemoglobin levels — essential in smoke-inhalation and nitrite-antidote-monitoring contexts, respectively, to distinguish/quantify co-toxicity. - Thiocyanate level — reflects cumulative/chronic exposure or antidote (thiosulfate) response; also relevant to diagnosing thiocyanate toxicity from prolonged nitroprusside infusion.

Imaging: - Brain MRI — in survivors of severe poisoning, bilateral T2/FLAIR hyperintensities (or T1 low-signal, hemorrhagic change) in globus pallidus and posterior putamen; diffuse white-matter injury in severe cases; used to characterize/predict delayed neurological sequelae (PMID/AJNR: AJNR 2002;23:1398). - Fluorodopa PET — decreased bilateral striatal uptake correlating with delayed parkinsonism.

Functional/electrophysiological tests: EEG (nonspecific encephalopathic slowing/seizure activity in severe poisoning); ECG (bradyarrhythmia, AV block, QTc changes — early vs. delayed QTc prolongation has prognostic relevance in acute poisonings broadly, PMC:PMC11386474).

Genetic testing: Not part of routine clinical diagnosis; TST/MPST genotyping is a research tool only, with no established clinical testing pathway, panel, or GTR listing specific to cyanide-poisoning risk stratification.

Clinical criteria: No formal DSM/consensus diagnostic-criteria instrument exists (this is an acute-poisoning diagnosis based on exposure history + clinical toxidrome + supportive labs, e.g., lactate); several clinical prediction scores/nomograms based on exposure circumstance (fire vs. industrial vs. ingestion), vital signs, and lactate have been proposed in the emergency-medicine literature to guide empiric antidote administration when confirmatory cyanide levels are unavailable in real time.

Differential diagnosis: Carbon monoxide poisoning (frequently co-occurs in fire victims and must be distinguished/co-treated), methemoglobinemia, hydrogen sulfide poisoning (also inhibits cytochrome oxidase, at a different binding site), severe sepsis/septic shock (lactic acidosis overlap), salicylate toxicity, other causes of anion-gap metabolic acidosis and coma.

Screening: No population newborn or carrier screening applies (not a genetic disease). Occupational medical surveillance (periodic thiocyanate monitoring) is used in some cyanide-handling industries as a biomonitoring/screening tool for chronic low-level exposure.

11. Outcome/Prognosis

Survival/mortality: - Case-fatality is highly dose- and treatment-timing-dependent. US poison-center surveillance (NPDS 2023) recorded 1 death among 145 single-substance exposures reported to poison centers (a population skewed toward milder/detected exposures); the 2021 AAPCC data recorded 4 deaths among 163 cases. These figures likely substantially underestimate true population mortality because many fatal exposures (suicide, homicide, mass-casualty industrial events, undiagnosed fire deaths) never reach poison-center reporting. - In a systematic review of 102 published patients (65 articles), most were severely ill (78% unresponsive, 73% respiratory failure, 54% hypotensive, 20% cardiac arrest), reflecting publication bias toward severe/notable cases. - Prognosis is generally good for patients with mild symptoms not requiring antidote, and reasonably good for moderate poisoning with rapid supportive care and antidotal therapy; prognosis is poor for patients who suffer cardiac arrest, even with prompt antidote administration. - Survival beyond ~4 hours after treatment initiation is generally considered a favorable prognostic marker for eventual recovery, assuming adequate hemodynamic/respiratory support was maintained (Medscape/StatPearls synthesis).

Morbidity/functional outcomes: - Hypoxic-ischemic brain injury from severe/prolonged poisoning can cause permanent cognitive impairment, and delayed basal-ganglia-mediated dystonia/parkinsonism is a recognized long-term morbidity in survivors of severe acute poisoning. - Konzo produces lifelong, non-progressive but irreversible spastic paraparesis/tetraparesis with major functional-independence and economic impact in affected rural communities. - TAN produces permanent sensory ataxia, visual impairment (optic atrophy), and hearing loss.

