 let's talk about nerve agents first of all what are nerve agents well first of all this you've seen this two or three times already just to remind you that we're going to be dealing with liquids and vapor nerve agents are liquid anybody that calls them nerve gas in this class will go stand in the corner for 15 minutes it's a bad word it's nerve agent so we're going to be talking about liquid exposure and vapor exposure a nerve agent something that causes biologic effects by inhibiting an enzyme that enzyme acetylcholinesterase thing cannot do what it's supposed to do which is to hydrolyze or break down a neurotransmitter acetylcholine which is the transmitter in the colonergic part of the nervous system this excess acetylcholine a normal neurotransmitter is what causes the damage so it's an indirect effect an effect on an enzyme which then doesn't do something in the resulting excess product is what causes the damage now if we accept that definition I'll bet each of you has dealt with or handled nerve agents there are two classes of compounds that do this one's the carbamates ones the organophosphates and among the carbamates are antilirium neostigamine or prostigamine pyridostigamine or mestinon what's the military revel relevance of mestinon of pyridostigamine okay the military specific use for this is pretreatment for nerve agents which dr. new martyrs going to explain to you in great detail on a little while mestinon of course has been used for many decades in treatment of myosinia gravis any of you use seven you know what it is bug spray good how about malathion use that any of you garden probably have used that and then there's what we refer to as nerve agents as though they're different than these other things all these things do the same thing biologically cause the same effects the major difference is that the nerve agents are many times more potent that is it takes much less of a dose a smaller dose smaller amount these are the nerve agents ga or taboon gb sarin gd so man gf no other name and vx this class of compounds been known for about a century and a half and the toxicity wasn't recognized too much until 1936 a german scientist dr. garard schrader who was looking for more potent insecticides in a private chemical company like dupont or wherever came across something that was extremely potent he knew it was potent because he got effects from just holding the test tube of it under his face the law of nazi germany at that time said these things had to be turned over the government which he did and the government developed it and put it in munitions two years later dr. schrader synthesized another compound even more potent than the first this was gb and this too was in munitions during world war two germans did not use them as I mentioned this morning in 1944 another german scientist for synthesized so-man or gd and in the early 50s a british scientist working again in private industry synthesized vx the british were not in a offensive chemical mode at that time or have they been sent so they gave that to the united states united states developed it put an awful lot of it into munitions which are now we're trying to destroy well the last class pointed out that you cannot have a lecture on a chemical agent without showing plenty of chemistry and a lot of chemical structures and they urged us to be sure and show you lots of chemistry and a lot of chemical structures so there's one I do have a point in showing this this is taboon or ga and I want you to notice this grouping up here I think it is this one off the oxygen that's an ethyl you look down here it's a little bit bigger and here on so-man it is very big and this comes into importance later on when we talk about therapy because because of this side chain this large group the oxyme 2-Pam chloride is relatively ineffective against so-man inhibited colon esterase so an oxyme does not work too well and this is the reason because of this side group the other thing on here is that onset is very rapid that's the vapor onset is almost instantaneous from vapor now this one the axe is a little bit different different structure it has a sulfur in it which is in material LD 50 we don't talk much about VX vapor because it's relatively non volatile although large amounts or with heat it will vaporize onset is much longer it has to go through the skin and the LD 50 is 10 milligrams well can you visualize 10 milligrams of VX I'll help you there it is covers two of the columns on Lincoln Memorial on a penny that were placed on the arms of everyone in here half of you would be dead in a short period of time these are the toxicities LCT 50s VX is the most toxic GA is the least toxic this is liquid on skin here 10 milligrams you saw and progressively a lot more as we go up into the more volatile agents this is quite large because GB will evaporate from the skin before it will penetrate through the skin unless it's occluded by clothing or something then it goes right through the skin nerve agents are clear colorless liquids not gases clear and colorless they are said to be tasteless and I'm not quite sure who said that they are said to be odorless most are said to be odorless and again I don't know who said that GA and GD are said to have a slight odor major Madsen says GB does but nonetheless no warning here all of them penetrate skin all of them penetrate normal clothing with the exceptions I said some of the G agents may evaporate off skin G agents most are volatile or evaporate readily GB is by far the most volatile and that evaporates like water they don't just go poof up into the air like gasoline does in fact that probably saved a lot of people in the Tokyo Subways because it evaporated relatively slowly if they're going poof and filled the whole car with all the GB they had on that car everybody would have had a high concentration all chemicals in munitions I was trying to think of somebody can get me on an exception to this but all chemicals in munitions are liquids and she all explodes off comes liquid off comes aerosol which quickly evaporates and off comes vapor so you end up with liquid or vapor but everything as far as I know everything munitions is liquid except for BZ which is not okay the most volatile evaporates like water these are a definite vapor hazard Vax on the other hand is like light motor oil not too volatile evaporates very slowly presents very little vapor hazard we could probably put a couple teaspoons of Vax out here on the floor and wouldn't hurt any of us you want to try trust me physiology we all know this I'm going to go through it quickly and electrical impulse goes down a nerve releases that neurotransmitter across the synaptic gap and stimulates the organ and the organ functions and the function of that organ is stopped because the neurotransmitter is gone it's destroyed by acetylcholin esterase and organ might be a muscle gland or another nerve and we know what each of these does a muscle contracts the gland secretes another nerves stimulated if that neurotransmitter acetylcholin isn't destroyed it accumulates it becomes an excess and it continues to stimulate the muscle which continues to contract the gland continues to secrete a nerve continues to stimulate another nerve so there's hyperactivity in all of those organs and the colonergic nervous system innervates a whole lot of things excess acetylcholin that excess acetylcholine continues contraction of nerves and this includes both the skeletal muscles those that we volunteer voluntarily move but also muscles that are internal what are large groups of muscles internal smooth muscles GI tract that's one where's the other where diaphragm is kind of a skeletal muscle more than the bronchioles the whole airway system arterioles but that isn't of major significance in this particular sequence so we have the airways and the gut are the two major things that are most clinically affected by too much acetylcholine secretions from glands what extra can glands can we be talking about here salivary