Post on 22-Dec-2015
Cyanide and Methemoglobinemia
Presented by: Dr. Aric Storck
Preceptor: Dr. Ingrid Vicas
Core Rounds
February 20, 2003
Cyanide
Anion (CN-)solid and gaseous formsImportant 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
Cyanide pollution
1997 - 4,513,410 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 1,800 - 5,000 deaths 200,000 injuries
Man carries his wife past the Union Carbide factory in Bhopal, India. Fumes from the factory killed her the previous day
Source: Greenpeace
Skulls from victims of the Union Carbide disaster in the Hamidia Hospital in Bhopal, India.
Source: Greenpeace
Cyanide … a potential disaster
500,000 hazardous materials shipments / day in the USA
Average 12,115 hazardous material accidents per year (1990-1996)
Large potential for significant industrial accident involving cyanide
Cyanide and terrorism
1984 - 7 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)
Cyanide and Fires
Cyanide is a combustion product of plastic rugs silks furniture construction materials
Significant correlation between CO levels and CN- levels in fire victims
estimated 35% of fire victims have toxic levels of cyanide
Cyanide and Fires
Source: Sauer S, Keim M. Hydroxocobalamin: Improved public health readiness for cyanide disasters. Ann Emerg Med. June 2001; 37:635-641.
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)
Cyanide - Pathophysiology
Other metabolic effects Less relevant (...because you die of anoxia first) Interferes with lipid metabolism Interferes with glycogen metabolism
Cyanide - Poisoning
Rapid absorption Respiratory tract Mucous membranes
Slow absorption Skin GI tract
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
Cyanide – Ingested Salts
Symptoms within minutes
Caustic – oral burns
Smell of bitter almonds
50 mg – has been reported to cause death
LD50 – 140-250 mg (untreated adult)
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)
Cyanide & Nitroprusside
Deterioration in aqueous solutions releases cyanide
Hydroxycobalamin and thiosulfate co-infusions used in critical care settings
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
Cyanide - Detoxification
Naturally occurs in small quantities tobacco cassava
Small amounts routinely cleared from body
Cyanide + thiosulfate = thiocyanate
Enzymatically Rhodanase Beta-mercaptopyruvate-cyanide sulfur transferase
Nonenzymatically Sulfane-albumin complex combines with cyanide
Cyanide - Detoxification
Cyanide – Clinical Presentation
Physiologic manifestations of hypoxia Metabolic acidosis Bradycardia Dyspnea CNS disturbances
Normal pulse oximetry
Ingestion with altered LOC and acidosis sodium azide salicylates iron Beta-adrenergic antagonists cocaine isoniazid toxic alcohols
Cyanide Poisoning - DDX
Cyanide – Clinical Presentation
Cardiovascular Effects Hypertension Tachycardia Hypotension Bradycardia Asystole Cardiac collapse
Laboratory Investigation
Electrolytes Elevated anion gap (lactic acidosis)
ABG Metabolic acidosis (lactic acidosis) Normal PO2
SaO2 Normal
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)
Cyanide Poisoning - Sequellae
Directly related to severity of exposure and delay in treatment
long term sequellae are those of hypoxia cerebral hypoxia / encephalopathy (common)
Cyanide - Treatment
Monitors
IV access
Administer 100% O2
Gastric lavage Indicated in very recent ingestion
Activated charcoal (1g/kg)
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
Cyanide Antidote Kit
Instructions 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
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
Sodium Thiosulfate 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
CAK - Children
0.33 mL/kg of 3% NaNO2
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
Cyanide Antidote KitEffectiveness 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)
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
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)
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
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
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
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
Advantages vs CAK less toxic does not produce MHb (thus appropriate for
smoke inhalation victims) may be administered out of hospital cheaper
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
Hydroxycobalamin (vitamin B12a)
Cyanide Poisoning - DispositionSymptomatic 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
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
MHb - Biochemistry
Hemoglobin tetrameric molecule
8 different dimers of MHb are produced when exposed to oxidative stress
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
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)
Spontaneous Methemoglobinemia
Autooxidation of Hb 0.5 - 3% 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)
A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous). B, The NADPH-dependent methemoglobin reductase system (therapeutic).
Source: Ford: Clinical Toxicology
Hemoglobin M rare autosomal dominant disorder stabilize heme iron in ferric (3+) state death in homozygotes lifelong cyanosis in heterozygotes
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 autosomal recessive
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
Congenital Methemoglobinemia
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 ….
Toxic Methemoglobinemia
side effect of therapeutic drugs
environmental nitrates in well water nitrates in spinach, carrots, beets, etc.
intentional OD
Factors influencing degree of MHb1) rate of entry of oxidant into circulation and
RBCs
2) rate of metabolism of toxin in body
3) rate of excretion of toxin
4) effectiveness of cellular MHb reduction systems
Toxic Methemoglobinemia
chloroquine
dapsone
local anaesthetics
methylene blue
metoclopramide
nitrates
nitrites
NTG
nitroprusside
phenacetin
pyridium
primaquine
rifampin
sulfonamides
vitamin K3
chlorhexidine
Toxins causing MHb
Symptoms vs MHb concentration
MHb conc. %MHb Symptoms
<1.5 g/dL <10 None
1.5-3.0 g/dL 10-20 Cyanotic skin
3.0-4.5 g/dL 20-30 Anxiety, lightheadedness, headache, tachycardia
4.5-7.5 g/dL 30-50 Fatigue, confusion, dizziness, tachypnea, tachycardia
7.5-10.5 g/dL 50-70 Coma, seizures, arrhythmias, acidosis
>10.5 g/dL >70 death
Chocolate-brown arterial blooddoes not become red with exposure to oxygenfilter 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
ABG
Measured - pH, pCO2, PO2
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
Pulse 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 630-631 nm (little
interference from oxyhemoglobin)
MHb - Treatment
Mild cases (no overt hypoxia) Supportive care Remove offending agent (half-life of local anaesthetic induced MHb in
normal individual = 55 minutes)
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.)
A. The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous). B, The NADPH-dependent methemoglobin reductase system (therapeutic).
Source: Ford: Clinical Toxicology
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
Ascorbic Acid 300-1000mg/day iv (divided tid-qid) Nonenzymatic MHb reduction
N-acetylcysteine Works in vitro, no in vivo studies yet
Treatment
Congenital MHb Generally asymtomatic due to compensatory
mechanisms Methylene blue – 100-300mg/day Ascorbic acid – 200-500mg/day
Illness associated MHb in infants Supportive care (hydration, etc.) Treat MHb >30%