cyanide poisoning

see also:

• toxicology
• metabolic acidosis
• https://emergency.cdc.gov/agent/cyanide/basics/facts.asp

• severe cyanide poisoning is a rare event in Western cultures
• fire is the most common source of cyanide exposure in Western countries
  • cyanide gas is less dense than air so it will rise
  • it is said that 35% of fire victims have toxic levels of cyanide
• cyanide may cause rapid onset of cardiorespiratory arrest via its interference with the ability of tissues to utilise oxygen by disrupting the mitochondrial oxygen pathway
• most deaths are likely to occur prior to hospital arrival due to the rapid onset of its effects in large exposures
• mouth-to-mouth resuscitation should be avoided in possible ingestions as there is a risk of toxicity to the rescuers
• it would seem that ideally, industrial sites should have access to the ability to give high dose iv hydroxocobalamin as soon as possible in severe cyanide poisonings
• most patients arriving to hospital alive will probably survive with intensive supportive care such as with mechanical ventilation, circulatory support and dialysis but appear to benefit from the low toxicity iv antidotes if available.

• significant cyanide exposure is most commonly seen from inhalation of smoke from residential or industrial fires
• industrial poisoning is rare in the developed world

• inhalation of hydrogen cyanide or other cyanide-containing gas, or dust
  • smoke from fires - combustion of plastics, acrylics, synthetic rubber, carpeting or upholstery
  • industrial sites eg. gold and silver mining, acrylic manufacture, electroplating, jewellery manufacture, steel fabrication, vermin eradication
• percutaneous absorption
  • industrial sites as above
• acute ingestion
  • suicidal or accidental
  • acute lethal dose of cyanide in humans is 0.5-3.5mg/kg
    • 60-90mg in adults
      • = 1 teaspoonful of a 2% solution of hydrocyanic acid (prussic acid), or,
      • = 200 mg of potassium cyanide
      • HCN levels in bitter almond (1062 ± 148.70 mg/kg) are approximately 40 times higher than levels found in sweet almond (25.20 ± 8.24 mg/kg) ¹⁾
        • thus consumption of 50 bitter almonds may be lethal in adults or 5-10 in children
      • concentrations of cyanide in apricot kernels can reach 2000 mg/kg of dry matter but average around 800mg/kg
        • maximum safe consumption is said to be eating only five kernels in one hour and no more than 10 per day but it is generally recommended not to eat more than 3 per day
• chronic ingestion
  • foods containing cyanogenic glycosides (cassava root, apricot seeds, bitter almonds)
  • content in cassava can reach up to 1500 mg/kg in bitter varieties poorly detoxified, which may explain the reported negative effects of daily consumption of cassava, such as diabetes, congenital malformations, and goiter neurological disorders such as Konzo, an epidemic paralytic disease, first described by G. Trolli in 1938, who discovered it amongst the Kwango of the Belgian Congo (now the Democratic Republic of the Congo). The outbreaks are associated with several weeks of almost exclusive consumption of insufficiently processed “bitter” (cyanide-rich) cassava. In northern Mozambique, the disease is known as mantakassa and it is induced by the daily consumption of gari (a popular food made from cassava) as a food staple, Konzo is a neurological disease which causes irreversible neuromotor damage and acute onset of paraparesis which affects mainly children ²⁾
• iatrogenic
  • prolonged, high dose iv sodium nitroprusside infusion

• rapidly absorbed and taken up into cells
• Vd 1.5 L/kg
• highly protein bound
• elimination half-life of cyanide is 2-3 hours via the liver enzyme rhodanese assuming sufficient stores of thiosulfate, and the relatively non-toxic metabolite thiocyanate is then excreted in urine
• toxic effects:
  • binds the ferric ion of cytochrome oxidase resulting in tissue hypoxia (histotoxic hypoxia) and lactic acidosis
  • pulmonary and coronary vasoconstriction
  • neurotoxicity and seizures via neurotransmitter release such as NMDA

• headaches, weakness, chest pains, abdominal pains, itch, rash

• oral irritation if ingested
• sympathetic activation - anxiety, tachycardias, tachypnoea, hypertension
• then headache, confusion, SOB, hypotension with bradycardia
• possible “bright-red cherry” skin and mucosa due to decreased tissue utilisation of oxygen

• reduced consciousness
• seizure
• opisthotonos
• trismus
• bitter almond smelling breathe but 18% of men and 4% of women are unable to smell this
• acute pulmonary oedema (APO)
• asystole

• recommendations other than supportive care are difficult due to paucity of evidence (mainly animal studies), variable presentations and severity, and access to the various antidotes. The following is derived from EMA (2012) 24, 225-238. Review article - Management of cyanide poisoning. Michael Reade et al on behalf of the Australian Resuscitation Council.

