 So let's talk a little bit about cyanide. Now, of most of the agents that you've encountered so far, they're agents that you won't really see in real life unless there's chlorine tanker or whatever, but they're not really things that you touch or feel or smell or taste every day. Cyanide's an exception. Is there cyanide in this room right now? Yes. There's some cyanide inside each of us. What we're going to talk about with cyanide is a little bit about where it's found, a little bit about its history. And using the general paradigm that we've talked about before, we'll talk a little bit about its physical chemical properties, about its toxicokinetics, its absorption, distribution, biotransformation and elimination, about its mechanism of action, that is the toxicodynamics of cyanide. And then, finally, of course, the most important thing is the clinical presentation because we need to know certain things about the agent in order to treat the patient. But the bottom line is we have to recognize what the patient has and treat the patient. Now, as I said, cyanide is found everywhere. Cyanide's an interstellar space. It's been on the earth for a long time. Organisms have had to develop strategies for dealing with small quantities of cyanide in the environment, in the external environment and in the internal environment. Usually, for us, if we took a blood sample, you have cyanide in your blood right now, small quantities. If you're a smoker, you have twice the quantities that you see on the slide. Now, cyanide's one of those things where, in small concentrations, not only can the body handle it, but in fact, the body actually requires it in larger concentrations. Once you overwhelm the body and pass a certain threshold, it becomes dramatically toxic. It's been a favorite of assassins for long periods of time. All sorts of great stories that we have about cyanide. And the other thing I wanted to remind you about is that with the nato codes, what's the nato code for cyanide? For hydrogen cyanide, it's AC. And for cyanogen chloride, it's CK. Sometimes, in referring to cyanide, the cyanide ion itself, we use CN with a little negative cyanide ion. Don't confuse that with the nato code CN, which stands for chloracetofinone. It's one of the riot control agents, and you'll hear about that from Colonel Newmark. Not meant to be confusing. I'm trying to outlay fears about this. Okay, now, in ancient Egypt, cyanide wasn't known as an isolated compound, but it was known that certain extracts, they had in Egypt what they called the penalty of the peach. And it was an extractive from peach pits, and that was administered to condemned criminals. And that was the method of execution. The Romans had something very similar. They used cherry laurel water. But, again, it was an extract from cherry pits, and we'll find out that plants, in just a few moments, we'll find out that plants contain cyanogenic compounds, compounds that release cyanide under certain conditions. But it wasn't really until 1782 when Fonshella actually isolated cyanide as a distinct compound. He purified it, noted it, didn't realize that it was poisonous until four years later when he accidentally dropped a flask of the stuff and became the first known fatality from purified cyanide. Sir, you may remember from the history lecture, from Dr. Seidel's history lecture, that Sir Lyon Playfair wanted to put cyanide in shells to be lobbed onto Sebastopol during the Crimean War. Napoleon III wanted to dip his... In fact, he did dip his soldiers' bayonets in cyanide. They're by antedating by, I guess, about 100 years the use of cyanide in bullets by the Symbionnes Liberation Army. Never mind that that would have vaporized, wouldn't have done any good, but they dipped their bullets in cyanide. Cyanide, obviously, has a very colorful history. In warfare, it was used in World War I by the French in a compound called Vincenite. It wasn't very effective. Not because cyanide is not very effective, but because the way in which it was put into the munitions was substandard. Munition wasn't filled as much as it should have been and because of the bursting charge. Cyanide, hydrogen cyanide, is extremely volatile, but more than that, it's explosive under certain conditions. And when the munition burst, most of the cyanide went as well, and so it was hard to achieve good concentrations on the battlefield simply by... for logistic considerations. It is possible to achieve higher concentrations if you know what you're doing. And of course, you're in World War II. We don't have documented evidence of its use on a battlefield, although there are certain reports that the Japanese may have used this. We're not really sure about that, but of course everybody knows that in World War II the Germans in gas chambers used Zuclone Bay, which was hydrogen cyanide absorbed onto a physical medium and then that. Now, that's slightly different from what happens in gas chambers today where a cyanide salt is dropped into an acid and releases hydrogen cyanide. Not quite the same mechanism, but the same result. And in the Middle East, we know... well, we know that the Iraqis used nerve gas. We know that the Iraqis used mustard. And part of the reason that we know that is because the compounds were persistent enough to