1. Cyanide and Methemoglobinemia
Presented by: Dr. Aric Storck
Preceptor: Dr. Ingrid Vicas
Core Rounds
February 20, 2003

2. Cyanide

3. Cyanide Anion (CN-) solid and gaseous forms
Important component of many industrial reactions
mining - recover silver and gold from ores
photographic - recovery of silver
plastic manufacturing
Naturally occurs in many plant products
Tobacco, apricot pits

4. Cyanide pollution
,513,410 cyanide released by top 100 polluters in USA
Bhopal, 1984
worst industrial poisoning in history
25,000 kg methyl isocyanate and combustion products released into atmosphere
1, ,000 deaths
200,000 injuries

5. Man carries his wife past the Union Carbide factory in Bhopal, India
Man carries his wife past the Union Carbide factory in Bhopal, India. Fumes from the factory killed her the previous day
Source: Greenpeace

6. Skulls from victims of the Union Carbide disaster in the Hamidia Hospital in Bhopal, India.
Source: Greenpeace

7. Cyanide … a potential disaster
500,000 hazardous materials shipments / day in the USA
Average 12,115 hazardous material accidents per year ( )
Large potential for significant industrial accident involving cyanide

8. Cyanide and terrorism
Chicago area residents killed after ingesting cyanide-laced Tylenol
Cyanide gas precursors (cyanide salt + acid) found in Tokyo subway bathrooms following sarin gas attacks
Cyanide believed to be involved in World Trade Center bombing (incinerated in attack)

9. Cyanide and Fires Cyanide is a combustion product of plastic rugs
silks
furniture
construction materials

10. Cyanide and Fires
Significant correlation between CO levels and CN- levels in fire victims
estimated 35% of fire victims have toxic levels of cyanide
Source: Sauer S, Keim M. Hydroxocobalamin: Improved public health readiness for cyanide disasters. Ann Emerg Med. June 2001; 37:

11. Cyanide - Pathophysiology
CN- has high affinity for metals
Complexes with metallic cations at catalytic sites of several enzymes
Binds ferric (3+) iron of mitochondrial cytochrome oxidase (cytochrome a-a3)
cytochrome a-a3 – mediates transfer of electrons to molecular oxygen (final step in oxidative phosphorylation)

12. Oxidative Phosphorylation
Figure 86-1 Cyanide inhibits oxidative phosphorylation at cytochrome a-a3 to block the
final step, which reduces oxygen to water. Other toxins that inhibit this step include
hydrogen sulfide, carbon monoxide, azide, and formic acid.
Source: Ford’s Clinical Toxicology

13. Blockade of oxidative phosphorylation
Tissue anoxia
Anaerobic metabolism
Lactic acidosis

14. Cyanide - Pathophysiology
Other metabolic effects
Less relevant (...because you die of anoxia first)
Interferes with lipid metabolism
Interferes with glycogen metabolism

15. Cyanide - Poisoning Rapid absorption Slow absorption Respiratory tract
Mucous membranes
Slow absorption
Skin
GI tract

16. Cyanide Poisoning - Inhalation
Hydrogen cyanide
Combustion of nitrogen containing polymers (vinyl, polyurethane, silk)
Immediate onset of symptoms
50 ppm
Symptoms after several hours
Anxiety, SOB, palpitations, headache
100 ppm
Death after 30 minutes
270 ppm
Immediate coma, asystole, death

17. Cyanide – Ingested Salts
Symptoms within minutes
Caustic – oral burns
Smell of bitter almonds
50 mg – has been reported to cause death
LD50 – mg (untreated adult)

18. Ingestion – Cyanide producing compounds
Compounds require metabolic activation to produce cyanide
Organic nitriles
Cyanogenic glycosides
eg: amygdalin – found in bitter almonds, apricot pits
Hydrolyzed to CN in small bowel
Not toxic if taken intravenously
Acetonitrile (solvent in artificial nail remover)
Oxidized by hepatic enzymes
Delayed onset of symptoms (up to 24 hours)

19. Cyanide - Dermal Exposure
LD50 = 100 mg/kg

20. Cyanide & Nitroprusside
Deterioration in aqueous solutions releases cyanide
Hydroxycobalamin and thiosulfate co-infusions used in critical care settings

21. Chronic Cyanide Poisoning
Clinical relevance controversial
Cassava – contains linamarin (cyanogenic)
Common food in many countries
Some evidence that B12 deficiency, goiter, demyelinating diseases may be related

22. Cyanide - Detoxification
Naturally occurs in small quantities
tobacco
cassava
Small amounts routinely cleared from body