where else I lacrimal right tear glands where else bronchioles good where else sweat where else got two more to go gastrointestinal tract has glands and what else now you guess the eyes guess the mouth but you left out something in between does your nose ever run the glands in the nose secret sure eyes nose salivary sweat airways and gastrointestinal tract all those have extra can glands all of them secrete too much with nerve agent poisoning now co-energic nervous system can be broken into muscarinic sites and nicotinic sites because these can be stimulated by muscarin these by nicotine muscarinic sites are the glands the smooth muscle and the cranial nerves primarily the Vegas now the importance of that is is that the major antidote which is what atropine block sees effects to some degree give atropine glands dry smooth muscle relaxes and so on the nicotinic sites are those can be stimulated by nicotine but they're primarily skeletal muscle and ganglionic connections pre ganglionic fibers atropine has very little effect on these and if you have somebody who's twitching a lot and salivating with bronchoconstriction you give them atropine salivation would decrease bronchoconstriction will relax but they'll continue to twitch you're going to have a laboratory exercise today you're going to do just that give atropine to an animal that's been given a nerve agent be careful when you handle that agent and you're going to see just that their lungs will clear your secretions will drive but they'll continue to twitch okay reminder skeletal muscle smooth muscle primarily airways and GI tract glands and other nerves ganglionic connections muscarinic effects most important contraction smooth muscles are the airways then we have the gut we also have the iris which is not on here stimulation of glands airway or stimulation of glands airways GI sweat I nose and mouth and it stimulates the vagus to cause a slowing of the heart rate skeletal muscles the first effect is fasciculations you only what fasciculations are little twitching muscle fibers look like ripples under the skin or worms under the skin very localized usually although generalized fasciculations are very characteristic of severe nerve agent poisoning and one of the last effects you go away twitching flailing about of large muscle groups finally muscles get fatigued and tired and they become flaccid paralyzed stimulation of autonomic ganglia preganglionic nerves to cause autonomic stimulation of the heart tachycardia and hypertension so we have braided cardio one mechanism and tachycardia another central nervous system sudden exposure to a large amount of agent will cause loss of consciousness within seconds that's followed within a minute or two by convulsions and depending on whether or not the individuals on periodostigmine those convulsions may or may not stop within a few minutes people not on periodostigmine their convulsive activity will stop in three to five minutes why do you want to guess they're dead that's one reason yeah and no more acetylcholine no there's plenty of acetylcholine muscle fatigue and paralysis do you convulse when you're paralyzed no you might have seizure activity in the brain but you don't convulse what's another reason apnea they stop breathing in about five minutes or seven minutes do you convulse when you're not breathing not too well two factors stop convulsive activity now someone who's taking periodostigmine does not stop breathing and they will continue to live and to seize for a long period of time and as dr. Newmore is going to tell you they may go on to have brain damage from prolonged seizure activity but without periodostigmine that doesn't happen they'll go on to die very quickly unless there's intervention right there seizure activity apnea flaccid paralysis and death another type of CNS effects can occur in anyone exposed to any amount of nerve agent large amount small amount tiny amount they may have a prolonged set of psychological effects forgetfulness inability to think clearly your ability sleep disturbances slowed thinking etc etc these have always gone away in a month to six weeks there's a case report in your red book telling of a patient like this that we followed actually we were able to reverse this with scopolamine oral scopolamine turned his thinking around and made him much better which is interesting because now they've found that scopolamine is a very good anti-convulsant for nerve agent convulsions but it makes sense it's a co-energy antagonist heart rate may go down it may go up so the heart rate is of no value in making a diagnosis death is a respiratory death from peripheral factors such as bronchial constriction and secretions in the bronchi muscular weakness no pump to move air and depression in the brain which is probably the biggest factor effects on the organs most common effect of vapor exposure is meiosis and this generally is in both eyes although once in a while it's in one eye this is accompanied by red eyes or conjunctivitis tearing patient will tell you his vision is dim small pupil but also interference and co-energy pathways blurred vision occasionally headache pain around the eye pain in the eye and nausea and vomiting Japanese had a significant number of people who were exposed to vapor well more exposed to vapor alone had a significant number of nausea and vomiting and they assumed that that meant that they'd had a severe exposure with systemic effects of nausea and vomiting and that probably wasn't so they probably would have relieved that nausea and vomiting if they'd put atropine or home atropine eye drops in it's a reflex action through the Vegas I can't explain it all to you but it does happen so nausea and vomiting may be the result of meiosis running nose salivation bronchial constriction bronchial secretions complaints of tight chest difficulty breathing may be relatively mild might be very severe gastrointestinal tract secretions muscular stimulation with vomiting diarrhea cramps and bellyaches we've all had this right anybody who hasn't we all know what that's like skeletal muscles again fisculations twitching of large muscle groups finally weakness and paralysis central nervous system large sudden exposure loss of consciousness seizures and then flaccid paralysis and apnea followed by death psychological effects after any exposure to nerve agent any amount now we're going to talk about vapor exposure and liquid exposure and the first effects are not the same the early signs and symptoms vapor effects come on within seconds to minutes of exposure you've all been exposed to CS right anybody hadn't been exposed to CS nobody it's going to admit it you realize how fast the effects occur right within a minute or two or within seconds after you are exposed same with nerve agents onset very fast onset doesn't start 10 minutes after exposure somebody comes to you in a medical facility and said I was exposed to GB 15 minutes ago they have no signs of exposure they're clear nothing's going to happen to them unless they've also been exposed to liquid after low concentrations eyes nose and airways probably in that order in Tokyo 95% of their casualties had meiosis in a study we did here that's in your book about the same number had meiosis nose and airways after high concentration the first effect in the simple nervous system the initial effects depend on the amount of exposure small exposure the response is local these effects on the eyes the nose and the airway are a direct effect of the agent on the organ you do not have to invoke the fact that the agent was absorbed systemically and then came back to cause the effects direct effect and since this does not require agent absorption there's very poor correlation with the coalescence race in the red cell this may be normal this may be close to zero and there's this again a study in your textbook showing this and it can be anywhere no correlation large exposure loss of consciousness secretions twitching so on death within five or ten minutes