stay around. We found munitions with them. Not so with cyanide, so we don't have any physical evidence for that. It is highly probable that people like these died in the 1980s from cyanide. Now, off the battlefield, do you all know what happened in 1978 in Guyana? Yeah, the Jonestown mass suicide where people added cyanide to great flavored Kool-Aid. 1982, Tylenol. What happened in 1982 with Tylenol? Right, somebody took apart the two halves of the gelatin capsule and put cyanide in there and caused several deaths, and that's why we have Tylenol caplets now instead of Tylenol capsules. But we still use cyanide for judicial executions. Cyanide is a very important component of smoke from fires. Theoretically, anything that has carbon and nitrogen in it together has the potential to produce cyanide on combustion. Wool, silk, lots of plastics, especially the polyurethane, polyacrylate kinds of plastics generate significant quantities of cyanide. There's enough cyanide that comes from a typical sofa that was manufactured maybe 10 years ago to cause fatality if you're in a room where that sofa is burning. Industrial processes, cyanide is used all over, just like phosgene. Cyanide is used for gold electroplating, for photo processing, for a variety of industrial processes and it's used by the tons. And you find it at home, you can, silver polish can generate this. PCP labs, cyanide is found in many, many places. Now, remember I said that some plants, remember I talked about cherry laurel water and the penalty of the peach? Well, it turns out that plants, especially some plant pits, contain compounds which, although non-poisonous in the form in which we find them in the pits, can be converted into cyanides, that is they release cyanide upon digestion. We have enzymes, there's an enzyme called emulsin, which we either produce ourselves, some animals produce that, or it's released by bacteria that are in the gut if the pH is right. Now, where do we find these glycosides? What plants? Well, for one thing, leitreal, the anti-neoplastic compound, which isn't why it's highly touted in Mexico against cancer, well, it was supposed to act because in fact it produces cyanide. If you were just to inject leitreal into a vein, you don't get any effect. But if you ingest leitreal, which is the way it's taken, and it gets to the duodenum and the pH rises, then you get the activation by emulsin, the release of cyanide, and then you get toxicity. Who else? Well, cassava. Cassava is the same name in Africa given to manioc or tapioca in Brazil. It's the major source of carbohydrates for 300,000 people in the world. And if that's improperly processed, you can get cyanide toxicity. And what that cyanide toxicity leads to is a series of chronic symptoms and signs and diseases. There's something that used to be called Nigerian ataxic neuropathy, now we generally call it tropical ataxic neuropathy, where there's a variety of bulbar and other neurological signs, probably because of cyanide release from improsper processing of cassava. There's tobacco amblyopia. The reason that many people who smoke have problems, subtle problems with night vision is probably because of the elevated cyanide in the blood and other tissues of smokers. Now, I remember studying cyanide many years ago and being confused by all of the biochemistry and how does it work and how does the therapy work, and I really couldn't understand it until I sat down and simplified things. Remember how I said all real teaching and learning involves some simplification of data. Cyanide enters into a variety of reactions with proteins and metals and all sorts of compounds in the body, but for our purposes there are two reactions that are really important, two general reactions. They are the following. Cyanide loves to react with metals, especially transition element metals. And where do we find those in the body? Well, we find molybdenum, we find zinc, we find copper in small amounts in various enzyme systems in the body, but especially we find iron in the body. Where do we find iron in the body? RBCs. Okay, RBCs. And in what form? It's hemoglobin. Excellent. But the iron in hemoglobin is in a ferrous or plus 2 form. Cyanide likes to react with ferrous ion, but it would prefer to react with ferric ion. It has an even greater affinity for ferric ion. Do we have ferric ion in red blood cells? Not normally. Normally, most of the hemoglobin is in fact in the form of straight hemoglobin, but very small quantities in the body are converted into what we call methemoglobin, which is where the iron is in the plus 3 form. We have vanishingly small quantities of that in the body normally because it doesn't carry oxygen. But when hemoglobin is present in the body, cyanide is really attracted to that. Keep that in mind. Now where else in the body do we have iron compounds? Well, in various enzymes, and notably in the cytochromes inside cells. What are cytochromes good for? Oxidation. In fact, the so-called oxidative phosphorylation. The cellular respiration where we... that's really where we use oxygen and generate ATP. That's important. And that compound actually cycles back and forth between a ferric and a ferrous form. And so cyanide will combine with both forms, but in our case, we're really dealing with the