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

Medical Aspects of Chemical Warfarecrosis at the site of injection 57,233 and may be associatedwith nephrotoxicity. 234 In a recent report from Germany,4-DMAP was administered to a subject exposed tomethyl isocyanate. Excessive methemoglobinemiaensued (86.7%), followed by major organ failure. 235The authors recommended against continued use of4-DMAP as a treatment for cyanide toxicity. 235Vandenbelt et al studied a group of aliphatic phenonesin dogs and identified PAPP as a potent, shortactingmethemoglobin former. 236 In subsequent reports,PAPP was shown to be efficacious against cyanidetoxicity in both dogs and rodents. 223,237–239 It was alsodemonstrated that PAPP formed methemoglobin inhumans. 221,222,240 Paulet et al noted the lack of deleteriouseffects of PAPP on psychological and physiologicalparameters, although several volunteers failed to respondto PAPP and did not exhibit elevated methemoglobinlevels. 221 PAPP has been described as safe andbenign, with little effect on the body other than methemoglobinemia.182 Although methemoglobin formerssuch as sodium nitrite are generally administered as atreatment for cyanide exposure, the toxicokinetics ofthe amiphenones may support preexposure prophylaxis.241 P-aminoheptanoylphenone appears to be thesafest of the amiphenones. Baskin and Fricke providean in-depth discussion on PAPP pharmacology. 227Thiosulfate and Other Sulfur DonorsThiosulfate is used for multiple conditions, includingpoisoning with sulfur mustard, nitrogen mustard,bromate, chlorate, bromine, iodine, and cisplatin. Incombination with sodium nitrite in a fixed antidotalregimen, thiosulfate has been used for cyanide poisoning.Thiosulfate is also used in combination withhydroxocobalamin. The standard dose of sodium thiosulfate,which is supplied in the standard US cyanideantidote kit in 50-mL ampules, is 50 mL of the 250 mg/mL (12.5 g), given intravenously. A second treatmentwith half of the initial dose may be given. The pediatricdose is 1.65 mL per kilogram of body weight. 186 Thepediatric dose equals the adult dose at about 21 kg ofbody weight. Thiosulfate functions as a sulfane donorto rhodanese and other sulfur transferases. However,rhodanese is located within mitochondria, and thiosulfatehas poor ability to penetrate cell and mitochondrialmembranes (although one rat study demonstratedthat thiosulfate can utilize the dicarboxylate carrierto enter the mitochondria). Whereas rhodanese isavailable in excess in the body, relative deficiency of asulfur donor capable of entering the mitochondria isthe rate-limiting factor for this route of detoxificationin cyanide poisoning. When a cyanide formulationis infused simultaneously with thiosulfate in dogs,a cyanide-sensitive species, the cyanide is detoxified“real time” (the actual time for the physical processof cyanide detoxification to take place in the body).The mechanism of thiosulfate protection appears tobe the exceptionally rapid formation of thiocyanatein the central compartment, which limits the amountof cyanide distributed to sites of toxicity. The mechanismof action of thiosulfate, when given after cyanideexposure, is uncertain. Nevertheless, thiosulfate substantiallyenhances survival from cyanide. There are nospecific contradictions to the use of sodium thiosulfate;its toxicity is low and adverse effects are mild. Sideeffects include nausea and vomiting with rapid infusion,headache, and disorientation. Rapid conversionto thiocyanate has resulted in reported hypotension.Excess thiosulfate is cleared renally. Premixed sodiumthiosulfate can be stored for a maximum of 3 years.Solid thiosulfate may be stored in an airtight containerfor 5 years without change.HydroxocobalaminLimitations associated with sodium nitrite (eg,hypotension and excessive methemoglobinemia)treatment and a desire for safer approaches to potentiallycyanide-intoxicated fire casualties have increaseddomestic interest in identifying alternative or complementaryapproaches to treat cyanide poisoning. 228,242–246Hydroxocobalamin is a major option. 145,247,248 Hydroxocobalaminis a registered antidote for cyanide poisoningin several European and Asian countries, and wasapproved by the Food and Drug Administration in2006 under the animal efficacy rule. The efficacy ofhydroxocobalamin versus the known effectiveness ofthe nitrite and thiosulfate combination in severe intoxicationsis still under study at the US Army Medical ResearchInstitute of Chemical Defense. Current doctrinein France is to initially administer hydroxocobalamin(5 g in 200 mL saline, IV) over 15 to 45 minutes. Baud 249has indicated that recovery often begins to occur beforethe full complement of hydroxocobalamin has beenadministered. Up to 15 g of hydroxocobalamin hasbeen used in some clinical cases. 249The most common side effect is an orange-red discolorationof the skin, mucous membranes, and urinethat lasts until the hydroxocobalamin is cleared fromthe body over several hours to a couple of days. 250In rare instances, urticaria can result from hydroxocobalaminadministration. Hydroxocobalamin isvolumetrically inefficient, and infusion volumes arevery large. The available packaging requires infusionof two full reconstituted bottles for the initial dose of5 grams. Hydroxocobalamin must be protected fromlight and maintained at temperatures below 25°C. Itsshelf life is 3 years. It is incompatible with reducing orbasic substances such as ascorbic acid, saccharose, sor-396