Complications: In smoke-inhalation cases specifically, combined cyanide + carbon monoxide toxicity, airway thermal/chemical injury, and ARDS materially worsen outcomes; prehospital hydroxocobalamin administration in smoke-inhalation victims is associated with decreased ventilator dependence time, reduced pneumonia rates, and shorter ICU stay (systematic reviews of prehospital hydroxocobalamin use, PMC:PMC12767669).

Prognostic factors: Degree/duration of hypotension and hypoxia before treatment, initial lactate level, presence of cardiac arrest, time to antidote administration, co-exposure to carbon monoxide (in fire victims), and pre-existing hepatic/nutritional/vitamin-B12 status (which affects endogenous detoxification reserve).

12. Treatment

Pharmacotherapy / Antidotes

Antidotal therapy targets three complementary mechanisms: (1) directly sequestering cyanide, (2) generating methemoglobin as a cyanide "sink," and (3) accelerating enzymatic detoxification to thiocyanate.

Hydroxocobalamin (Cyanokit®) — first-line/gold-standard antidote (2023 American Heart Association guidance recommends hydroxocobalamin for cyanide poisoning-associated cardiac arrest or life-threatening toxicity). Mechanism: the cobalt(III) center of hydroxocobalamin directly binds CN⁻ to form cyanocobalamin (vitamin B12), which is renally excreted — non-toxic and safe for prehospital/field administration, including in smoke-inhalation victims with unknown CO co-exposure (does not impair oxygen-carrying capacity the way nitrites do). NCIT suggestion: closest available NCIT clinical-action term would be Pharmacotherapy (NCIT:C15986) with therapeutic_agent bound to the specific compound; note that NCIT has a code for hydroxocobalamin as an agent (search via OAK). Supply note: as of November 2024, hydroxocobalamin (Cyanokit) was placed on the ASHP drug-shortage list with no anticipated resolution date at that time — a clinically important recent development affecting antidote availability.
Sodium nitrite — recommended when hydroxocobalamin is unavailable (2023 AHA guidance); oxidizes hemoglobin iron (Fe²⁺→Fe³⁺) to form methemoglobin, which competitively binds cyanide (higher affinity than cytochrome oxidase) to form cyanomethemoglobin, sparing cytochrome oxidase. Risk: induces methemoglobinemia, which itself impairs oxygen-carrying capacity — relatively contraindicated as first-line in smoke-inhalation victims with concurrent carboxyhemoglobinemia (compounds hypoxia).
Sodium thiosulfate — reasonable adjunct to either hydroxocobalamin or nitrite (2023 AHA); serves as sulfur donor accelerating the endogenous rhodanese-mediated conversion of cyanide to renally excreted thiocyanate; slower onset than hydroxocobalamin but synergistic in combination, and safe to combine with hydroxocobalamin.
Amyl nitrite — inhalational bridge therapy (pending IV access) with the same methemoglobin-forming mechanism as sodium nitrite; part of older-generation "Cyanide Antidote Kits."
Dicobalt edetate — used in some countries (particularly UK, historically); direct cyanide chelator; narrower therapeutic index/higher toxicity than hydroxocobalamin, so used less in North America.

Supportive Care

100% supplemental oxygen (even though the core lesion is utilization-, not delivery-limited, hyperoxia may partially overcome the reversible cytochrome oxidase inhibition by mass action); aggressive correction of hemodynamic instability (vasopressors, fluids); mechanical ventilation for respiratory failure; sodium bicarbonate for severe acidosis (adjunctive, not primary therapy); seizure management (benzodiazepines); extracorporeal support (ECMO) has been used in refractory cardiogenic shock in case reports; a recent case report highlighted early blood purification (hemoperfusion/hemodialysis) as an adjunct in a lethal cyanide poisoning with multimodal management (PMC:PMC13311073, Frontiers in Pharmacology 2026).