combination of the ferrous form. Now the other thing, sulfur-containing compounds, cyanide will react with almost anything that has sulfur in it that has two sulfurs connected by a partially covalent bond with polarity. Don't worry about the details of that. They're called sulfanes. The point is this is catalyzed by an enzyme called rodentase. One of the few enzymes that doesn't end in an A is it ends in an E. And it's an irreversible reaction. So when cyanide goes through that process, it has gone forever. Whereas this reaction with metals is a back-and-forth kind of thing. Now here's an example. Here's a compound called hydroxycobalamin, or vitamin B12A. It exists in the body. It contains cobalt. Cyanide reacts with that cobalt, and the resulting compound is cyanocobalamin, which is just another name for vitamin B12. So here's a case where cyanide participates in the normal of the metabolism in the body. And we need it. Cyanide, again, with sulfanes, as you'll notice, that's a one-way reaction. And the rate-limiting step for that reaction is not usually the amount of enzyme. It's the amount of sulfur in the body. Keep that in mind, too. If we supply more sulfur to the body, more cyanide reacts with the sulfur that we administer. Just keep that in the back of your mind. Now, the gases that we're worried about on the battlefield are AC and CK. AC is hydrogen cyanide. That's the needle code for hydrogen cyanide. It's an acidic compound in the sense that it has the capacity to dissociate into hydrogen ions and cyanide ions. In point of fact, that dissociation is so weak that the resulting solution, hydrocyanic acid, doesn't even turn litmus paper pink. And so we talk about the cyanide ion as if that's the bad actor. And in fact, it by itself does do bad things to the body. But hydrogen cyanide with the hydrogen attached can also act in the same way. Very volatile. And the fact that the acid is called hydrocyanic or prusic acid reminds me to tell you that the reason that cyanide is called cyanide. What does cyanide mean? What does the root mean? Blue. The same root. There's the Greek Quran from which we get cyanosis. So cyanide, cyanosis, hey, that's an easy association, right? It's an association I want you to break because there's no association. Cyanide is not classically associated with cyanosis. The reason we call cyanide cyanide is because the starting material that von Scheller used for his synthesis was ferrocyanide, which is prussian blue. And so the resulting compound, he added a blue name to it. Cyanide is not blue. It does not cause cyanosis except in the terminal stages. Now, it's very volatile. The gas rises, it's lighter than air. And its boiling point is about 78 degrees Fahrenheit. So in this room, I think some of you are feeling a little cold. It's probably not 78 degrees in here. In what form would we find cyanide? In what physical state would we find cyanide? Okay, it'd be a liquid. We haven't yet reached its boiling point. But we're pretty close to the boiling point and so it would evaporate fairly quickly. So we would encounter cyanide as a liquid and a gas. And it's possible to come in contact with liquid cyanide. It's been used in assassinations that way. It's thrown in the face, immediate death. But on the battlefield, more likely it would be contact with the vapor from that liquid. Now people describe classically this. Oh, cyanide, yeah, that's the one that smells like almonds. Smell is a very subjective sensation. In fact, the first people that smelled this thought it smelled like burning rope, you know, all sorts of things. But more than that, there are a couple of things that are wrong with smell. Quite apart from the fact that it's difficult to come up with an objective description of the smell. First of all, about half of us have a genetic defect that prevents us from detecting that odor at all. So it may be well that some people can say, oh yes, I can recognize cyanide unless you've smelled it. You don't know whether you can smell it or not. The other thing is, what's the sense of our five senses that accommodates the most quickly? It's olfaction. And so yes, you can smell something and, yeah, it smells a little odd to me and you try again, you know, well, but I don't smell it anymore. Well, of course you don't smell it anymore because you've accommodated it. And so smell is, except for some things like mustard, is not a very good warning sign. Onset time dramatically rapid. And look at the LCT50. 2,500 to 5,000 milligram minutes per cubic meter. By comparison, phosgene was 6,000, so this is much lower than that. Oh, half as much as that. Look at the variation. One of the things that we'd said before is that CT is a useful estimate of the effects of a gas or a vapor. And it's fairly constant. The reason that this has so much variability in, and actually the variability extends on both ends of that 2,500 to 5,000 number, is because when small quantities, the body can deal with cyanide. It's been dealing with cyanide for years. It's only when you overwhelm that. So if you were to present the same amount of cyanide to somebody over a long period of time, no problem. The body can metabolize that. If you present the same amount, the same CT product to somebody, over a period of seconds, it overwhelms the