23. Cyanide - Detoxification
Cyanide + thiosulfate = thiocyanate
Enzymatically
Rhodanase
Beta-mercaptopyruvate-cyanide sulfur transferase
Nonenzymatically
Sulfane-albumin complex combines with cyanide

24. Cyanide - Elimination Thiocyanate Relatively non-toxic
Renal elimination (half life 2.5 days)

25. Cyanide – Clinical Presentation
Physiologic manifestations of hypoxia
Metabolic acidosis
Bradycardia
Dyspnea
CNS disturbances
Normal pulse oximetry

26. Cyanide – Clinical Presentation
CNS
Headaches
Drowsiness
Dizziness
Seizures
Coma

27. Cyanide – Clinical Presentation
Pulmonary
Dyspnea
Tachypnea
Apnea

28. Cyanide Poisoning - DDX
Ingestion with altered LOC and acidosis
sodium azide
salicylates
iron
Beta-adrenergic antagonists
cocaine
isoniazid
toxic alcohols

29. Cyanide Poisoning - DDX
Inhalational Exposures
hydrogen sulfide
carbon monoxide
simple asphyxiants

30. Cyanide – Clinical Presentation
Cardiovascular Effects
Hypertension
Tachycardia
Hypotension
Bradycardia
Asystole
Cardiac collapse

31. Laboratory Investigation
Electrolytes
Elevated anion gap (lactic acidosis)
ABG
Metabolic acidosis (lactic acidosis)
Normal PO2
SaO2
Normal

32. Laboratory Investigation
AVO2
Decreased (decreased tissue oxygen utilization)
Cyanide levels
Not rapid enough for clinical utility
Serum cyanide level
Toxic = >0.5mg/L
Fatal = >3.0 mg/L
Erythrocyte cyanide level
Normal = <1.9 uM/L (50ug/L)
Fatal = > 40 uM/L (1mg/L)

33. Laboratory Investigation
Serum lactate – elevated
ECG
Sinus bradycardia
Sinus tachycardia

34. Cyanide Poisoning - Sequellae
Directly related to severity of exposure and delay in treatment
long term sequellae are those of hypoxia
cerebral hypoxia / encephalopathy (common)

35. Cyanide - Treatment Monitors IV access Administer 100% O2
Gastric lavage
Indicated in very recent ingestion
Activated charcoal (1g/kg)

36. Cyanide Antidote Kit Manufacturer: Taylor Pharmaceuticals
Cost: $317 USD

37. Cyanide Antidote Kit Contents Amyl nitrite 0.3 ml x 12
Inhaled while IV access established
Not necessary if immediate IV access
Can be given in pre-hospital setting
Sodium nitrite 300mg/10cc x 2
Sodium thiosulfate 12.5g/50cc x2
syringes, needles, tourniquet, stomach tube, instructions

38. Cyanide Antidote Kit Instructions Caution
Crush and inhale one ampoule (0.3ml) of amyl nitrite q15-30 seconds until iv access achieved
Rapid infusion sodium nitrite 300mg
Infuse sodium thiosulfate 12.5g over 10 minutes
Repeat sodium nitrite and thiosulfate infusion at half dose prn x 1
Caution
Sodium nitrite infusion limited by hypotension

39. Cyanide Antidote Kit - Mechanism
Nitrites
Therapeutic induction of methemoglobinemia
NO2 + Hb = MHb
Methemoglobin binds strongly to CN- and removes it from tissues
CN- + MHB = cyanomethemoglobin
cyanomethemoglobin relatively non-toxic

40. Sodium Thiosulfate Na2S2O3 + HCN + O = HSCN Oxygen
donates sulfur molecule to rhodanese (enzyme which catalyzes formation of thiocyanate)
Na2S2O3 + HCN + O = HSCN
Synergistic effect
Oxygen
Synergy of 100% O2 with nitrites/thiosulfate

41. CAK - Children 0.33 mL/kg of 3% NaNO2 1.65 mL/kg of 25% Na2S2O3
Adjust dose if anemic
Hb 70 – 0.19mL/kg
Hb 100 – 0.27mL/kg
Hb 120 – 0.33mL/kg
Hb 140 – 0.39mL/kg
1.65 mL/kg of 25% Na2S2O3

42. Cyanide Antidote Kit Effectiveness Complications
able to detoxify 20 lethal ingested doses in dogs
effective even after respiratory arrest as long as no cardiac arrest
Complications
Hypotension
Related to vasodilatory effects of nitrites
Methemoglobinemia
Death reported in asymptomatic cyanide poisonings (NB: only use CAK if symptomatic poisoning)

