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

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Medical DiagnosticsHuman blood collection in heparin/EDTA (control ororganophosphorus-exposed) for cholinesterase measurementWRAIR whole blood assay 1US Army Delta pH, Michel assay 2Test-Mate ChE assay 3Blood volume finger prick (minumum10 μL) for AChE and BChEApprox 1 mL of whole blood tocentrifuge, only AChE routinelymeasured20 μL whole blood minimum volumefor AChE and BChEBlood can be frozen or kept at 4°C;hemolysis not problematicBlood suitable for analysis within15 days when kept at 4°C;no hemolysis toleratedFresh blood for immediate analysis;blood kept at 4°C to minimize AChEreactivation can be usedNo sample preparation required;whole blood usedBlood centrifuged at 1,000 g for20 min at 4°C, plasma discarded andpacked RBCs retained for analysisIncubate whole blood with specificinhibitor for plasma BChE (As1397)for measurement of AChEWRAIR assay using standard 96 wellformat and UV plate reader, manualand semi-automated (Biomek roboticplatform), determines both AChE andBChE activity simultaneously at 25°CCompletely manual (AChE valuesrecorded by hand every 20 sec)using pH meter at 25°CManual assay kit using a hand-heldphotometric analyzer to obtainAChE and BChE values separatelyat ambient temperatureAverage sample throughput perhour: manual, 40; semiautomatedrobotic, 48; both AChE and BChESample throughput: up to 51 samplesevery 38 min by staggering additionof substrate; AChE onlyAverage sample throughput perhour: 12. Each kit contains reagents/tubes for 96 samples; AChE or BChECalculate activity in internationalenzyme units (U/mL)Calculate activity in delta pH unitsper hCalculate activity in U/mL or U/g HbFig. 22-3: Laboratory and field cholinesterase assays routinely used by the US Army and their required blood processing.AChE: acetylcholinesteraseAs1397: 10-(α-diethylaminopropionyl)-phenothiazoneBChE: butyrylcholinesteraseChE: cholinesteraseEDTA: ethylenediaminetetraacetic acidg: gravityHb: hemoglobinRBCs: red blood cellsUV: ultravioletData sources: (1) Gordon RK, Haigh JR, Garcia GE, et al. Oral administration of pyridostigmine bromide and huperzine Aprotects human whole blood cholinesterases from ex vivo exposure to soman. Chemico Biol Interact. 2005;157–158:239–246.(2) Ellin RI, Burkhardt BH, Hart RD. A time-modified method for measuring red blood cell cholinesterase activity. ArchEnviron Health. 1973;27:48–49. (3) Taylor PW, Lukey BJ, Clark CR, Lee RB, Roussel RR. Field verification of Test-mate ChE.Mil Med. 2003;168:314–319.703
Medical Aspects of Chemical Warfarenecessary for AChE and BChE determination (andcorrection for hemoglobin content, which is alsomeasured in each blood sample; see Figure 22-3). Thekit is easy to use by a relatively untrained operatorand matches the sensitivity of the laboratory-basedEllman methods, but has relatively low throughputbecause it is performed manually. Although the Test-Mate ChE kit is designed primarily for field use, whereit is widely used for monitoring pesticide exposurein agricultural workers, longer processing times arerequired for complete AChE and BChE screening andhemoglobin measurement.Electrometric ChE Assay (delta pH)A manual method still widely used by the USDepartment of Defense to measure RBC-AChE isa modification 65 of the end-point delta pH methodoriginally described by Michel. 66 This assay monitorsthe decrease in pH (using a simple pH electrodeand pH meter) that occurs when AChE catalyzes thehydrolysis of acetylcholine to choline and acetic acid.The assay is initiated by the addition of substrate (acetylcholine)and the change in pH is monitored over 17minutes. This method is slow and laborious, althoughthroughput can be increased by staggering additionof substrate to each sample (see Figure 22-3). Up to 51blood samples can be analyzed in 38 minutes, and theRBC-AChE activity is reported as a change (delta) inpH units per hour. 67 However, the delta pH methodrequires centrifugation of blood to pellet RBCs, followedby removal of the plasma (containing BChE)prior to analyzing AChE activity. Lysis of the bloodsample is precluded, so blood must be iced (not frozen)before centrifugation and AChE analysis. Furthermore,because plasma BChE is not determined, the completespectrum of blood inhibition is unknown. Althoughthis technique was developed nearly 60 years ago,it is reliable, and the US Army (through the Departmentof Defense Cholinesterase Reference Laboratory)has a quality assurance testing program for primaryRBC-AChE monitoring of more than 25,000 militarypersonnel per year. 68Pretreatment Therapy for Nerve Agent Poisoning:Protection and Sequestering of CholinesterasePyridostigmine Bromide. The US Army’s currentpretreatment against potential nerve agent poisoningis the reversible and fairly short-acting AChE inhibitorpyridostigmine bromide (PB), which was reviewedearlier. 69 PB is a quaternary ammonium compound thatprovides temporary protection (by carbamylation) ofperipheral tissue and RBC-AChE. However, PB doesnot penetrate the blood-brain barrier, and thus doesnot afford protection against seizures and subsequentneuropathological states induced by a nerve agent suchas soman. 70 During the Gulf War (1990–1991), morethan 100,000 US and allied troops received PB (a singleoral dose of 30 mg given every 8 h) as a pretreatmentagainst exposure to soman. This method of pretreatmentwas demonstrated 62 in an FDA-supported clinicaltrial of human volunteers given PB as a single 30-mgdose (Table 22-5). Maximal RBC-AChE inhibition ofabout 27% was seen after 2.5 hours, with recovery ofactivity to almost 100% after 24 hours. To demonstrateprotection and sequestering of AChE, the volunteers’PB-pretreated blood was exposed ex vivo to soman,followed by PB and soman removal from the blood usinga small spin column, and monitoring the recoveryof RBC-AChE (decarbamylation) (Figure 22-4). All ofthe AChE activity protected by PB pretreatment wasrestored to control levels within 3 hours. Plasma BChEwas also inhibited in the same volunteers, albeit to alesser extent (approximately 11%, about one third ofthe inhibition observed for AChE). 