Clinical Aspects of Percutaneous Poisoning by the Chemical Warfare Agent VX: Effects of Application Site and Decontamination

Military Medicine, Nov 2004 by Hamilton, Murray G, Hill, Ira, Conley, John, Sawyer, Thomas W, Et al

O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) is an extremely toxic organophosphate nerve agent that has been weaponized and stockpiled in a number of different countries, and it has been used in recent terrorist events. It differs from other well-known organophosphate nerve agents in that its primary use is as a contact poison rather than as an inhalation hazard. For this reason, we examined the effects of application site and skin decontamination on VX toxicity in anesthetized domestic swine after topical application. VX applied to the surface of the ear rapidly resulted in signs of toxicity consistent with the development of cholinergic crisis, including apnea and death. VX on the epigastrium resulted in a marked delayed development of toxic signs, reduced toxicity, and reduction in the rate of cholinesterase depression compared with animals exposed on the ear. Skin decontamination (15 minutes post-VX on the ear) arrested the development of clinical signs and prevented further cholinesterase inhibition and death. These results confirm earlier work that demonstrates the importance of exposure site on the resultant toxicity of this agent and they also show that decontamination postexposure has the potential to be an integral and extremely important component of medical countermeasures against this agent.

Introduction

Recent world events have highlighted the use of chemical weapon agents not only by military combatants, but also by terrorist organizations. The Japanese religious cult Aum Shimyko pioneered this latter phenomenon by using the organophosphate nerve agent sarin in Matsumoto'4 and Tokyo5"12 with resultant deaths and massive casualties. In addition, this same group has also been reported to have used 0-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) on at least three separate occasions.13'14 This particular agent, also weaponized militarily (as is sarin),15 differs from the other "classic" organophosphate nerve agents in that it is nonvolatile and therefore considered to be primarily a contact poison rather than an inhalation hazard. The demonstration that this agent has a variable and delayed absorption from the skin16"18 has important implications for military or civilian first responders with respect to triage, decontamination, therapeutic drug regimens, and the potential for secondary contamination of caregivers.

Important work characterizing the skin penetration of VX was carried out by Sim16'17 in the 1960s using human volunteers. However, since that time, the majority of work with this agent has been carried out using rodents. In this article, we use an anesthetized domestic swine model to investigate a variety of parameters potentially impacting the absorption (and the resultant toxicity) of VX. This model system has been shown to be a good surrogate for human skin penetration as well as an excellent animal model with which to predict changes in human physiological parameters.19-21

Methods

Animals

Thirty-one 9- to 10-week-old castrated juvenile male Yorkshire-Landrace cross pigs (Sus scrofa domestica) weighing approximately 20 kg (20.3 ± 1.41 kg; mean ± SD, N =31) were obtained from a single local commercial supplier and were housed indoors at the vivarium complex at the Defense Research and Development Canada-Suffield. Animals received 16% hog grower (United Grain Growers, Okotoks, Alberta, Canada) and were allowed tap water ad libitum. They were allowed to acclimatize before experimentation with a 12-hour light cycle.

Anesthesia and Instrumentation

Animals were fed until the evening before surgery and were allowed tap water ad libitum until the time of the experiment. The animals were not premedicated. After being weighed, all animals underwent an isoflourane (Abbott Laboratories, Montreal, Quebec, Canada) inhalation induction in the transport container. Postinduction, the animals were placed in the dorsal recumbent position on a heated operating table and were intubated with a 6.5-mm internal diameter (internal diameter) cuffed oral endotracheal tube (Ruschelit, Willy Rusch, Kernen, Germany). Core body temperature was maintained at approximately 38.5°C with a Therm-o-matic heated operating table (Sage-London Industries, London, Ontario, Canada). Rectal temperature was monitored continuously. Venous access was established by inserting a 22-gauge intravenous catheter into an ear vein not used for exposure. A 20-gauge intravenous catheter was inserted into the right carotid artery for blood pressure measurement and blood sampling.

All animals received normal saline intravenously (0.9% sodium chloride, Baxter Corporation, Toronto, Ontario, Canada) at a rate of 9.2 mL kg^sup -1^ hour^sup -1^ ± 0.50 (mean ± SD, W= 31) via a volumetric infusion pump (Travenol FloGard 8000, Travenol Laboratories, Deerfield, Illinois). Capnography and pulse oximetry (%; SpO^sub 2^) were performed (Nellcor N1000, Nellcor Inc., Hayward, California). Data were collected with a Coulbourn Instruments LabLinc S computer interfaced (Coulbourn Instruments, Allentown, Pennsylvania) to an Optiplex 590 (Dell, Round Rock, Texas) IBM-compatible personal computer. Data were displayed and stored using WinGraph for Windows software (Coulbourn Instruments). Respiratory variables were monitored using a Bicore CP 100 pulmonary monitor (Bear Medical Systems, Riverside, California), which was, in turn, connected to a Dell Optiplex 590 IBM-compatible PC. Data were displayed and stored using custom-programmed software (Pulmonary Monitor 1.01, African American Cat Software, Calgary, Alberta, Canada). After the monitors were placed, the animals were stabilized for at least 30 minutes, during which time steady-state anesthesia (SSA) was established. Continuous baseline physiological parameters were obtained. Nonrespiratory physiological measurements included heart rate and mean arterial pressure. Respiratory parameters included respiratory frequency, tidal volume minute ventilation (V^sub E^: mL min^sup -1^), peak inspiratory flow rate, peak expiratory flow rate, airway resistance (R^sub aw^), dynamic compliance work of breathing, duty cycle (T^sub I^:T^sub TOT^), and mouth occlusion pressure (P^sub 0.1s^).