43. Cyanide Antidote Kit Limitations
MHb production prevents its use in unconfirmed cases
not practical for smoke inhalation victims (bad idea to induce MHb when already high level of carboxyhemoglobin)
many hospitals poorly supplied
81% of Tennessee hospitals unable to treat two 70 kg patients

44. Cyanide – other antidotes
Hyperbaric Oxygen
No therapeutic effect
Useful if concomitant CO inhalation
Dicobalt edetate
Widely used in UK
Effective antidote with significant toxicity (esp. when cyanide not present)

45. DMAP (4-dimethylaminophenol)
Produces very rapid methemoglobinemia
Used widely in Germany
No more effective than sodium nitrite
Less hypotension than sodium nitrite
Linked with renal failure in animal models

46. Hydroxycobalamin (vitamin B12a)
Widely used in France
Very effective and non-toxic
precursor of B12 (cyanocobalamin)
ideal choice for vegan victims of cyanide poisoning
Recognized by FDA for cyanide poisoning
Used in ICU settings to mitigate nitroprusside toxicity

47. Reduces cyanide to cyanocobalamin
B12a + CN- = B12
5g B12a will treat patients with up to 40 umol/L
Low concentrations available in US mean very large quantities required

48. Hydroxycobalamin (vitamin B12a)
When combined with sodium thiosulfate end product is thiocyanate
Na2S2O3 + B12 = HSCN + B12a
Recycling of hydroxycobalamin
Renally cleared
Synergistic effect of thiosulfate and B12a

49. Hydroxycobalamin (vitamin B12a)
Advantages vs CAK
less toxic
does not produce MHb (thus appropriate for smoke inhalation victims)
may be administered out of hospital
cheaper

50. Hydroxycobalamin (vitamin B12a)
Available in Europe as Cyanokit
2.5 and 5.0 g doses
very concentrated (5g/100 ml)
in USA hydroxycobalamin available in 1mg/mL (5L infusion required for 5g dose)
No pharmaceutical company willing to sponsor FDA approval and development in North America

51. Cyanide Poisoning - Disposition
Symptomatic
ICU admision until complete resolution of metabolic acidosis
Inhalation exposure
Discharge if asymptomatic in ED
Cyanide Salt Ingestion
Discharge if asymptomatic at 4 hours
Cyanogenic glycosides / organonitriles
24 hours of inpatient observation for symptoms
Suicidal patients
Psychiatric evaluation

52. Methemoglobinemia

53. What is methemoglobinemia?
Oxidation of iron within heme from Fe2+ to Fe 3+
Methemoglobinemia is due to an imbalance of MHb production and MHb reduction

54. MHb - Biochemistry Hemoglobin tetrameric molecule
8 different dimers of MHb are produced when exposed to oxidative stress

55. Oxidized (Fe3+) heme cannot carry oxygen
Allosteric changes cause non-oxidized heme to bind oxygen more tightly
Left shift of oxygen dissociation curve
Thus 30% methemoglobinemia has <70% of original oxygen carrying capacity

56. Leftward shift of Hb-Oxygen dissociation curve
Impaired oxygen delivery to tissues

57. Biochemistry, continued …
Positively charged MHb has high affinity for negative anions (cyanide, fluoride, chloride)
Neutral Hb has high affinity for neutral ligands (CO, O2. CO2)
….thus MHb is not particularly good at transporting oxygen (functional anemia)

58. Methemoglobinemia - etiology
Spontaneous
Congenital
Transient (illness associated)
Toxic
Iatrogenic

59. Spontaneous Methemoglobinemia
Autooxidation of Hb
% Hb converted to MHb each day
Autoreduction of MHb
99% occurs via NADH-dependent cytochrome b5 reductase (b5r) pathway
Ascorbic acid, glutathione – minor role in reduction
Conversion of MHb to Hb is 15% per hour (assuming no ongoing production)

60. B, The NADPH-dependent methemoglobin reductase system (therapeutic).
A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous).
B, The NADPH-dependent methemoglobin reductase system (therapeutic).
Source: Ford: Clinical Toxicology

61. Congenital Methemoglobinemia
Hemoglobin M
rare autosomal dominant disorder
stabilize heme iron in ferric (3+) state
death in homozygotes
lifelong cyanosis in heterozygotes

62. Congenital Methemoglobinemia
cytochrome b5 reductase deficiency
autosomal recessive
lifelong cyanosis in homozygotes
…but very few symptoms due to other adaptations
very sensitive to xenobiotic oxidizing agents
cytochrome b5 deficiency
very rare

63. Congenital Methemoglobinemia
NADPH-MHb reductase deficiency
exceedingly rare
Does not cause MHb
Enzyme only reduces MHb in presence of exogenous catalyzing agent (ie: methylene blue)
Patient would not respond to therapeutic methylene blue

64. The Fugates of Troublesome Creek

65. Fugate pedigree with genotypes
Congenital NADH-diaphorase deficiency

66. Transient (illness-associated) Methemoglobinemia
MHb common in septic infants with gastroenteritis and acidosis
Infants <6 months
NADH-dependent reductase deficiency
Presence of fetal Hb
Thus infant Hb more prone to oxidative stress
Exact mechanism poorly understood
altered flora, RTA, low Cl, UTI, protein intolerance ….