Experimental/Emerging Therapeutics (active research, 2024–2026)

Cobinamide — a vitamin B12 precursor/analog lacking the "tail" of cobalamin, giving it higher water solubility and cyanide-binding capacity; found more effective than hydroxocobalamin, thiosulfate, nitrite, or thiosulfate-nitrite combination in mouse models (PMID:20704457); under continued development as a next-generation antidote, notably attractive for mass-casualty/military stockpiling due to smaller required dose volumes than hydroxocobalamin.
Platinum-based complexes (hexachloroplatinate, platinum-methionine [Met2Pt]) — investigational metal-based cyanide scavengers showing efficacy in mouse and swine lethal-inhalation models, with intramuscular route feasibility of interest for battlefield/mass-casualty use (2024–2025 preclinical publications, PMC:PMC6660183; PMC:PMC13458706).
Molybdenum-based [Mo₂O₂(µ-S)₂]²⁺ metallodrug — a novel cyanide-neutralizing compound evaluated pharmacokinetically in mice (2025), rapidly absorbed with elimination within 8 hours.
Dimethyl trisulfide — a sulfur-donor small molecule investigated as a faster-acting alternative/adjunct to sodium thiosulfate (patented formulations).
Metabolic-redirection strategies — the 2025 FASEB Journal paper by Bebarta and colleagues explores "redirecting intermediary metabolism" (e.g., providing alternative metabolic substrates/cofactors) as a countermeasure strategy distinct from direct cyanide chelation.

Surgical/Interventional, Rehabilitative, and Chronic-Disease Treatment

Not applicable for acute poisoning beyond supportive/ICU-level intervention. For delayed dystonic-parkinsonian syndrome, symptomatic management follows standard movement-disorder approaches (levodopa — often with limited efficacy, since the lesion is post-synaptic striatal rather than nigral dopaminergic — anticholinergics, botulinum toxin for focal dystonia, physical/occupational therapy). For konzo, management is rehabilitative/supportive: physical therapy, orthotics/mobility aids, and — critically — public-health-level prevention (see Section 13) rather than a curative individual treatment, since the upper-motor-neuron injury is established and largely irreversible.

Clinical Trials

Given the acute, rare, and often lethal nature of cyanide poisoning, prospective randomized controlled trials in human poisoning are essentially infeasible; the evidence base is built on animal efficacy studies, observational/registry data (e.g., prehospital hydroxocobalamin cohorts), and case series. No disease-specific ClinicalTrials.gov interventional RCTs for acute cyanide poisoning antidotes were identified in this session; most relevant "trials" are preclinical animal pharmacology studies. NCIT suggestion for pharmacotherapy generally: NCIT:C15986 (Pharmacotherapy); for the antidote class specifically, consider a therapeutic_agent binding via CHEBI for hydroxocobalamin/thiosulfate/nitrite.

Pharmacogenomics

No established CPIC/PharmGKB guideline exists for cyanide-antidote dosing based on genotype; TST/MPST genotype-guided dosing remains theoretical/research-stage rather than clinically implemented.

13. Prevention

Primary prevention: - Engineering/occupational controls in cyanide-handling industries (mining, electroplating): closed-system processing, ventilation, personal protective equipment, biological monitoring (urinary/blood thiocyanate). - Fire-safety measures reducing combustion of cyanide-releasing synthetic materials, and building-material regulation limiting nitrogen-containing polymer combustion products, are indirect but relevant primary-prevention levers for smoke-inhalation cyanide exposure. - Cassava-processing interventions (soaking, sun-drying, fermentation, "wetting method") to reduce cyanogenic glycoside content before consumption — the central, evidence-based primary-prevention strategy against konzo/TAN in affected sub-Saharan African communities, promoted through community health education programs. - Restriction/regulation of cyanide salt sales and access reduces suicidal/homicidal ingestion opportunity in some jurisdictions.

Secondary prevention: - Prompt recognition and empiric antidotal treatment protocols for suspected cyanide exposure in fire victims (many EMS systems and burn centers now have standing protocols for empiric prehospital hydroxocobalamin administration in smoke-inhalation patients meeting clinical criteria — altered mental status, soot in airway, hypotension — rather than waiting for confirmatory testing). - Community-based clinical surveillance for early konzo case detection in cassava-dependent regions during drought/food-insecurity periods, enabling rapid public-health cassava-processing intervention.

Tertiary prevention: Rehabilitative care (physical therapy, mobility aids) to minimize secondary complications (contractures, pressure injuries) in established konzo/TAN cases; movement-disorder management to reduce morbidity from delayed dystonic-parkinsonian syndrome.