and in this case these are systemic effects and there is a good correlation with the red cell coalescence race which is always under 20 to 25% of the normal value big innovation inhibition let me tell you another story again a true story many years ago we were conducting open air testing of nerve agents and on this particular day they were spraying GB from a spray tank from an airplane something happened to the spray tank they had a droplet so they jettison it landed in the middle of a military installation it went plop and there's a big puddle of GB out there hundred gallons of it so they landed there playing they thought well we better do something about this so they went to the post commander and said sir we we had a little problem out there and you've got a hundred gallons of GB out on the south 40 what should we do about it well now the post commander was post commander high-ranking government officials and what the high-ranking government officials do when they have a problem think about it cover it up what huh consult their aids barrier come on you guys are being cynical here aren't you come on you know what high-ranking government officials do when they have a problem then to the Pentagon appoint a special prosecutor he appointed a committee to investigate okay so we have the safety are you point the safety officer and he got a bunch of his people they thought well we're going out there there's GB out there it's a warm day it's volatile and maybe we better take the doctor with us they got the post surgeon he got a couple of his medics they all went out they parked up when a couple hundred yards got out of their vehicle safety officer said well that stuff's volatile there's vapor and even though we're up when you know when my change or whatever so let's put our mask on before we get close to it now they weren't concerned about full body protection right why because they figured they were going to be dealing only with vapor and it takes an awful lot of vapor five or ten times the lethal amount of vapor to do anything to bear skin don't need to worry about your skin when you're a nerve agent paper so everybody put their mask on but one person who do you think refused to mask are all you people nurses all I all I heard was the doctor come on you mean to tell me you don't think the doctor would do what he was told to do nope well a person refused to put his mask on was a doctor and he was kind of a macho guy anyway said I want to be the first one to see that puddle marching down there he was seen ten feet away from the puddle you seen the turn clutch his chest and fall a minute or two later he started convulsing in about four minutes later he stopped convulsing now why did he stop convulsing apnea what'd you say he was fried paralysis and apnea now he still may have had seizures but he did not have motor movement well his aidman had been well-trained they managed with great difficulty to save his life but I tell you that story for a couple reasons one that guy was walking down there turned around fell from a hundred percent to zero percent within a couple seconds now if he had his mark ones in his pocket could he have helped himself absolutely not he couldn't have found them he couldn't even think about him completely gone that quickly after vapor effects again with begin within seconds maximize in a couple minutes they're not going to get worse a long time later they're not delayed non-set and the other thing is they may actually improve if they're not too severe we used to have an aid station here and we used to see a lot of people come in in fact as you're going to see the eyes of one of them in a minute this guy came in he said all of a sudden was like I put sunglasses on everything got dim said my nose started running I started having a lot trouble breathing but now doc here it is 15 20 minutes later I'm in your aid station my breathing is much better fact is it's almost back to normal he didn't receive any antidote he hadn't received any we didn't give him any the only thing really wrong was his vision okay vapor exposure local effects eye effects myosis injection nose effects rhinorrhea airway effects and then systemic effects and the nausea and vomiting probably should go up there under local effects because they're caused by the myosis muscular hyperactivity weakness convulsions depression the CNS apnea death this is our experience with some of the people we've seen with small vapor exposure 59 and 62 had myosis very characteristic okay what was this guy exposed to atropine say what someone said okay could be is that what atropine would do to a normal person how about somebody had had myosis from nerve agent and you gave him a mark one with atropine would it do that everybody say no a mark one with atropine or atropine in the arm in the vein will not reverse nerve agent caused myosis you have to put it in the eye and when you put atropine in the eye what does it cause big pupils but what else blurred vision for about 24 hours so you don't want to treat everybody that has myosis they'll do well with myosis they have trouble with dim vision or with dim light but they can see pretty well and you put at the end you're gonna blur the only indications for putting atropine in the eye are severe pain in the eye or head and nausea and vomiting this guy wasn't exposed atropine you something exposed exposed to something each of you is exposed to within 24 hours darkness he sat in the dark for five minutes what happens when you sit in the dark for five minutes pupils get big right sure this guy sat in the dark for five minutes his pupils didn't get big why he'd been exposed to nerve agent today before said he walked in dim vision trouble seen he didn't have any pain didn't have a nausea and vomiting his breathing was okay by the time he got there it had improved a little bit running nose was no no factor so we took his picture now that's what you do when you don't treat him you know take your picture anyway that's the same guy how long do you think it was between those two pictures between no response to darkness and full response to darkness it's about 60 days skin exposure now keep in mind the size of that lethal droplet that you saw right remember that size of that first effects of exposure to a droplet on the skin are localized they are sweating and maybe fisculations at the site and these may be the only effects if the droplet is very small one-twentieth of the size of that droplet you saw and that's those are local effects get a little bigger one-tenth of that droplet or maybe one fifth of that droplet start getting systemic effects the agent gets absorbed it causes gastrointestinal effects vomiting nausea diarrhea and the blood colon esterase inhibition is below 30% again there's a table in the textbook pointing this out onset of these effects up to 18 hours after exposure so if you have a casualty who may have been exposed to liquid you have to watching for 18 hours because he may get sick these may occur even after decontamination I'll tell you a story about that in a minute full droplet or bigger on set within 30 minutes first effect loss of consciousness convulsions apnea there once was a chemist here at Edgewood in fact as he may still be here who one day was pipetting a dilute solution of soman you all know how to pipette right you hold it in a bulb or have a pipette dropper like device you all know how to do that not too many agreeable faces out there anyway he was doing it the old fashion way the loot soman he did a little too much sucking first thing you know he had some in his mouth and on his cheek now he did exactly what he was taught to do and he did exactly the right thing which was decon he ran immediately to the fountain which is an eyewash actually I think stuck his face in a rinsed his mouth out continued flushing for five or ten minutes within 30 seconds of exposure he had done that started that you can't do it much faster he then got a friend to drive him up to our age station he walked in