67. Toxic Methemoglobinemia
side effect of therapeutic drugs
environmental
nitrates in well water
nitrates in spinach, carrots, beets, etc.
intentional OD

68. Toxic Methemoglobinemia
Factors influencing degree of MHb
rate of entry of oxidant into circulation and RBCs
rate of metabolism of toxin in body
rate of excretion of toxin
effectiveness of cellular MHb reduction systems

69. Toxins causing MHb chloroquine dapsone local anaesthetics
methylene blue
metoclopramide
nitrates
nitrites
NTG
nitroprusside
phenacetin
pyridium
primaquine
rifampin
sulfonamides
vitamin K3
chlorhexidine

70. Therapeutic Methemoglobinemia
Iatrogenic induction of MHb in cyanide poisoning

71. Methemoglobinemia - Diagnosis
Physical Exam
cyanotic
“Chocolate brown” lips

72. Symptoms vs MHb concentration
<1.5 g/dL
<10
None
g/dL
10-20
Cyanotic skin
g/dL
20-30
Anxiety, lightheadedness, headache, tachycardia
g/dL
30-50
Fatigue, confusion, dizziness, tachypnea, tachycardia
g/dL
50-70
Coma, seizures, arrhythmias, acidosis
>10.5 g/dL
>70
death

73. Chocolate-brown arterial blood
does not become red with exposure to oxygen
filter paper test
place drop of blood on filter paper - MHb will not turn red
Potassium cyanide test
MHb turns red when CN added, sulfhemoglobin does not

74. ABG Measured - pH, pCO2, PO2 Calculated
Remember … PO2 refers to dissolved oxygen and has nothing to do with Hb
Calculated
SaO2 – from normal Hb-oxy dissociation curve
Assumes all Hb is normal
Abnormal Hb (MHb) which do not interfere with pulmonary diffusion with falsely elevate SaO2
“Saturation gap” = measured – calculated sats
>5% discrepancy suggests MHb, carboxyhemoglobin, or sulfhemoglobin
HCO3 – from Henderson-Hasselbach equation

75. Pulse oximetry Co-oximetry Not accurate in MHb!!
Only measures 2 wavelengths: 660 & 940nm
100% MHb will read 85% saturation
Co-oximetry
Measures four wavelengths
Maximal absorption peak at nm (little interference from oxyhemoglobin)

76. MHb - Treatment Mild cases (no overt hypoxia) Supportive care
Remove offending agent
(half-life of local anaesthetic induced MHb in normal individual = 55 minutes)

77. Severe Cases overt hypoxia, CNS depression, CVS instability
manage more aggressively in patients with coexisting medical problems (CAD, etc.)
Recommend antidote for MHb > 30% (or 20% in symptomatic patients)
100% oxygen
GI/skin decontamination (charcoal, etc.)

78. Methylene Blue Specific antidote for MHb 1-2 mg/kg over 5 minutes
Repeat doses to maximum 7mg/kg

79. B, The NADPH-dependent methemoglobin reductase system (therapeutic).
A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous).
B, The NADPH-dependent methemoglobin reductase system (therapeutic).
Source: Ford: Clinical Toxicology

80. Methylene Blue G6PD deficiency – Contraindication
Enzyme used in formation of NADPH
Insufficient NADPH produced to reduce methylene blue (oxidizing agent) to leukomethylene blue (reducing agent)
Relative buildup of methylene blue (oxidizing agent)
Can get paradoxical methemoglobinemia and methylene blue induced hemolysis

81. Ascorbic Acid N-acetylcysteine 300-1000mg/day iv (divided tid-qid)
Nonenzymatic MHb reduction
N-acetylcysteine
Works in vitro, no in vivo studies yet

82. Treatment Congenital MHb Illness associated MHb in infants
Generally asymtomatic due to compensatory mechanisms
Methylene blue – mg/day
Ascorbic acid – mg/day
Illness associated MHb in infants
Supportive care (hydration, etc.)
Treat MHb >30%

83. Clinical decision making in methemoglobinemia