Medical Aspects of Chemical Warfare (2008) - The Black Vault

Cyanide PoisoningHCNCCOHbO 2MetHbHCNSTEP 1CNMetHbCNMetHbS 2 O 32–SCN – +SO 32–RhodaneseSTEP 2Sodium NitriteAmyl Nitrite(Methemoglobin formers)HydroxycobalaminThiosulfate(sulfur donor)RenalClearanceThiocyanate(measurablemetabolite)Fig. 11-4. Fundamentals of cyanide antidote therapy. Clearanceof excess cyanide is essentially a two-step process. Thefirst step restores mitochondrial aerobic energy productionby accelerating cyanide removal from cytochrome c oxidase.The second step enhances conversion of cyanide into a formsuitable for renal clearance. It should be noted that theclearance process crosses multiple compartments and organsystems, and it works efficiently in the presence of adequatesubstrate and intact hepatic and renal function.CCO: cytochrome c oxidaseHCN: cyanideMetHb: methemoglobinCNMetHb: cyanomethemoglobinS 2O 3 2- : thiosulfate ionSO 3 2- : sulfiteSCN - : thiocyanateThe two substances intravenously injected, one afterthe other, namely, the nitrite followed by the thiosulfate,are capable of detoxifying approximately twentylethal doses of sodium cyanide in dogs, and areeffective even after respiration has stopped. As longas the heart is still beating, the chances of recovery bythis method of treatment are very good. Since dogsare more susceptible to the poison than man, theseobservations are especially significant. When sodiumnitrite is used alone, about four lethal doses of thecyanide are detoxified. Sodium thiosulfate, when injectedalone, nullifies about three lethal doses of thecyanide. Thus, there is not only a summation but adefinite potentiation of action when the nitrite andthe thiosulfate are administered together . . . . Anothernitrite, namely amyl nitrite, by inhalation has thesame detoxifying value as sodium nitrite by intravenousinjection. 129More recent case experience confirms early reports. 137Because nitrite formers elevate methemoglobinlevels and are powerful hypotensive agents, bothmethemoglobin levels and hypotension must bemonitored during the course of therapy and nitriteswithheld if necessary until recovery of acceptableblood pressure and treatment of methemoglobinemia.Therapeutic levels of methemoglobin are usually wellunder 10% when measured, often 3% to 5%. Inducedcyanomethemoglobin levels are usually unknown;available oxygen carrying capacity is always less thanmethemoglobin levels alone predict.The two chief formations of cobalt antidotes are hydroxocobalaminand dicobalt edetate. Although cobaltEDTA is quite toxic, hydroxocobalamin appears to havea safety profile preferable to the nitrites, particularlyin settings in which induction of methemoglobin isundesirable. No efficacy studies compare performanceof nitrites against that of cobalts.Oxygen is an important medicament for cyanideintoxication. It significantly enhances the antidotalvalue of nitrite plus thiosulfates, increasing the LD 50dose 6-fold (drugs alone) to over 8-fold. 49 Oxygen’smechanisms of action are uncertain. The additionalgain afforded by hyperbaric oxygen is uncertain, withsome patients responding well and other attemptsunsuccessful unless carbon monoxide intoxicationcoexists. 138 Patients should receive 100% humidifiedoxygen. If a mask is used, it should be a nonrebreathingmask to prevent rebreathing of exhaled cyanide.Several case reports have been published in whichfull recovery occurred in the absence of specific antidotaltherapy. In each case, indicated general supportivemeasures were otherwise provided. 126,133,139,140 Bloodlevels of cyanide in these individuals ranged from 2.14to 7.7 mg/L. Levels exceeding 3 mg/L are usuallyconsidered potentially lethal, and levels exceeding2 mg/L severe. These cases do not, however, justifywithholding specific antidotal therapies if antidotesare available. 56 These survivors likely were more tolerantof the exposures than is typical. In addition, theirpostacute recovery statuses are not reported. Yen etal report the only published English language epidemiologicalcase comparison between severe cyanideintoxications receiving nitrite/thiosulfate antidotesand those receiving supportive care alone. 137 In theabsence of anoxic encephalopathy, administration ofspecific antidotes offered clear survival advantage.Full treatment, including antidotes, should beadministered to pregnant women who are seriouslyimpaired by cyanide. Fetal effects other than methemoglobininduction have not been reported. Risks to thefetus from maternal incapacitation override concernsfrom possible fetal methemoglobin induction. In addition,the evidence suggesting the teratogenic riskof antidotes during pregnancy is very limited. 141 In alife-saving situation, therapies should not be modifiedas a consequence of pregnancy.In summary, the fundamental principles of toxicologictherapies apply to treatment of cyanide-injuredcasualties. The first is to recognize the situation and385