defenses and kills the patient. So that's really the chief exception to our idea that CTs, CT products, are good estimates by themselves of exposure. Cyanogen chloride, CK. CK is just like cyanide with chlorine added. It dissociates to form chlorine and cyanide. So what do you think the additional effects are going to be now that you've had the pulmonary agents lecture? What are the effects of chlorine? They're irritation, aren't they? Of the upper airway, and you'll know this. In fact, cyanogen chloride has sometimes been used as a warning or irritant gas, marker gas for other things that are even more toxic than it is. And why? Well, it's pretty toxic, too, isn't it? Well, the LCT50 is 11,000 milligram minutes per cubic meter. So it's twice as potent as cyanide, right? Half as potent as cyanide. Remember, as the LCT50 goes up, it takes more of the substance to kill you. Now, you'll notice from this graph, here again, this is a graph that you've seen before, where I've put agents in their order of introduction into warfare. So we have chlorine in it, about 6,000 milligram minutes per cubic meter. And we have phosgene, which is about 3,000, and then cyanide with its variability, but let's say that it's 2,500, which is more potent cyanide or mustard? Mustard's the next one, which is H. Mustard. Mustard is more potent than cyanide. And you've heard that point made by Colonel Hearst, that, yes, we think the cyanide's bad, well, mustard is more potent. So what makes cyanide such a bad actor? Cyanide's far worse than mustard on one account. Well, because of its speed of action. Rapid onset. If somebody dies from mustard, that death is unlikely to be immediate. It's going to be down the road. The first 24 hours, if you have the massive exposure with this formation of pseudomembranes in the trachea and the bronchi, but more likely it's going to be a few days or maybe even weeks down the road. But cyanide, if you get enough of it, death is almost instantaneous. Well, within minutes, anyway. And that's why it has such a bad reputation. Now, we talk about cyanide and we say it's a blood agent. And remember, in the introduction I said, yeah, one of the classifications is blood agent, but later why that's a bad name? The reason that it's a bad name is that it implies that cyanide does its dirty work in the blood. And it does do some things there, but the chief action is elsewhere. Now, why were these agents called blood agents to begin with? Well, it's the same distinction we made at the beginning of the lecture. The first agents used in World War I besides the minor use of riot control agents were what? Chlorine. Phosgene. The pulmonary agents. And the pulmonary agents act locally. Now, here we then have cyanide introduced. Cyanide is distributed systemically throughout the blood. So therefore it's a blood agent. So it's correct to say it's a blood agent. But is mustard distributed through the blood? Mustard came along a little later. Sure, it was. It is. Are nerve agents systemically distributed? You bet they are. So to say that cyanide is a blood agent is correct, but it's no longer very specific, because that term could also equally well apply to mustard and to nerve agents. And as I said again, the other reason I don't like it is that it implies that it somehow binds with something in the blood and that its mechanism of action is there. Now, we know that carbon monoxide, for instance, binds with oxyhemoglobin to form carboxyhemoglobin. Now, cyanide will react a little bit that way, but its main site of action, we think, is in the cells. And what it does is to interrupt that process of cellular respiration to which we alluded a few minutes earlier. Here is the mitochondrion. Here we have the various elements of the cell and we have the nucleus up here and here are some ribosomes and here's the endoplasmic reticulum and the Golgi apparatus and all of this. What we're really interested in is this little organelle here with the outer membrane and the inner membrane and the crusty. This is a mitochondrion. And the mitochondrion is the powerhouse of the cell. That's where oxygen is finally taken, converted into hydroxyl ions and hydrogen ions and where ATP is taken and generated and ATP is generated. So this is where energy is produced in the cell and where oxygen is used. And how does that happen? Now chemically it happens through a process that we'll talk about in just a few slides, but we say that cyanide binds to an enzyme in the mitochondrion. The enzyme complex is called cytochrome A3 and this particular enzyme in that complex is called cytochrome A3. You don't have to remember this, just the general idea. But what's important to know is that it's a stable binding, but it's not irreversible. Cyanide can bind to that and it likes to bind with metals. And here's a metal ion in the ferrous form most of the time. What are the two reactions that cyanide likes to participate in? It likes to react with metals and sulfur. Ooh, very good. Okay, that's what I wanted you to remember. And cyanide actually has a higher affinity for ferric ion if it could find it. Okay, what do we do? We interrupt oxidative phosphorylation. This is the terminal end of the electron chain process that you may remember from biochemistry and it's not my intention to