the age station he was standing there talking to us and we were standing there pulling up atropine and the end of syringes and hanging up some two-pam chloride while he was talking perfectly normal and suddenly in mid sentence he collapsed started twitching and started gasping for air two points number one onset of effects was sudden no preliminary things he didn't say oh I'm starting to feel sick to my stomach or you know I'm starting to salivate too much nothing preliminary straight to zero percent function second point he had decon as fast as he could almost as fast as humanly possible and he still had very severe effects now if he hadn't deconned he probably would not have made it out of his laboratory he probably had such an amount that he probably would have died before you could have gone anywhere so decontamination diminished his illness but it did not prevent it and that's an important point you decon to get rid of the agent yes but you're not going to prevent all of its effects now in some circumstances you might but generally no exposure to an LD 50 or better which he probably had first effect loss of consciousness seizure activity is going to occur within minutes and the acetylcholinesterase activity in the red cells going to be close to zero which this guy's was skin exposure increased muscle activity localized sweating systemic effects GI first skeletal muscle breathing and finally central nervous system these might be the first ones and usually are after a large exposure now management of nerve agent casually in no particular order decontamination ventilate lock the excess acetylcholine remove the agent from the enzyme and some other things in treating any kind of chemical casually what's the most important thing for you to do rule one and don't ever forget this rule one protect yourself you know in the Iran-Iraq war Iran sent some casualties out of the country for medical care mostly to Europe they weren't too careful and how they decontam and these were mustard casualties not nerve agent sometimes they didn't remove all their clothing such as their underwear and they sent these patients partially contaminated to other countries where upon the people on the airplanes and these were commercial planes and people in receiving hospitals allegedly got contaminated from cross contamination from these people they did not protect themselves couple of these casualties five as a matter of fact were sent here to the states and several of the physicians here and I got to visit and see them at the time a man a woman and three children even though they were from different families protecting yourself common sense right not always common sense common sense is not always common but even dumb animals know to protect themselves basic instinct several weeks ago I was rummaging around in a closet at home where I keep things like ammonia and Clorox and Drano and all that stuff we all keep around kind of toxic my dog came in the room came to the door saw what I was doing immediately turned and ran away she recognized the hazard a few minutes later my dog came back trying to tell me she had more sense than I did you protect yourself by wearing appropriate apparel or by ensuring the casualties been thoroughly decontaminated two ways to do it ventilation well when you use periodostigmine in primates at least they don't stop breathing despite large doses of agent despite large doses of so-man I have to be specific on that they don't stop breathing so you don't need to ventilate if that applies to humans but sometimes casualties do stop breathing and what do you do for them out on a battlefield what can you do for nothing what can you do form in a battalion aid station well yeah what do you have two or three ambo bags and maybe one ventilator so that's not much help but whatever you have keep in mind the airway resistance is extremely high if you put a tube in these people and try to bag breathe them you won't tell they have atropine I've tried to bag breathe somebody I tried to mouth to mouth an animal dog well don't sit there and visioning my my mouth on a dog snout actually you had it it had a tube in and their trapezoid to give a nerve agent we tried to breathe it just like breathing against that wall just solid so you have to give them atropine before you're going to do any good ventilating and that kind of goes counter to the usual teaching the first thing you do is ABCs you have to make that a ABC antidote airway breathing and circulation because you can't breathe them until the atropine works a little bit the best and quickest decon is physical removal now you're going to hear a lot about fancy equipment decon kits and everything off everything else but the plain thing is get the stuff off what do you do when you spill something toxic on your arm and home you run to the faucet turn it on full blast and flush it right same thing with chemical agents you know hypochlorite the M258A1 they all have nice chemicals and those chemicals break down or decompose agents but they don't do it immediately it takes minutes and you put Clorox on somebody and leave it on for 10 minutes and I've heard this taught the stay time of 10 minutes what's that do it gives the agent 10 more minutes to penetrate your skin doesn't it if it's not immediately broken down which it isn't so get it off whatever you have okay lock the excess acetylcholine the drug of choice is atropine atropine is chosen as a trade-off 40 45 years ago because it's effective and it's side effects now a lot of anti-cholinergics or anti-cholinergic blocking drugs are effective some of them have too many side effects BZ is an excellent antidote for nerve agents but you don't want to give BZ to soldiers to carry around in injectors do you they might discover they can have fun with that although I've never really seen somebody who'd been exposed to BZ who wanted to do it again quite honestly but nonetheless trade-off it's effective minimal side effects what's potentially the most serious side effects effect from atropine come on you know what atropine does tachycardia now you're a young healthy person aren't you you're in the military so by definition you're a young healthy person how much does an injection of atropine increase a heart rate of a resting person by 35 beats a minute now can you increase your heart rate by 35 beats a minute without any adverse effects absolutely fact is you'd hardly know it if your heart rate went up 35 beats so that's not the answer good answer but wrong what else does atropine do huh stop sweating and what does that do eat if it's a one-day and if there's work or exertion and you've taken atropine you can get in a lot of trouble some years ago they sent 35 soldiers to march around this air strip on an August day at 85 degrees and 85 percent humidity they did it they were all hot and sweaty they were unhappy but their core temperatures were below a hundred a couple days later they gave him two milligrams of atropine they did that again and two or than half of them finished it core temperatures above a hundred three and a half so that's what after being after being blocks the effects of the muscarinic sites and tricycretions it reduces smooth muscle contractions including the airways does not do anything to skeletal muscles and does not do anything to myosis unless you put it in the eye by means of eyedrops starting doses two milligrams usual total dose is no more than 20 milligrams don't interpret this as saying you can't give more than 20 but that's the most it's been given now with pesticides much larger doses are required a hundred five hundred four thousand milligrams a day for pesticides so nerve agents require significantly less after you have atropine at five to ten minute intervals until secretions are drying looking the mouth and until the airways are better somebody's conscious he'll certainly tell you hey doc I'm breathing a lot better now or if they're unconscious you can tell by how much resistance there is to ventilation those are the