Immunization: Not applicable (non-infectious).

Screening/early detection: No individual genetic or newborn screening applies. Population/community-level cassava-processing-adequacy surveillance and biomonitoring (urinary thiocyanate) in at-risk communities functions as an early-warning/risk-stratification tool.

Behavioral interventions: Dietary diversification programs to reduce dependence on cassava monoculture and improve sulfur-amino-acid/protein intake in food-insecure regions.

Counseling: Not classically "genetic counseling" (non-Mendelian disease), but occupational-health counseling for at-risk workers and public-health education for cassava-dependent communities serve an analogous risk-communication role.

Public health/environmental interventions: WHO/FAO guidance on maximum permissible cyanogenic-glycoside content in cassava-derived food products; occupational exposure limits (OSHA/NIOSH permissible exposure limits for hydrogen cyanide and cyanide salts); mining-sector cyanide-management protocols (e.g., the International Cyanide Management Code for the gold-mining industry).

Prophylaxis: No standing pre-exposure chemoprophylactic agent is in routine clinical/public-health use; military/first-responder research continues to explore pre-treatment countermeasures (e.g., pre-exposure hydroxocobalamin or dicobalt edetate has shown only "modest and variable efficacy" in porcine models — PMC:PMC7034532 — underscoring that prophylactic pretreatment is not currently a robust strategy compared to rapid post-exposure antidote administration).

14. Other Species / Natural Disease

Taxonomy/species affected: Cyanide toxicity is essentially universal across aerobic organisms possessing cytochrome c oxidase, given the conserved nature of the mitochondrial electron transport chain. Documented natural/veterinary cyanide poisoning occurs in: - Cattle, sheep, goats (NCBITaxon:9913, 9940, 9925) — most frequently reported livestock cyanide poisoning, typically from grazing on cyanogenic forage plants (sorghum/Sudan grass, Johnson grass, white clover, wild cherry leaves) under stress conditions (drought, frost, wilting) that increase cyanogenic glycoside concentration and hydrolysis (Merck Veterinary Manual). - Dogs (NCBITaxon:9615) — reported cases from cyanide-containing pesticide or rodenticide exposure, or ingestion of cyanogenic plant material; rhodanese distribution across canine respiratory-tract tissue has been specifically studied. - Horses, pigs — less common but documented cyanogenic-plant poisoning. - Wildlife — documented mortality from illegal cyanide use in poaching (e.g., elephant/wildlife poisoning at waterholes in parts of Africa) and from cyanide-based fishing practices in some regions (though the latter is more an ecological/conservation concern than a formally studied "natural disease" model).

Breed: No specific Vertebrate Breed Ontology (VBO) susceptibility differences were identified as well-characterized in the literature reviewed; susceptibility in livestock relates more to forage/pasture management than breed genetics.

Orthologous genes: TST/rhodanese orthologs are highly conserved across mammals (bovine and canine rhodanese have been extensively studied biochemically, in some cases predating and informing human enzymology); NCBI Gene entries exist for Tst orthologs in mouse (Mus musculus, NCBI Gene ID for Tst) and other model species.

Comparative pathology: The core molecular mechanism (Complex IV inhibition, histotoxic hypoxia, lactic acidosis) is conserved across mammalian species, supporting direct translational relevance of animal antidote-efficacy studies to human treatment. Species differences chiefly involve dose sensitivity, respiratory rate/uptake kinetics, and possibly rhodanese tissue distribution/activity levels (e.g., sheep and dog respiratory-tract rhodanese distribution has been specifically mapped).

Evolutionary conservation: Cytochrome c oxidase and the rhodanese/TST detoxification system are ancient, highly conserved across eukaryotes (and rhodanese homologs exist even in some bacteria/archaea, reflecting an ancient sulfur-metabolism origin), consistent with cyanide sensitivity being a near-universal aerobic-life vulnerability rather than a human-specific trait.

Zoonotic potential/transmission: Not applicable — cyanide poisoning is a direct chemical toxicity, not a transmissible infectious disease; there is no cross-species "transmission," only shared environmental/dietary exposure risk (e.g., livestock and humans sharing exposure to the same cyanogenic forage/food sources in a given region).