• benefits of using ANY of the recognised cyanide antidotes (whatever is available) probably outweighs the risks, however, preferentially use low toxicity antidotes if available
• 100% oxygen seems to be of benefit but hyperbaric oxygen does not

• consider using a low toxicity cyanide antidote if either:
  • smoke inhalation with unexplained metabolic acidosis and either:
    • carboxyHb level of > 10% (an indicator of likely high inhalation)
    • a plasma lactate > 10 mmol/L (in the absence of burns which would otherwise account for this)
    • neurologic impairment
  • raised blood cyanide levels
• theoretically avoid antidotes that induce methaemoglobinaemia in cases of smoke inhalation where patient may already have high carboxyHb levels

• very high dose hydroxocobalamin:
  • for severe poisoning:
    • adults: 5g iv over 15 minutes with repeat dosing up to 15g
    • paed: 70mg/kg iv over 15min, repeated twice if needed
  • the usual Australian PBS approved ampoule for Rx of pernicious anaemia is only 1mg - a “Cyanokit” has 2x 2.5g ampoules
  • causes pigmentation of serum resulting in interference with photometric bioassays such as carboxyHb, metHb and many other biochemical assays
  • no significant toxic effects
  • causes red-orange urine

• sodium thiosulphate:

• “eliminates” cyanide by converting it to thiocyanate via the mitochondrial enzyme rhodanese which uses thiosulphate as a substrate
• slower onset of efficacy, presumably as it needs to get into mitochondria first and this process is slow
• can be used as a sole agent for sodium nitroprusside poisonings but usually is recommended as 2nd line Rx if hydroxocobalamin Rx is inadequate
• adults: 12.5g (50ml of a 25% solution) iv at 1.25g/min (5ml/min)
• paeds: 412.5mg/kg at 0.625-1.25g/min to max. dose 12.5g
• if signs of cyanide toxicity are still present 30-120 minutes after administration, half the original dose may be repeated
• can cause local irritation and pain, nausea, vomiting, headache and disorientation but life threatening adverse effects have not been reported.
• may be used prophylactically for patients on high dose prolonged nitroprusside infusions

• general notes:
  • aim is to keep methaemoglobinaemia levels below 40%
  • consider avoiding if smoke inhalation as likely to also have high levels of carboxyHb
  • avoid or reduce dose in anaemic patients as oxygen carrying capacity is further reduced
• sodium nitrite:
  • may be useful as an adjunct to sodium thiosulphate when hydroxocobalamin is unavailable
  • adult: 300mg over 2-4 min, half this dose may be repeated after 30 minutes if required
  • paed: 4mg/kg (max. 10mg/kg) at 75-150mg/min to a max. of 300mg, with half this dose may be repeated after 30 minutes if required
    • anaemic children under 25kg require a LOWER dose
• amyl nitrite
  • cheaper than sodium nitrite but shelf life only 6 months-2yrs, and appears to have little efficacy in humans when inhaled (usually attaining only 7% methaemoglobinaemia), while also causing hypotension, and in patients with G6PD deficiency, haemolysis
  • it is also a drug of abuse, further making its use difficult to justify
• 4-dimethylaminophenol (4-DMAP)
  • more rapid rise of methaemoglobinaemia than with sodium nitrite
  • not marketed in Australia
  • can cause tissue necrosis or phlebitis at site of iv injection
  • may cause nephrotoxicity and excessive levels of methaemoglobinaemia

• dicobalt edetate
  • binds to cyanide
  • appears to be effective, but less so than 4-DMAP and use is limited by serious adverse effects:
    • vomiting
    • urticaria
    • anaphylactic shock
    • hypotension
    • ventricular arrhythmias
  • adverse effects can be reduced with concomitant glucose administration
  • avoid this agent unless confirmed cyanide poisoning and patient has lost consciousness