two criteria for stopping atropine oxymes remove the nerve agent from the colon esterase remember the basic problem is the agent attaches to this enzyme acetylcholin esterase in the absence of aging aging is a process by when the agent becomes irreversibly attached to the enzyme and an oxyne cannot remove it it's refractory to reactivation by the oxyme this is the nerve agent these are the active sites on colon esterase the oxyne comes along picks it off lifts it up the enzymes back to normal can function and the nerve agent gets detoxified very simple except because of that large glob on GD or cell man that I pointed out to you this becomes irreversibly attached and the nerve agent or the oxyne cannot get in there to pull it off that happens in two minutes with so many now it happens with other agents too but the time time is much longer for example with sarin it's three or four hours oxymes have no muscarinic effects they help it nicotinic sites improve the smooth muscles skeletal muscles we have two PAM chloride or preludoxymer protopam other countries have other oxymes the dose IV is about one gram given in 20 to 30 minutes if you give it faster than that the blood pressure is going to go up to 250 and that can be quickly reduced with fintolamine seizures are brief in the absence of periodostigmine because they're stopped primarily by death or intervention with periodostigmine they're prolonged and may lead to permanent damage cardiac effects there are some brief arithmias most serious one is one that's caused by intravenous atropine given to somebody who's hypoxic this will produce ventricular fibrillation so don't give atropine intravenously until you ventilate it casually recovery usually occurs in a couple of hours by recovery I mean they start gaining consciousness they start breathing spontaneously and in all cases except where there is irreversible brain damage like that young lady in Tokyo this has happened within a couple of hours it may not feel good for a couple of days return to duty they will have a visual problem dim vision for a couple of weeks and they may have psychological problems and these can be extremely subtle if you have an individual who's been exposed to nerve agents even a very small amount and want to return them to duty and his duty is an air traffic controller you better do a very careful mental status exam long-term no real no long-term effects there's a study done a number of years ago in which they took a group of people who had been exposed to sarin group of controls they did EEGs on them they couldn't tell the difference on individual records somebody read all the records couldn't pick out which one had been exposed when they averaged the groups they could tell a slight difference between the average it's not individual rule 2 what was rule 1 good rule 2 in the presence of loss of consciousness and or severe signs and 2 or more systems that is airway CNS gastrointestinal or skeletal muscle you have 3 mark 1s and diazepam immediately don't question it do it rule 3 when it casually requires 3 mark 1s at one time always give diazepam now let's talk about a couple cases what we would do about it and then we're going to demonstrate the mark 1 small vapor exposure somebody who has myosis and rhinorrhea and walks into your clinic what do you do for them observe do they need any therapy no not unless they have pain in the eye or unless they have nausea and vomiting then you put what what do you do in that case atropine or home atropine eye drops I am or IV atropine will not help myosis they're short of breath what do you do for them mark 1 1 or 2 they're mild to moderately short of breath 1 real severely short of breath maybe 2 but atropine is a wonderful drug it does wonderful things as you will see with your own eyes this afternoon so you can almost always start with one and then wait a few minutes before giving a second a severe exposure unconscious seizures apnea airway problems gi problems or moderate to severe symptoms in two or more systems as problems in gi tract airways skeletal muscle or CNS three mark ones immediately with diazepam small liquid exposure with localized fascination and sweating one mark one because the stuff has gotten into the skin it's past the epithelial barrier vomiting and diarrhea definite systemic effects requiring a mark one and a severe liquid exposure loss of consciousness seizures disturbances in two or more systems three mark ones and diazepam now this is just a starting dose this individual is undoubtedly going to need more but as they start I'm going to follow up what dr. Seidel has presented to you partly by way of review and partly by way of introducing pretreatment to which he's already alluded we can treat nerve agent poisoning we have to treat it very quickly the reason why you need before you leave here to know something about these things is that you don't have the time you had with the bio agents that you heard about earlier in the week you probably realize now there's not a single bio agent that acts really fast seb maybe you get a big slog maybe four or five six hours but if you get an anthrax casualty and you make the diagnosis and you're starting to think about oh gee you know do I want to treat all these other people I have lots of time I can look that up in the book in the case of a nerve agent casualty is I think you now realize the kinetics are such that you don't have the time to do that in fact as dr. Seidel mentioned to you if you have a nerve agent casualty in front of you and you've got two hands and nobody around you in one hand has a ventilator and the other hand has a mark one which one goes in first the mark one because I can't even get unless I'm Charles Atlas I'm probably not going to be able to ventilate that patient very well because of the airway collapse so by means of segueing into talking about pretreatment let me pretend for the moment that this is a neurology class or that that wouldn't work at all let me pretend for the moment that you guys are preparing for boards and you've called me as the neurologist to remember some of the physiology of diseases you already know what you just heard all about botulinum toxin poison okay you should understand the physiology of botulinum toxin poisoning what happens in Botox poisoning where does it act you get paralysis but I'm going to be more specific where does botulinum toxin act it acts pre-synaptically so I can't release acetylcholine for the moment let's just talk about neuromuscular transmission so we're only talking about colonertial transmission for the moment so what kind of weakness does a botulinum toxin casualty develop flaxet exactly the the muscle simply cannot contract now let me remind you about another disease that we haven't talked about this week at all but it is of some relevance and that's the disease near and dear to my heart because I get paid to take care of a of it exactly myasthenia gravis what's wrong with people in myasthenia gravis anybody remember say again you develop antibodies against the receptor on the postsynaptic side and so acetylcholine is normally released but it doesn't have enough receptors to interact with and therefore you get a similar kind of weakness although it's usually more cute than a botulinum toxin again the muscle just can't contract normally hold that thought how do we treat myasthenia gravis we prolong the length of time that acetylcholine is present and the way we do that is by giving an acetylcholinesterase inhibitor well dr. Seidel has now exposed you are a terrible word for this context he has exposed you to the two categories of acetylcholinesterase inhibitors they are the carbamates and the organophosphates and the major difference for the moment between those two is that carbamates are relatively reversible inhibitors whereas organophosphates are relatively irreversible inhibitors but they basically work on the same action so I can take a carbamate and the one that we use for diagnosis in myasthenia is physo stigmine