go into this in a lot of detail. Just to remind you that this is where ADP is taken and changed into ATP. This is where oxygen is taken and changed into essentially the components of water. This is where energy is generated. And this is also where cyanide acts. So now you can tell me what cyanide does. What would be the effects on a cellular level of cyanide? Here's shutdown energy production in the cell. So no more ATP. What about the oxygen presented to the cell? Can't be used. So the cell says high to it and buy to it and the oxygen goes into the venous blood. So we're not going to have any ATP generated. There will be no extraction of oxygen from the blood. So venous blood can be just as healthy pink looking as material blood. Now using oxidative phosphorylation that's what happens when we get compounds from the Krebs cycle from the Cystric Acid cycle from oxidative metabolism. Is that the only way the cell can generate energy? No. We can generate energy via glycolysis. We have fermentation cells can ferment. The only problem is when they do that they generate lactic acid. Because if that gets into the blood we have an lactic acidosis and a high anion gap. Now here are normal mitochondria here are mitochondria that are unable to use oxygen. They swell, the inner membranes get bloated. There are real problems with that. The mitochondria just don't work anymore. And that's what happens with cyanide. Now at an organ level, cyanide affects various things. I'm going to ask you, what is the organ or tissue in the body that receives more blood and oxygen per gram of tissue than any other tissue in the body? The brain! Wrong. The heart! No. The liver! Ooh, good guess, not right. The lungs! That's another good one. The tissues in the body that receive more oxygen and blood per gram of tissue than any other are two small nubbins of tissue at the bifurcation of the common carotid into the internal and external carotids. They're the carotid bodies. They're there to monitor the partial pressure of oxygen in the blood. And when they sense that there's not enough oxygen they send signals to the brain to say, spit out epinephrine! Send messages to the adrenal medulla to spit out epinephrine to increase the heart rate and to increase the blood pressure. And they say to the brain, send messages to the respiratory center to increase the rate of breathing. And so one of the first effects of cyanide poisoning will be intense stimulation from these carotid and their similar receptors on the aortic arch, these chemoreceptors. Now cyanide damages, cyanide is systemically distributed to every cell in the body. And it affects almost every cell in the body, but it affects some more than others. It affects the nervous system. And eventually the neurons in the respiratory center of the brain die. What happens when the neurons in the respiratory center of the brain die? Right, central apnea. And if untreated, that is the mechanism of death for people with cyanide intoxication, even though the cause of death is cellular hypoxia. But the mechanism of death is, cellular hypoxia in the respiratory center that the diaphragm doesn't work. Now if you can ventilate these people, you can actually keep them alive long enough for cyanide to kill the heart, which it does, given enough time. But what happens first in a patient that receives a really high concentrate now, if you're splashed in the face with liquid cyanide, some people collapse immediately from that. We have case reports. And probably from massive release of epinephrine generating a terminal cardiac dysrhythmia. But in the usual case, inhalation of high concentrations causes, first of all, stimulation of the carotid bodies and a brief period of hyperventilation. Now if I were to say, gas, what's the first thing you do? Hold your breath, stop breathing. Now this is such an overwhelming urge that people exposed to cyanide may have difficulty obeying this first and very important part of the mask donning drill. The onset is very fast. We have this transient increase in rate and depth of respiration. The blood pressure goes up. Why? Because of the epinephrine that's released and the heart rate goes up. And eventually, we have from hypoxia, we have convulsions, we have rigidity, we have apostatnes, which is the head back like this. We have trismas, which is the tepne of the balakja. And all this happens within a minute, within a half a minute or so. Patient loses consciousness, goes into convulsions, and then because of hypoxia, the heart rate slows, the blood pressure drops, the heart stops, and the patient dies. But after this respiratory depression. Now, what about, yes? Do you have a question? Yes. Did I get some of these clinical trials or have they done autopsies for prisoners that get executed via the gas chamber? I mean, is this honest? Yes, the answer to that is yes. And I don't have time to discuss this in detail, but there is quite a literature on people, on gas chamber victims who have been, who have been observed medically during executions. We have an even greater wealth of data from animal experiments, but this has been confirmed in humans, too. This is what happens. Not everybody's the same, but classically, this is what happens. Now, in the skin, what about the skin? The skin can look