15. Model Organisms

Model types and their applications (nearly all model-organism work in this space is acute pharmacology/antidote-efficacy testing, not a chronic-disease or genetic model, since cyanide poisoning is an induced toxic exposure rather than a heritable phenotype):

Mouse (Mus musculus) — the dominant small-animal model for antidote screening, typically via intraperitoneal, subcutaneous, or inhalational KCN/NaCN or HCN-gas challenge with survival/time-to-death as the primary endpoint. Example: cobinamide efficacy studies used mouse lethal-challenge models to demonstrate superiority over hydroxocobalamin, thiosulfate, and nitrite (PMID:20704457). C57BL/6 mice (commonly 8–10 weeks old) are frequently used given established physiological/toxicological reference ranges. Limitations: small blood volume limits serial biomarker sampling; interspecies differences in cyanide metabolism kinetics and respiratory physiology limit direct dose-extrapolation to humans; mouse models generally test bolus/rapid lethal challenge rather than the sustained lower-dose inhalational exposure typical of structure fires.
Rat (Rattus norvegicus) — used in some cyanide/thiocyanate pharmacokinetic and chronic-dietary (cassava-simulating) toxicity studies, including studies of cross-species cyanide detoxification-rate variation under protein-restricted diet conditions — directly relevant to modeling the konzo/malnutrition interaction (ScienceDirect reference on cross-species/tissue detoxification rate variation in rodents and non-human primates on protein-restricted diet).
Swine/porcine models — considered the most clinically translatable large-animal model given closer cardiovascular and pulmonary physiological similarity to humans; used for lethal cyanide-salt-poisoning and inhalational (fire-simulating smoke) antidote studies, including recent (2025) pilot studies of platinum-methionine complex countermeasures (PMC:PMC13458706) and earlier studies of pre-exposure hydroxocobalamin/dicobalt edetate efficacy (PMC:PMC7034532). Limitations: cost and ethical/regulatory burden limit sample sizes; still imperfect recapitulation of human basal-ganglia vulnerability patterns for delayed neurotoxicity endpoints.
Non-human primates (cynomolgus macaque) — used in some smoke-inhalation/HCN-gas exposure models, particularly for U.S. military/countermeasure development programs (referenced in the 2025 bioRxiv preprint on fire-related toxic gas detection and antidote efficacy in controlled smoke-inhalation models), given closer physiological homology though with substantial ethical/cost constraints limiting widespread use.
Cell-based/in vitro models — isolated mitochondria and cultured cells (e.g., neuronal or cardiomyocyte cell lines) are used to study cytochrome c oxidase inhibition kinetics, oxidative stress, and candidate-antidote binding chemistry directly, without whole-organism confounds; not a disease "model" per se but mechanistic tool.
Genetic models: No knockout/knock-in mouse model of TST or MPST deficiency was identified as a well-established, widely used model for studying cyanide-poisoning susceptibility in this search; this represents a potential research gap, since a Tst-knockout mouse would directly test the hypothesis that reduced rhodanese activity increases cyanide lethality/sensitivity.

Resources: MGI (Mouse Genome Informatics) for Tst/Mpst mouse gene and allele records; IMPC/KOMP for any existing or planned Tst knockout lines; standard toxicology-testing facility protocols (OECD acute-toxicity guidelines) rather than a disease-specific model registry, since this is a chemical-toxicant model rather than a genetic-disease model organism community.