that's our little tensilon test the one we use for treatment is puridostigmine and that will prolong the action of acetylcholine and if you treated myasthenics you know that you can't just give a dose of puridostigmine how long does it last how often we give it we give it usually TID because it tends to wear off and that's going to come in here and again now let's go back to nerve agents how do nerve agents work what's the the location at which the nerve agent works it works directly on the enzyme okay it is an acetylcholinesterase inhibitor and so we have so much acetylcholine around that we have an over stimulation in fact when nerve agents do is to convert acetylcholine from a neurotransmitter into a poison that's what they do you're basically poisoning somebody with his own acetylcholine and so what is the effect of that on muscle it's over stimulation remember you saw that cat in the video the cat was over stimulated and eventually became paralyzed but only because all the juice had run out of the muscle now this is for the amide center in school the purpose of the next little presentation is to explain why we would want to pretreat for nerve agent poisoning now dr. Seidel's already alluded to this there's a side reaction that occurs once I have formed the complex of a nerve agent with acetylcholinesterase the agent enzyme complex over a period of time a side reaction occurs which I personally think is a real misnomer that's that aging reaction which dr. Seidel referred to I don't like that term but we're stuck with it's an old term we're not going to change it and what aging actually is is the liberation of an extra side group but what aging basically does is it converts that complex into one which oxyne from one which oxyne can hydrolyze into one which oxyne can't hydrolyze so it converts this complex into something I from something that I could treat with my mark one does something that I can't and the rate at which that occurs is predictable and as dr. Seidel mentioned for sarin and tabloid you have several hours in which to do that well in the case of sarin and tabloid similar to the tokyo subway victims does it matter that it takes a couple of hours do I care about that reaction if I've gotten a lethal dose I don't care at all because I'm going to die of the dose okay the patient's going to be alive or dead in that two or three hours and in the case of GA I think it's even longer in the case of GD the average length is two minutes and the chance that I'm going to get to that victim whether it's in tokyo subway or on a battlefield within two minutes is relatively small and so back quite a long time before the Gulf War this problem was recognized how are we going to protect our troops against GD our oxyne won't work and that's where pretreatment came along therapy for soman is relatively ineffective because of this aging side reaction which we know is going to take place very quickly by the way Iraq had a lot of soma still does now what carbonates do is to bind to acetylcholinesterase you would say why in the world would that be helpful after all that's what nerve agents do carbonates in fact in high doses produce exactly the same cholinergic excess that nerve agents produce what in the world is the value of this well after I've been exposed to nerve agent the answer is there's no value at all and that's of an important teaching point treating somebody with carbonate once they've gotten a dose of nerve agent is absolutely useless because I'm just going to be potentiating that effect I'm going to make them worse not better but the difference is that the carbonates and the one that has been chosen is pyridostigmine they form a complex which spontaneously dissociates let me give you an allergy Dr. Ramadson is not all that fond of this analogy but I'll give you an idea if I take my bank of acetylcholinesterase and I bind it up with nerve agent I have invested in a stock that's going downhill I can't get my money back out of that bank that bank is going bankrupt and all I can do if I'm very lucky I can pry it open with the two-pam crowbar as Colonel Atson sometimes refers to it which is sort of like the federal deposit insurance corporation may be liberated a little bit of it before it ages now if I instead invest some of that money in carbonate pyridostigmine being the one that we have chosen what I'm doing is I'm essentially safeguarding it I'm hiding it because I know that although I won't have access to it for a period of time it will be coming back online at a very predictable rate now if I am not in any danger of having a big assault from nerve agent then that doesn't really do me much good but it probably won't do me much harm either and I'll show you why but if I know that I'm going to be getting a hit with a nerve agent I can protect some of my native enzyme I know that I'll be getting it back at a predictable rate and this is the rationale for pretreatment now you see why it's called pretreatment it is not a treatment neither it is it an immunization it is a pretreatment and it turns out I don't have to use up a great deal of my acetylcholinesterase in this pyridostigmine or carbamate enzyme complex in order to really increase my ability to survive an nerve agent challenge that's the theory these are kernel Madsen's okay Pacman is the good stuff Pacman is acetylcholinesterase that's what you want it happens to be membrane bound to the post synaptic membrane but we won't even deal with that here and pyridostigmine attaches to it isn't that this is very high-tech and on the right you see the small blue diamonds are nerve agent nerve agent also attaches and if the nerve agent happens to be flavored so man it gets sewed up that's a nice little way of remembering it it gets sewed and attached and my 2-Pam chloride or whatever oxy might have around isn't going to be able to liberate it but the stuff that I have concealed by my temporary binding to pyridostigmine the carbamate of choice that's available well that's all very nice that's all theory and you know perfectly well there's a lot in biology that we don't necessarily see in the living organism that really works well in the test tube but this is at least the theory now have we ever tested this in people and exposed them to a nerve agent challenge no we haven't but we certainly have done it in animals and this is the you are about to go over to the building where this work was carried out and you will be seeing the intellectual descendants of the monkeys who were used for this they are rhesus monkeys it's the same experimental system and what the the experimental design was was that you take monkeys you expose them to an LD 50 of soma then you have another group and you expose them to an LD 50 of soma and you give them all the atropine and 2-Pam chloride that looks clinically valuable and you can increase the amount that the LD 50 now equates to by a factor of 60% in other words 1.6 times as much soma on average is required to kill the monkey if I'm sitting there giving all of my treatments if I give the pretreatment with puretostigmine and I conceal some of my acetylcholinesterase from the nasty nerve agent I can increase the LD 50 40 times put it another way I can survive 40 times as much put it another way I can protect against 40 lethal doses on average so that's the take-home message I need a lot more soma to kill me once I have been pretreated now is there any value to this in sarin not really because sarin is something which ages very slowly and the same thing is true for the nerve agent VX tactically the three nerve agents of which we are most concerned based on our intelligence estimates are sarin GB soma and GD and VX now am I going to know which agent is going to be put down against me no I'm not and in the case of the Iraqis we know that soma and was an agent of tremendous interest in the case of the North Koreans it turns out to be mostly VX but we never are going to know now how safe is puretostigmine how many people here have ever given it