nice and pink, even flushed. Why? Because blood in the veins and the capillaries still has plenty of oxygen in it. It's not for the same reason in carbon monoxide poisoning, because there, the compound itself, carboxyhemoglobin, is kind of a cherry red color. But here, it's simply because oxygen is not being extracted from the blood. You may have this bitter almond smell on your breath, but remember, cyanide poisoning is not characterized by cyanosis early in the course. Now, terminally, yeah, all sorts of things can happen, and the patient can turn blue. And not everybody has a classic presentation. So some people may be cyanotic at the beginning, but classically, no cyanosis. Now, it's often said that cyanide is an all or nothing thing. Either you're exposed to a lot of it and you die, or you're exposed to not very much and you're going to live. And so, why do we even worry about therapy? Well, there is a continuum with cyanide. We know there is a continuum because we know that there are people with tropical ataxic neuropathy from eating just a little bit more cyanide from baseline. Now, there are all sorts of symptoms you can get if you ingest small amounts of cyanide over a long period of time. But even if you inhale quantities that are not immediately lethal, you can develop ataxia, headache, confusion, panic, a variety of symptoms that are really nonspecific and some that you might expect to find on the battlefield anyway. So, the classic signs. Somebody who has, you look inside their fungi, they have veins that are the same color as their arteries. Well, that's one sign, you know, the skin, the profound metabolic acidosis, the odor if you can detect that. Now, the patient himself or herself is going to have this transient hypertension, this transient tachypnea as well. You know, it's a patient that goes ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah, ah. And within a few minutes, it's all over. Now, what does that remind you? Okay, I'm a pathologist and I can die on camera. Okay, whatever. What difference, does that remind you of anything else that we've studied? What else can look like that? Nerve agent. We hear Dr. Seidel's stories of people who just collapse like that. Do nerve agent casualties convulse? Sure they can't. Do nerve agent casualties, you know, so how do you tell the difference? What about the differential diagnosis? That is, what about the A on our asbestos list? What happens if it's cyanide rather than nerve agent? If you see a patient acting like that? Now, for very long, it can happen that nerve agent casualties can stop breathing within a little while, within a few minutes. So can cyanide casualties? No cyanosis. Okay, that's one key. No cyanosis. Now, I say that, that's classically true. Now, there will be some cyanide patients who will be cyanotic. But yeah, if you see somebody who has that presentation but is not cyanotic but is not breathing, cyanide moves up the ladder a little bit in the differential. What else? Myosis. Nerve agents cause myosis. Does cyanide cause myosis? Not at all. In fact, the patient, pretermily, will have the fixed and dilated pupils characteristic of hypoxia. There will be some medriosis. Not that cyanide specifically causes that, but they'll get that from hypoxia. Okay, and we could go through this whole mnemonic about, okay, what state would we, if we do come to the conclusion that cyanide, what state are we likely to be thinking about? Vapor, right? Or gas, if it's above 78 degrees. Okay, body sites, we're mostly talking about inhalation, although there are plenty of other ways, other routes of getting cyanide. The effects, are they local or systemic? Well, they're systemic, they're dilated throughout the body. That's what makes it different from the inhalational agents that Colonel Baxter told you about. And of course, we can run the gamut from mild to severe cyanide intoxication. Time course, these patients will not get better if they're already convulsing, unless you can provide some good treatment. And let's talk about the treatment. You already know the first step is to protect yourself. And with any agent, there's general supportive therapy. Some agents have specific antidotes. And some agents are so important that you need to know about the specific antidotes without consulting a book. There are two classes of agents like that. Because there are only two classes of agents that kill you so dramatically quickly that you don't have time to consult a book. What are those two kinds of agents? Nervin cyanide, they're the two people that can cause somebody to go down like that really quickly. And can kill them very quickly. Let's talk about what we would do generally. Of course, for any agent, terminate the exposure, separate the patient and the agent, put a mask on the patient, drag the patient out of the area, whatever. Airway breathing and circulation, extremely important. But beware, unprotected mouth to mouth respiration. I have a story that I often tell, and I don't have a lot of time about a medical student that found his dog collapsed, administered mouth to snout respiration. He himself collapsed, was taken to the hospital, somebody smelled bitter almonds on his breath. He got there, he was transported, he was revived, he had cyanide. And so elimination