62 Although it wasformally approved by the FDA as a specific pretreatmentfor soman poisoning in February 2003, 71 PB wasnot ordered to be taken by troops during the 2003Iraq war.Huperzine A: Potential Next Generation Peripherallyand Centrally Acting Protection and Sequesteringof Cholinesterase. Another pretreatment drug,physostigmine, can cross the blood-brain barrier andprotect brain ChE in addition to RBC-AChE. However,psychological and behavioral side effects (althoughpartially offset by a low dose of scopolamine to blockmuscarinic cholinergic receptors) preclude its use asan effective pretreatment against OP exposure. Furthermore,its use as an Alzheimer’s drug to improveshort-term memory has been discontinued becauseof multiple unwanted side effects, including nausea,dizziness, headaches, and sweating.In contrast to PB, huperzine A (Hup A), an alkaloidisolated from the moss Huperzia serrata, is a reversibleAChE inhibitor in both the peripheral and central nervoussystems. 72,73 Hup A has been shown to be superiorto physostigmine in its anti-ChE activity and hasa longer biological half-life in humans and animals.Hup A is currently undergoing extensive clinical trialsin the United States as a drug for Alzheimer’s disease(it is already used for this purpose in China), thoughit is already sold as an over-the-counter nutraceuticalsupplement for memory enhancement (FDA approvalis not required for this type of sale). Pretreatmentwith Hup A (in addition to postexposure treatment704
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The Coat of Arms1818Medical Departm
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Textbooks of Military MedicinePubli
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MEDICAL ASPECTS o fCHEMICAL WARFARE
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ContentsContributorsForeword by The
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ContributorsMICHAEL ADLER, PhDResea
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DONALD M. MAXWELL, MSResearch Chemi
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ForewordThe US military has been co
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PrefaceA significant concern for th
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PrologueThe original edition of Med
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xxii
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Medical Aspects of Chemical Warfare
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Nerve AgentsChapter 5NERVE AGENTSFR
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Nerve AgentsAbout 10,000 to 30,000
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Nerve Agentsphorofluoridate (DFP) w
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Nerve AgentsFig. 5-2. This schemati
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Nerve AgentsExhibit 5-1 continuedis
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Nerve Agentsactivity but only 15% t
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Nerve AgentsTABLE 5-3CHEMICAL, PHYS
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Nerve AgentsTABLE 5-4EFFECTS OF EXP
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Nerve Agentsaffecting the other eye
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Nerve Agentsmay cause severe rhinor
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Nerve Agentsof jerks and tremor.Cen
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Nerve Agentsand they were decreased
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Nerve Agentsnerve agent toxicity on
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Nerve Agentspatient. Decontaminatio
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Nerve AgentsFig. 5-5. The Mark I ki
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Nerve Agentsadministered intramuscu
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Nerve Agentsthat hydroxamine reacti
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Nerve AgentsOral administration may
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Nerve AgentsTABLE 5-7RECOMMENDED TH
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Nerve Agentsimpairment such as whee
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Nerve Agentssuboptimal, manner. The
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Nerve Agentsthan those who did not.
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Nerve Agentssible for binding nerve
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Nerve Agentsfor comparison was not
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Nerve AgentsTABLE 5-11EFFECTS OF PY
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Nerve Agentstivity of smooth muscle
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Nerve Agents38. Grob D, Lilienthal
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Nerve Agents77. McDonough JH, Shih
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Nerve Agents117. McLeod CG Jr, Sing
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Nerve Agents154. Tryphonas l, Veino
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Nerve Agents193. Funckes AJ. Treatm
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Nerve Agents235. Suzuki T, Morita H
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Nerve Agents274. Pellegrini JE, Bak
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PROCESSMedical Aspects of Chemical
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Triage of Chemical CasualtiesChapte
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Triage of Chemical Casualtiesreceiv
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Triage of Chemical Casualtiesentran
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Triage of Chemical Casualtiescatego
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Triage of Chemical CasualtiesIn a f
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Triage of Chemical Casualtiesnose)
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Triage of Chemical CasualtiesWith n
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Triage of Chemical Casualties14. Sa
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Decontamination of Chemical Casualt
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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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