not very many I'm surprised but then again I'm an urologist so what do I know you know to me everybody's got nerve disease a puretostigmine has been out there it is manufactured by Hoffman the Roche has messed it on it's been on the United States Pharmacopoeia since sometime in the 1940s okay therefore it's we have a lot of clinical experience with it in myesthetic patients and we know a lot about its side effect profile can you imagine what the side effects might be just hazard to guess what might I do if I give somebody something that ties up a certain percentage of their acetyl cohenesterase the side effects are going to be the side effects of too much acetyl cohen so what are those smooth muscle contraction so I have GI side effects it turns out to be the one that most people report nausea vomiting diarrhea diarrhea is actually the most common I think and then you can also have rhinorrhea you can have all the signs and symptoms of nerve agent poisoning just relatively mild how often do we run into that well I'm the urologist here so you're gonna have to take my clinical experience for but I've traded a lot of patients with puretostigmine the fact of the matter is most of them have very very little if they really need it yes if you push it high enough they'll all get this but the safety of this drug this is not an experimental drug guys this has been out there for a very long time we all feel very comfortable with it and we give it generally TID some of my myesthetics need it more why do they have to take it more than once a day you should understand that now the dissociation is a regular one once I take a dose of puretostigmine whether it's the large slug I give to the myosthenic or the relatively smaller slug that I'm giving as pretreatment to a healthy soldier humping around in the desert after a certain number of hours that complex will dissociate and so if I want to keep a high level or an effective level I have to give it several times a day the average turns out to be TID and that turns out to be the dosage scheduled that the military recommends and uses for nerve agent pretreatment in terms of well we've already mentioned that this was shown in animal studies now remember those animal studies were not the same as taking a person and giving them nerve agent that may be something of importance from the point of view of regulation we have at the FDA in this country they do as a general rule a superlative job probably the best of any country in the world the FDA routinely requires proof of safety and efficacy in humans do we have proof of efficacy of puretostigmine against myosthenia gravis in humans yes lots of it do we have proof of efficacy of puretostigmine for nerve agent pretreatment in humans if it exists we don't have it it's probably sitting there in some Nazi or Iraqi or North Korean laboratory but we don't have access to that and ethically we cannot create that data for the FDA now what we see in terms of side effects is based upon our experience in the Gulf War when this actually was used how many people took puretostigmine in the Gulf War not nary many I'm relatively surprised it was the people in this room who really took the lead on this Dr. Seidel was running all over the theater teaching people how to use this stuff Lieutenant Colonel Keeler who is one of our predecessors was called the pill lady she was all over Saudi Arabia and Dr. Seidel Dr. Keeler Dr. Dunn Colonel Dunn who was at the time the commander here tried to pool the experience of people in the United States forces after the Gulf War to find out how well this was tolerated the feeling was there was no decrement in military tasks in fact it turns out you can bind up about 30% of your acetylcholinesterase and you'll have no clinical observable defect in a young healthy military population that's the population which was done side effects we're seeing now this is reported by the medical officers PAs battalion aid station level and so forth less than 5% there are some long-term issues with puretostigmine and they have to do again with having so much of your enzyme bound up that you can't regenerate it quite as fast but they're the same side effects you've always seen and this is not really an issue for pretreatment because pretreatment is envisioned and it was used this way in the Gulf War as something that used for a very restricted period of time when you think tactically that you're under a real threat of a nerve agent attack you do not put your troops on this the minute they come into theater keep it there for 179 days and take it off the way the military envisions pretreatment and the way that they used it in the Gulf War was as a command decision based on the tactical situation you take your troops off it because they will have some side effects mostly gi the dose is interesting does anybody know what the myosthenic dose is average starting myosthenic dose once I diagnose myasty in my patient I say you need Mestin on I put you on how much okay we can use Dr. Urbanetti's 30 milligrams 60 milligrams 120 milligrams multiple choice 30 wrong turns out to be 60 the FDA approved starting dose for myosthenia for pure distigming is 60 milligrams TID based on animal studies and some of the people who did that or their successors in the back of the room they'll correct me if I'm wrong major golden content of Colonel Meyer it was decided that we don't need that much and therefore we have even less side effects to worry about the military dose for pretreatment for nerve agent attack was 30 milligrams TID hold that thought because unfortunately the FDA has approved this for myosthenia at a higher dose now the command makes the decision that's what our doctrine states Reginald is the other brand name of pure distigming used not too often anymore for anesthesia and I must tell you if you really want to know about its use in anesthesia I ask you to wait till tomorrow when Lieutenant Colonel Baxter comes back because he's the nurse anesthetist and he knows all about that I don't put people to sleep I just you know admire their disease right so I admire their disease with Mestinon rather than with Reginald but it's the same stuff it's pure to stick me okay now pure to stick mean is bioavailable 8 to 29% but that's it turns out to be enough it's fine goes out in about three and a half hours and the enzyme will dissociate in about the same time so that's why we need TID dosing now here is the Gulf War data which was compiled largely by Dr. Seidel and colleagues and if you want to see all of his reports on this just take a look in the big textbook military medicine where his data is all repeated in detail yes people had side effects almost all of them were GI GU they said 5 to 30% some people say possibly less but only one-tenth of 1% of these people were reported by their medical officers to have been told to discontinue it for medical reasons the vast majority of these people essentially everybody was able to stay on it now since this was reported by Dr. Seidel and his colleagues there's been a study done by the I think was the Institute of Medicine or the VA I forget which which study people retrospectively sort of sent out a questionnaire saying what did you know about this and it now appears that we did as an army as a Navy as an Air Force a less than perfect job of explaining the rationale and explaining the pluses and minuses of this therapy to people they claim that they thought it was experimental they claim that they're medic their PA's over did not explain it to them that's a take home point for all of you because every one of you is basically at risk of advising some tactical commander some non-medical commander in one of the three services and explaining why we're using this stuff if he doesn't understand it he doesn't know when to order his troops to take it and he sure isn't going to support you in going around and explaining to the troops and compliance is probably something we will have to worry about so that's a lesson learned we hope that