through the breath is actually important in cyanide. You'd think that oxygen wouldn't help these people. Because they can't utilize oxygen. But in point of fact, using 100% oxygen does seem to help them. Maybe it's a mass effect of having so much oxygen that pushes the cyanide off the enzyme. We're not sure. But don't neglect to give oxygen, even though you'd think it wouldn't do any good. Correct the metabolic acidosis and observe, because these patients can sometimes crump after they have been apparently resuscitated. What are the two reactions that cyanide likes to participate in? Likes to react with? Metals. Metals and sulfur. That's what we're going to do. We're going to give it a metal, and all we're going to give it is met hemoglobin. And we're going to form met hemoglobin from the hemoglobin that's already in the body by administering a compound, a nitrite, that will generate met hemoglobin and the cyanide can react with that. And the second thing we're going to do is to use this enzyme rodinase. We're going to administer a sulfur donor. We're going to let the enzyme already in the body convert some of that cyanide to a less toxic compound by reacting it with a sulfur. Let's talk about the first process. You know what happens here, even though this looks complicated. Oxygen is taken in by the lungs. It reacts with hemoglobin to form oxihemoglobin. And in the tissues, oxihemoglobin gives up oxygen and becomes the oxihemoglobin again. Both of these are in the ferrous form. Cyanide doesn't like them very much. Cyanide, given to the body, if it doesn't see, if all it sees is this and this, it'll go to this because it likes to combine with the cytochrome A3. So we want to give cyanide something else, something that's definitely in the ferric form. And we can do that by administering a nitrite. The nitrite generates, changes some of this oxihemoglobin to met hemoglobin. The cyanide then has a choice and it says, can I react with this or this? I'd rather react with this, and it does. It forms a temporary depot of a compound called cyanamin hemoglobin. How many of you have Windows 95? Use that. Okay, so you all have a trash can. I used to have to restrict this to Macintosh users. You have a recycling bin. Okay? When you put your e-mail or a document you don't want in the recycle bin and then you say, ooh, I really wanted that. Can you get it back? Sure, you open the recycling bin and out it comes if you want it to. That's exactly what I want you to think of this as. This is a recycling bin. Because this is a reversible reaction. If all you do is give the nitrite, this will stay here for a while and then it will come off and you'll have more nitrite in the blood again. And that may be the reason for delayed toxicity in some patients that appear to do well and then crump later on. How do we use it? We use it in a kit that used to be called the Lily antidote kit, cyanide antidote kit. Now somebody else who prepares it now and it's called the Pasadena cyanide antidote kit, but it's a standard kit that's used in emergency rooms and it has some sodium nitrate. It actually has in it and I'll let you see this afterwards. It has some aspirol or purls in here. They're just, they're little vials of amyl nitrite. You know all about amyl nitrite. And that's given by inhalation by crushing the vials and putting it under the patient's nose. What's wrong with that? In a military setting. Well first thing they're going to have a mask on and the other comment is to the point too. They may not be breathing and there are other problems with amyl nitrite so it's not a component of the military antidote kits. Instead we use another nitrite. We use sodium nitrite. Converts some of the oxy hemoglobin to methemoglobin. We're not really sure how it works because it has a therapeutic effect before we can detect really elevated levels of methemoglobin. So maybe there's another mechanism of action for this. But for purposes of instruction let's say that it acts by this route by generating methemoglobin. This is how much you give. Now I can ask you to memorize this and remember I said this is one of the, this cyanide is one of the components where you need to know what to do immediately. But you don't necessarily have to remember the dosage if you have a kit and what that means is you administer one of these vials and then you administer the second antidote that we'll discuss. If the symptoms recur, symptoms and signs recur, you administer half of the second little vial and that's the easiest way to remember this. What you need to do is to find an antidote kit and practice with it. So there's the antidote kit and this is what we've done. We've created a temporary depot, we've put something in the recycling bin. Now what we want to do is empty the recycle bin. That is, we want to get rid of the cyanide once and for all and we can do that by adding a sulfur donor. And the sulfur donor we use is the second component of the military version of the antidote kit. It's the sodium thiosulfate. This reacts with cyanide via the enzyme rodentase to form thiosyanates and sulfites which are less toxic and which are excreted in the urine. And here's the, this is what we do as fairly safe medicine, used to be, here's the administration. You can either memorize that or