Summary of Key Ontology Term Suggestions

Category	Suggested terms
Disease/condition	MONDO:0018754 (cyanide poisoning); ICD-10-CM T65.0; T57.3 (hydrogen cyanide specifically)
Chemical entities (CHEBI)	CHEBI:18407 (hydrogen cyanide); CHEBI:32035 (potassium cyanide); CHEBI:75504 (sodium cyanide); CHEBI:9539 (sodium nitroprusside); CHEBI:2637 (amygdalin); CHEBI:15672 (linamarin)
Genes (HGNC)	hgnc:12362 (TST); hgnc:7386 (MPST)
GO Biological Process	GO:0006123 (mitochondrial electron transport, cytochrome c to oxygen); GO:0045333 (cellular respiration)
GO Cellular Component	GO:0005751 (mitochondrial respiratory chain complex IV); GO:0005739 (mitochondrion)
Cell types (CL)	CL:0000746 (cardiac muscle myoblast/cardiomyocyte); CL:0000182 (hepatocyte); relevant striatal/upper-motor-neuron CL terms
Anatomy (UBERON)	UBERON:0002349 (myocardium); UBERON:0001873 (globus pallidus); UBERON:0001874 (putamen); UBERON:0002107 (liver); UBERON:0000966 (retina); UBERON:0001846 (cochlea)
Phenotypes (HP)	HP:0001259 (Coma); HP:0002615 (Hypotension); HP:0002093 (Respiratory failure); HP:0001695 (Cardiac arrest); HP:0001250 (Seizure); HP:0003128 (Lactic acidosis); HP:0001300 (Parkinsonism); HP:0001332 (Dystonia); HP:0001258 (Spastic paraplegia); HP:0000648 (Optic atrophy); HP:0000407 (Sensorineural hearing loss)
Treatment (NCIT)	NCIT:C15986 (Pharmacotherapy) with `therapeutic_agent` for hydroxocobalamin, sodium thiosulfate, sodium/amyl nitrite

Notes on Evidence Gaps and Caveats

No dedicated OMIM entry exists because this is not a Mendelian disease; genetic-susceptibility data (TST/MPST polymorphisms) come from a single well-cited functional-genetics study (PMID:16790311) and have not been validated in large clinical outcome cohorts.
Precise contemporary global incidence/prevalence figures for cyanide poisoning (overall, or split by fire/occupational/suicidal/dietary etiology) are fragmented across poison-control registries, forensic series, and regional epidemiological studies; no single authoritative global-burden-of-disease figure specific to cyanide poisoning was located in this session, and this should be flagged as a gap rather than filled with an unsupported number.
Konzo/TAN current prevalence was not independently re-verified with current-year survey data in this session; cite the primary konzo epidemiological literature directly (PLOS Neglected Tropical Diseases review; Lancet Global Health commentary) for up-to-date figures before curating specific rate values.
Some PMIDs above were located directly via search and are provided with confidence; where a specific PMID could not be independently confirmed in this session (e.g., some classic Baud et al. NEJM/Hall & Rumack reviews cited by convention in the toxicology literature), the claim is attributed by author/journal/year rather than by an unverified PMID, consistent with anti-fabrication practice.

Sources: - Interaction of cyanide and nitric oxide with cytochrome c oxidase (PMID:17906319) - Cyanide Toxicity - StatPearls - The two faces of cyanide: environmental toxin and potential gasotransmitter (PMC9291117) - Cyanide Beyond Toxicity: vascular function systematic review (PMC12486351) - Redirecting Intermediary Metabolism to Counteract Cyanide Poisoning, FASEB J 2025 - So Long, Cyanide, Utah Poison Control 2025 - Acute Cyanide Poisoning: Hydroxocobalamin and Sodium Thiosulfate (PMID:26543483) - Cyanide poisoning in victims of fire: 364 cases (PMID:8150843) - Elevated Blood Cyanide Concentrations in Victims of Smoke Inhalation, NEJM 1991 - Evidence for a functional genetic polymorphism of human TST/rhodanese (PMID:16790311) - Orphanet: Cyanide poisoning - ICD-10-CM T65.0 - Cyanide poisoning - Wikidata - Konzo: From Poverty, Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease, PLOS NTD - Cassava food toxins, konzo disease, and neurodegeneration (PMC3653209) - Lathyrism, konzo, and tropical ataxic neuropathy - MedLink Neurology - A case report of acute cyanide poisoning treated with lactate as an indicator (PMID:41204534) - Delayed cyanide induced dystonia (PMC1014725) - Dystonic-Parkinsonian syndrome after cyanide poisoning: clinical and MRI findings (PMC1032927) - Surviving acute cyanide poisoning: longitudinal neuropsychological investigation (PMC3962856) - MR Changes after Acute Cyanide Intoxication, AJNR 2002 - Protection from cyanide-induced brain injury by carnosic acid (PMC4465065) - Cobinamide superior in mouse model of cyanide poisoning (PMID:20704457) - Pilot study in swine model of lethal cyanide intoxication: platinum-methionine complex (PMC13458706) - Intramuscular hexachloroplatinate reverses cyanide-induced metabolic derangements (PMC6660183) - Pharmacokinetics/efficacy of molybdenum-based metallodrug in NMRI mice - Modest and variable efficacy of pre-exposure hydroxocobalamin/dicobalt edetate in porcine model (PMC7034532) - Forensic toxicology perspective on cyanide poisoning from natural seeds - EFSA: Acute health risks of cyanogenic glycosides in raw apricot kernels, 2016 - Case Report: multimodal management of lethal cyanide poisoning with blood purification (PMC13311073) - Sodium Nitroprusside - StatPearls - Evidence for Hydroxocobalamin in Cyanide Toxicity from Smoke Inhalation: Updated Systematic Review (PMC12767669) - Prehospital hydroxocobalamin for inhalation injury and cyanide toxicity in the US (PMC5627550) - Cyanide Toxicity - Medscape - Cyanide Poisoning in Animals - Merck Veterinary Manual - Health risk management framework for heavy metals and cyanide in Kwekwe, Zimbabwe (PMC10069024)