we've learned from the Gulf War but an important lesson that the slide does mention is that this stuff is very very well tolerated we had no serious problems that we know of directly attributed to a pair of the same and actually that's exactly what we would have expected because we're using a lot less than we use in my aesthetic we're using it for a much much shorter period of time nobody in the Gulf War was on this for more than three or four weeks most of the time it was on for shorter periods of time than that so we would not have expected to have anything worse than we did see now dr. Seidel has alluded in detail to questions of seizures because we didn't have period of stigmine years ago we assumed that certain doses we're just going to kill you people were going to as you'll hear tomorrow when dr. and colonel Baxter talks about triage they're going to self-triage they're not going to present they're gonna be dead with period of stigmine animal data and there's a lot of it and it comes from across the street and from other places shows that the animals survive they continue to breathe they continue to live on and they go into prolonged status epilepticus it was because period of stigmine was going to be used that the doctrine changed to the doctrine that you've just been taught by dr. Seidel and that is that when you give when you need three mark ones you either are seizing or you have a very high likelihood of seizing and the seizure will not stop on its own with the death of the patient or with the hypoxia or whatever and so you have to give the anticonvulsant and the kind of convulsant of choice that we field is diazepam now I can call it valium because my father invented the stuff but you have to call it diazepam I was raised by hop on the road that's fine that's just personal aside you can call it diazepam and that's where that piece of doctrine came from now that completes all the stuff that I wanted to talk about that's testable but for the next five minutes just for the fun of it I thought I would explain to you a little bit more about how this stuff gets studied and what nerve agent seizures do to you this is a friend of mine friend is a guinea pig and he lives across the street he doesn't live all that long I'm afraid he has a relatively short life expectancy because dr. McDonough has equipped him with all sorts of things he has everything he needs for a complete and and happy life although it is a short one he has bedding he has food he has water and he's actually very healthy and he's had a surgical operation and that surgical operation is implanted an EEG electrode that sits right on top of his durable and so dr. McDonough can do whatever he likes to this friend of mine and we know whether that brain is seizing or not whether or not the animal is convulsing because as dr. Seidel has correctly pointed out to you and as I know well from being a neurologist you can have seizure activity and you may not see it either because it's non-convulsive status or because the patient no longer has enough juice in the muscles to show you muscle movement so dr. McDonough and dr. Tony shee across the street study this with implantable dural electrodes and from their work on nerve agents usually the standard model is a puritive stigme pre-treated guinea pig exposed to nerve agent they have learned a lot of very interesting things about the brains of animals that go into status epilepticus with these agents very interesting particularly for those anybody here working in ICU dr. P and I know and so forth you know a lot about people who are brain dead and you know a lot about people who have strokes and people who have ischemic or anoxic encephalopathy turns out that status epileptic is caused by nerve agents is physiologically in some ways much closer to that than it is to status epilepticus that you routinely see your status epilepticus patient usually comes in is usually somebody with pre-existing brain lesion pre-existing seizure disorder and they have a little area that fires too much or slows down too much in the brain and then that sets up a discharge that travels all over the brain and most of our anti-convulsants treat that patient by preventing the spread that's a dilantin works tegratol all the anti-convulsants that you would routinely use that is not the mechanism of seizure propagation in nerve agents and you can think about it here we have a young healthy trooper basically we're not sending people onto the battlefield with epilepsy we're sending them without epilepsy generally speaking at least I hope so I don't want the guy you know keeping me safe with his m16 to be seizing all the time there's profile issues but anyway they're not epileptic to begin with and I suddenly turn on all of their co-energic synapses because that's what nerve agents do remember I told you you take acetylcholine you convert it from a neurotransmitter into a poison see poison all the synapses simultaneously so stopping the spread isn't gonna help and we should have predicted exactly what Dr. McDonough has now convincingly shown that most of the standard anti-convulsants don't work diazepam does work in fact all the benzodiazepines work and I am here to tell you that one of the interesting issues that's recently come up here in the Institute and Dr. Colonel Hearst and I are trying to take the lead on this along with the people who are really doing the work across the street is possibly to replace diazepam with a better benzodiazepine but none of the other ones turned out to work what actually does work is anticholinergics which are not anti-convulsant in almost any other situation but the other interesting thing that comes out I'm mentioning it here because we really don't have any other time in the course to mention it is for those of you who deal with ischemic brain people who take care of stroke patients and so forth if you allow these animals to go on and seize for 40 minutes or so their brains look like stroke patient brains they have apoptotic change and they don't look anything like the brains of people who routinely go into status epilepticus in fact they look a great deal worse although it's regional and so there's an interest in possibly protecting them and one of the things that doctor that Colonel little didn't mention in his briefing to the last class when talks about research so I don't expect he will this time so I'm mentioning it to you now we're thinking about is a neural protection initiative where we might add something to our field formulary where we can protect these very very vulnerable neurons with the same sorts of drugs that are being worked on by drug companies for the kind of change that you see around a stroke in order to reduce the size of the ischemic penumbra I would not be going into this if I didn't know that the vast majority of you are doctors and nurses I don't talk about this up to the medics because it's really not stuff that they're ever going to see but that's sort of a preview of coming attractions so at any rate the important things that I want you to get out of this 20 minutes or so are all the stuff that's in your book and none of the esoteric research minutiae the important thing is pure to stick mean is a it is not a treatment for nerve agent poisoning if I have a nerve agent casualty and I give him pure to stick me to I make him better or worse I make him worse so I'm not going to be doing that nor are they immunizations now that seems perhaps a little crazy after you all you just come from you sandwiched up at Frederick and you know exactly what an immunization is I get a vaccine I build up antibodies and you say well why am I even mentioning that the reason is that Colonel Little will tell you that we have a scavenger program which in a sense is a chemical immunization against nerve agent which is certainly not up to being fielded yet but that may come but this is not that either this is taking an existing medication and hiding concealing some of our target enzyme from the bad stuff.