Overview

Definition

Cyanide is a highly lethal mitochondrial toxin causing death within minutes to hours of exposure.

Epidemiology

• Human exposures to cyanide 1993–2002: 3165 exposures (2.5% fatal)
• Annual incidence in the United States: 5,000–10,000 smoke inhalation deaths
• Industrial exposure and suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide by cyanide poisoning occur mostly in men.

Etiology

• Domestic fires: 
  • Most common cause of cyanide poisoning
  • Byproduct of synthetic product combustion (plastic, paints)
• Diet: ingestion of amygdalin (cyanogenic glucoside in apricot seeds)
• Medical: 
  • Side effect of nitroprusside use (either a high dose or long-term use) 
  • Short-acting medication for hypertensive emergency results in cyanide release
• Suicide or homicide: potassium cyanide, sodium cyanide
• Industrial: manufacturing workplace exposure

Pathophysiology and Clinical Presentation

Pathophysiology

• Absorbed through the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, mucous membranes, or GI tract
• Quickly distributed throughout the body
• Major mechanism of action:
  • Inhibits the mitochondrial electron transport chain Electron transport chain The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC) by the inhibition of complex IV (cytochrome c oxidase, a3 subunit) as it binds to ferric iron (Fe³⁺)
  • Result: blockage of oxidative phosphorylation and inhibition of aerobic ATP production
  • ATP is then produced primarily by the anaerobic pathway, resulting in lactic acid production and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis.
  • Result: functional histotoxic hypoxia:
    • Inability to use O₂ due to poisoned electron chain
    • Especially deleterious to the cardiovascular and central nervous systems
• Additional contributing mechanisms of cyanide:
  • Inhibition of antioxidants
  • Induction of apoptotic cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Inhibition of gamma-aminobutyric acid (GABA) formation → risk of seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Binds to hemoglobin → cyanohemoglobin (unable to transport O₂)
• Cyanide metabolism:
  • Detoxified by the rhodanese enzyme
  • Converts cyanide to water-soluble thiocyanate (needs sulfur), which is excreted in urine

Clinical presentation

Symptoms develop within seconds to minutes.

• Breath may have a bitter or almond odor.
• Skin:
  • Flushed or cherry red
  • Cyanosis (more common)
  • Irritant dermatitis
• Cardiovascular:
  • Tachycardia/ hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Progression to bradycardia/ hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Dysrhythmia, cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest
• Respiratory:
  • Tachypnea/hyperventilation (reduced PaCO₂)
  • Progression to respiratory depression/failure 
  • Pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
• Neurologic:
  • Headache
  • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
  • Dizziness
  • Seizures
  • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Anoxic brain injury and permanent brain damage
• Nausea and vomiting 
• Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
• Renal failure
• Hepatic necrosis

Diagnosis and Management

Diagnosis

History and physical exam:

• History of exposure
• Bitter/almond smell
• Color change of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin (flushed/cyanotic)
• Characteristic symptoms

Laboratory tests:

• Severe metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis with anion gap
• ↑ Lactic acid
• Narrowed venous-arterial PO₂ gradient (venous hyperoxia)
• Blood cyanide level (not very reliable test)
• Glucose (to evaluate for hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia)
• Other tests to obtain:
  • Carboxyhemoglobin and methemoglobin: Rule out concomitant carbon monoxide (CO) exposure and ingestion of other drugs.
  • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen and salicylate levels: Rule out coingestion of other drugs.

Management

General considerations:

• Address any suspected cyanide poisoning quickly because of high mortality.
• Can be hard to diagnose/recognize
• Suspect in any smoke inhalation victim.

Decontamination:

• Remove patient from the source.
• Remove clothes.
• Cleanse wounds.
• Administer activated charcoal in the case of oral ingestion.

Resuscitation:

• Assess airway, breathing, circulation (ABC).
• Secure airway and provide high flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure O₂ (use of hyperbaric oxygenation is controversial).
• IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids and pressors if needed
• Glucose administration if hypoglycemic
• Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines for seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures 

Antidotes:

• Hydroxocobalamin (vitamin B₁₂) directly binds cyanide molecules and is the preferred treatment. 
• Sodium thiosulfate acts as a sulfur donor for the enzyme rhodanese to convert cyanide to excretable thiocyanate.
• Nitrites (sodium nitrite or amyl nitrite) induce methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia:
  • Converts ferrous iron (Fe²⁺) to Fe³⁺
  • Fe³⁺ binds cyanide and avidly forms cyanmethemoglobin.
  • Do not use for concomitant CO poisoning CO poisoning Carbon monoxide (CO) is an odorless, colorless, tasteless, nonirritating gas formed by hydrocarbon combustion (e.g., fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than oxygen, forming carboxyhemoglobin (COHb). Increased levels of COHb lead to tissue hypoxia and brain damage. Carbon Monoxide Poisoning as induction of methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia can be lethal.

Differential Diagnosis

• Methemoglobinemia: a condition of elevated methemoglobin containing oxidized Fe³⁺ instead of Fe²⁺. Methemoglobin does not bind O₂. Methemoglobinemia can be caused by nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates, dapsone, and local anesthetics Local anesthetics Local anesthetics are a group of pharmacological agents that reversibly block the conduction of impulses in electrically excitable tissues. Local anesthetics are used in clinical practice to induce a state of local or regional anesthesia by blocking sodium channels and inhibiting the conduction of painful stimuli via afferent nerves. Local Anesthetics and causes tissue hypoxia. Presentation includes cyanosis, headache, dizziness, nausea, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, shortness of breath, and/or arrhythmias. Methemoglobinemia is diagnosed with blood gas and treated with methylene blue and vitamin C administration. 
• Carbon monoxide poisoning Carbon monoxide poisoning Carbon monoxide (CO) is an odorless, colorless, tasteless, nonirritating gas formed by hydrocarbon combustion (e.g., fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than oxygen, forming carboxyhemoglobin (COHb). Increased levels of COHb lead to tissue hypoxia and brain damage. Carbon Monoxide Poisoning: an odorless, tasteless, colorless, nonirritating gas formed by hydrocarbon combustion (fires, car exhaust, gas heaters). Carbon monoxide has a higher affinity to hemoglobin than O₂ and forms carboxyhemoglobin, which results in impaired O₂ transport and utilization. Features include confusion, headache, dizziness, rosy cheeks, coma, and death. Diagnosis is established clinically and confirmed by blood gas. Management is 100% O₂ and, if failed, hyperbaric oxygenation. 
• Drug ingestion: various drugs can produce symptoms of poisoning similar to cyanide. The drugs include tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants, salicylates, organophosphates, isoniazid, and strychnine. Detailed history and a high index of clinical suspicion are essential for correct diagnosis. Management depends on the offending agent.