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	26
Resolved	26
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	26
On topic	7
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	58
Resolved	55
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	39
Terms named correctly	25
Terms named as a different term	10
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0100660 (1 mention) - the report calls it "Camptocormia — not exact"; HP calls it Dyskinesia
HP:0007015 (1 mention) - the report calls it "Symmetric limb weakness — approximate"; HP calls it Poor gross motor coordination
HP:0002061 (1 mention) - the report calls it "Progressive spastic paraparesis, though konzo is characteristically non-progressive once established"; HP calls it Lower limb spasticity
HP:0007281 (1 mention) - the report calls it "Sensory neuropathy"; HP calls it Developmental stagnation
CHEBI:75504 (2 mentions) - the report calls it "crystalline salts used in mining/electroplating, common in intentional poisoning"; CHEBI calls it pyranoside
CHEBI:9539 (2 mentions) - the report calls it "iatrogenic cyanide source via hepatic/enzymatic release of 5 CN⁻ per molecule"; CHEBI calls it Thiarubrine B
CHEBI:15672 (2 mentions) - the report calls it "cassava, lima beans, flax"; CHEBI calls it D-tartaric acid
UBERON:0001769 (1 mention) - the report calls it "corticospinal tract"; UBERON calls it iris
UBERON:0001791 (1 mention) - the report calls it "optic nerve"; UBERON calls it inner nuclear layer of retina
UBERON:0001846 (2 mentions) - the report calls it "cochlea"; UBERON calls it internal ear

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005751 (obsolete mitochondrial respiratory chain complex IV) (2 mentions) - replaced by GO:0045277

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002072 (1 mention) - the report calls it "Chorea, if choreiform component present"; HP calls it Chorea, and lists "Choreiform movements" among its other names
HP:0001272 (1 mention) - the report calls it "Cerebellar/sensory ataxia"; HP calls it Cerebellar atrophy
GO:0005751 (2 mentions) - the report calls it "mitochondrial respiratory chain complex IV"; GO calls it obsolete mitochondrial respiratory chain complex IV
UBERON:0001873 (2 mentions) - the report calls it "globus pallidus"; UBERON calls it caudate nucleus, and lists "nucleus caudatus" among its other names

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Related Datasets

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References & Deep Research

References

Deep Research

Cyanide Poisoning: Comprehensive Research Report

1. Disease Information

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Acute Cyanide Poisoning — Symptoms/Signs

Delayed/Chronic Neurological Phenotypes

Quality of Life Impact

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal Chain (Acute Cyanide Poisoning)

Category Detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

Pharmacotherapy / Antidotes

Supportive Care

Experimental/Emerging Therapeutics (active research, 2024–2026)

Surgical/Interventional, Rehabilitative, and Chronic-Disease Treatment

Clinical Trials

Pharmacogenomics

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions

Notes on Evidence Gaps and Caveats

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look