you can just remember that in the old kits you give one of these great big vials, 50 mils in the vial, or in the new kit you give the entire contents of one of the bottles, IV. And then if symptoms and signs recur you give half of the little vial and half of the second big bottle. Okay. Now, studies have been shown, that show that this combination can detoxify up to 20 lethal doses of sodium cyanide even after breathing is stopped as long as the heart is still beating. The chances of recovery by utilizing this method are very good. So just as nerve agent casualties can be immediate, they can appear almost to be dead and they can be dramatically salvaged by appropriate administration of nerve agent antidotes. So cyanide casualties can be dramatically resuscitated even almost at the point of death if you use the antidotes and use them correctly and have enough experience with the kit to know, okay, this is what's where, this is where I start the IV. Now, in other countries, especially other NATO countries, other antidotes are used. But you know, you can understand how they work because you know how our antidotes work. There are other hemoglobin formers and there are cobalt compounds and a variety of miscellaneous things. The other hemoglobin compounds, the other hemoglobin formers work the same way that nitrates work. They generate metahemoglobin. The one used in Germany is four-dimethylaminol phenol or DMAP. It generates metahemoglobin really quickly. So we generate this depot really quickly. The only problem is the depot degenerates really quickly too. So we can have more cyanide back in the blood. But this is what's used in Germany. Now, there's another compound, the second one on the list, peraminopropiofenone, PAPP. This forms metahemoglobin too, but it forms it so slowly that it's of very little use after cyanide has been presented to the body. So why do I even talk about it? How could we use a compound like that? For pretreatment. In fact, some of the studies in the institute that we're doing in the institute are studies leading to pretreatment with PAPP and other similar agents against cyanide. Not yet fielded, but studies are in progress. Now, in Britain, France, and Holland, cobalt compound is used, chelocyanar, which is cobalt edta or dicobalteditate. And this is what's cobalt? Cobalt's a transition metal, isn't it? Cyanide will react with that. And that's used as an antidote, but the adverse effects are sometimes pretty serious. Laryngeal edema, that can be a serious problem. And what is that? That's simply cobalt toxicity. Now, in France, France uses the precursor to vitamin B12. You've already heard about this. Hydroxylcobalamin can react with cyanide to form vitamin B12, but it's really difficult to add to administer adequate amounts because the solution's fairly diluted. This is a big molecule, and cyanide's a small molecule and this is stoichiometric reaction. Okay, so what do we know about cyanide? I've presented you a lot of biochemistry, well, as little as I could, but as much as I could to show you that it's interesting and to show you the mechanism of action and why the antidotes work. What do you need to remember about cyanide? It's a gas, okay? Usually, in fact, it could even be a liquid and a vapor. And above 78 degrees Fahrenheit, it will be a gas. Does it act locally or systemically? Systemically, dramatically. And what makes it such a bad actor? Why does it have such a bad reputation? Speed of onset. Speed of action. Short onset. Speed of death. Okay? Not really a blood agent, even though we call it a blood agent. It's a cellular poison. And what does a patient look like? He looks almost like a nerve agent, casually. But probably won't have a cyanosis. Will not have myosis. Few other discriminating signs unless you have time to draw blood for labs. And you won't, in this situation, you don't have time to draw blood for labs. You have to diagnose quickly and treat. And how do we treat? We treat with nitrites. Don't say nitrates. Get it right. Say nitrite. And with phyosulfates. We'll talk to you about how they work. Do you have any questions? Sir, how many successful resuscitations have they had with the kit? Oh, this kit has been used in... Okay, on the battlefield, we don't have... I'm not aware of any situation on the battlefield because we don't know about battlefield use of cyanide before the 1930s when this kit was developed. And in fact, before that, they used to use methylene blue, which is actually what you'd administer after giving too much met hemoglobin form. But we have quite a body of information from emergency rooms where people who have ingested toxic quantities of cyanide have been treated with this regimen with success. And it seems really to work. Now, some people do well if they're coming out of this. Some people do well just with observation. But we have an enormous quantity of literature of people who have been treated well with the antidotes and survived in this country and in many other countries. Yes. Can you use any of the antidotes, I.M., or via YouTube? No. No. The antidotes are not well-absorbed I.M. and in particular for DMAP, used in Germany. If it's given I.M., it causes necrosis of the muscle. So you never want to give that I.M. But these antidotes are I.V. antidotes.