Rella Cyanide 9.16

MEMC V:Cyanide Toxicity from Common Housefires

Joseph Rella, MDAssistant Professor, Emergency MedicineNew Jersey Medical School2009

Environmental Emergencies

Chemistry of CN

Various salts pKa ~ 9.2 Na-, K-, Ca-

Various routes of access Often a massive poisoning Ingestion, inhalation, transdermal

Cellular inhibition CN readily complexes with metals Cytochrome oxidase complex (4) (myoglobin, nitrate

reductase)


Oxidative Phosphorylation


Intermembranespace

Matrix

I

II

Q III IV

ATP synthase

SuccinateFumarateNADH NAD + H+

4 H+ 4 H+ 2 H+

pH pH pH pH and

H+

ADP + Pi

ATP

e-

e-e-

e-cyto C

O2

+ 2 H+ H2O


Intermembranespace

Matrix (pyruvate dehydrogenase and Krebs cycle stop as well!)

I

II

Q III

ATP synthase

SuccinateNADH+

Pyruvate

pH pH pH pH and

H+

ADP + Pi

e-

e-

cyto C

O2

+ 2 H+

CN

Lactate


Inhibitors of the System

Electron transport inhibitors CN (azide, CO) binds to Cu ligands in complex IV

Uncouplers Some dissipate

Energy transfer inhibitors Inhibitory uncouplers


Physical effects of CN

A potent neurotoxin White matter is the more sensitive tissue Histotoxic anoxia Sudden loss of electrical activity in brain

Inhibits glutamate decarboxylase! Severe metabolic acidosis Clinical effects:

Headache, agitation, confusion, dyspnea, seizures, cardiovascular collapse - arrest


Clinical symptoms among 36 cyanide intoxications

228Respiratory arrest

176Psychomotor retardation

145Post-anoxic coma and death

5018Metabolic acidosis

176Convulsions

3613Coma

2810Cardiovascular collapse

228Asymptomatic% of totalnSymptom

Boron SW, Baud FJ. Acute cyanide poisoning: clinical spectrum, diagnosis, and treatment. Arh hig rada toksikol 1996;47:307


Sources of CN

Industrial/laboratory reagents Plastics, electroplating, mining, photography,

precious metal reclamation Fumigants

And


Combustion!

Silk, wool, nylon, polyurethane, melamine, polyacetonitrile,polyamide plastics


The Part CN Plays in Housefires

Product of combustion Acts as a knockdown agent

Decreases patients ability to evacuate Now more vulnerable to flame, CO, smoke,

etc.


Supporting Data of the Risk Symington I Lancet 1978 Clark CJ Lancet 1981 Birky MM Bull NY Acad Med 1981 Silverman SH J Trauma 1988 Baud FJ NEJM 1991 Jones J Am J Emerg Med 1987 Kulig K NEJM 1991 Chaturvedi AK J Appl Toxicol 1995 Shusterman D J Toxicol Clin Toxicol 1996 Ferrari L Forensic Sci Int 2001 Alarie Y Crit Rev Toxicol 2002 Yeoh M J Toxicol Clin Toxicol 2004 Borron SW NEJM 2004


The Controversy: How good are the data?

Varied exposures Complicated sampling, storage, analysis Animal models of smoke inhalation

Years of relying on CO and MetHbmeasurements


Evaluation of Potentially Exposed Patients

Clinically: comatose patients are easy to identify Be suspicious of awake, confused/agitated patients BP < 100mmHg without trauma

Emergency laboratory testing: Save blood in a heparinized tube at 4C for later an alysis Elevated lactate is the best we have for now

Baud FJ, et al. Crit Care Med 2002;30:2044


Antidotal Therapies

Taylor kit


Taylor Kit

Amyl nitrite / Sodium nitrite Cyanomethemoglobin outcompetes CN for Cyto aa3 to

restore function MetHb lags toxicity resolution Works despite methylene blue Possibly due to vasodilation, NO Some side effects

Sodium thiosulfate Sulfur supplier for sulfurtransferase transformation and

detoxification Very safe to give


Hydroxycobalamin

Actively complexes cyanide Directly detoxifies


(Fe) Cyto aa3CN

Nitrites

Cyanomethemoglobin

OxyHb

MetHb CN CN

CN

S2O32-

SCN- + SO32-

Rhodanese

Hydroxycobalamine

Cyanocobalamine


Summary

CN is a potent, rapid acting toxin CN is commonly found in victims of

housefires Be suspicious that seemingly mildly ill

persons may be toxic Save blood, get lactate Taylor or Hydroxycobalamine Good supportive care

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Rella Cyanide 9.16