Good evening. I think we'll go and get started. Welcome to the presentation, and although the title is talking about acute cyanide poisoning, I think a more apt title to the symposium this evening is "New Approaches for Patients With Severe Smoke Inhalation."

I'm going to talk about the prehospital aspects and recognition of cyanide poisoning in smoke inhalation victims, then I'll turn it over to my colleagues, Dr Borron and Dr Guy, to talk about ED management, and then the in-hospital and burn intensive care unit (ICU) management.

We'll talk about recognition of patients with severe smoke inhalation. We'll talk about why cyanide is important to know about in smoke inhalation, and why we need to think about cyanide in these types of patients; describe the signs and symptoms, when you need to think about cyanide for patients with severe smoke inhalation, and what treatments are available; and talk about the role of some possible antidotes for patients with severe smoke inhalation.

Smoke inhalation actually takes a much more deadly toll in this country than burn injuries. There are about 4000 deaths per year in this country from smoke inhalation, much higher than actual thermal burns. Interestingly enough, though the number of structural fires has gone down rather steadily year after year the last several decades because of very effective fire prevention, the number of fatalities per year in this country from fires, ie, smoke inhalation, has actually remained pretty constant, which is opposed to other industrialized countries where it's continued to go down. Of course the injuries from fires are about 20,000 per year, and no surprise that a lot of those, up to a fourth of those, are from firefighters themselves.

Interestingly enough, the anatomy of fire smoke as you might imagine is kind of a toxic soup, and of course it is the particulate matter, the dust and soot, but there's lots of bad actors here: hydrochloric acid, sulfur dioxide, and ammonia. Everyone's been trained and thinks about carbon monoxide poisoning, but we haven't really thought about hydrogen cyanide gas in structure fires. I'm a medical director of a large fire department, and I think the classical teaching for physicians, for paramedics, for firefighters, for any type of prehospital responder is if I'm going to treat patients, or I'm the person running into a burning building, when am I thinking about cyanide poisoning? Typically, the only time I've been thinking about it is if I see a hazmat placard on the outside, and the chemical number tells me it's cyanide. But usually, unless you see that hazmat placard outside a building, which of course invariably is an industrial building, we haven't really been thinking aboutcyanide poisoning. I think that's the paradigm shift, that we're learning now more and more that cyanide is present almost universally in smoke inhalation.

We'll talk first a little bit about carbon monoxide, because you can't talk about smoke inhalation without talking about carbon monoxide as well. As you might well imagine the most common cause of deaths from acute poisoning in general is carbon monoxide, because it's tasteless, odorless, colorless; it's the great imitator and it's very hard to diagnose, if you will, unless you're thinking about it, or have some kind of detector available, or blood test available. Most fatalities from carbon monoxide are from fires, but again there are quite a number of fatalities and severe injuries from carbon monoxide poisoning from suicides, and also more commonly in the wintertime, from people using space heaters inappropriately, or using hibachis indoors. Or, we've seen a number in southern California, people who have old pickup trucks and they put a shell on the back, a camper shell on the back of their pick up truck. There's a leak in the exhaust system, and the unfortunate souls in theback, and sadly often kids, actually succumb to carbon monoxide poisoning from a leak in the exhaust system that gets trapped in the camper shell in the back. So, that's fairly common as well.

As you know, the clinical features of carbon monoxide poisoning are fairly nonspecific, and therein lies the challenge of diagnosing patients with carbon monoxide poisoning. They're very nonspecific. If people have fairly low-level exposures, or ongoing fairly low-level exposures, their signs and symptoms really mimic that of the common cold or flu. They have general malaise, headache, lethargy, mild shortness of breath, nausea, so very, very nonspecific. Because I mentioned a plethora of CO poisoning cases from space heaters occur, as you might imagine, in the winter time, it's also flu season, it's very easy to attribute patients with significant carbon monoxide poisoning to the flu, and it's easy to miss. It takes the astute clinician to think about it. I think it's more reason to make the diagnosis when several members of the same household come in for flu symptoms, and before you label them as the flu, think perhaps this could be CO poisoning. And, obviously there's somefairly easy ways now to make that diagnosis. I think the most important way to make the diagnosis CO poisoning when it's not from somebody being pulled out of a burning building is to first think about it. Entertain that as a possibility in the diagnosis. Delayed neurologic symptoms, as we're learning now, are fairly common as well.

What about cyanide? This has been, I think, the educational gap for emergency medicine, and the core content of emergency medicine and toxicology, that we're really learning now that cyanide is indeed a common product of combustion in products that are found in just about every home and apartment in America. Natural substances, wool and cotton, paper, and of course plastics, which are truly ubiquitous. Very few of us have thought about hydrogen cyanide being released when you burn plastics, cotton, and wool, but therein lies the challenge. Virtually any house fire, any structure fire, whether it's a residential or commercial, irrespective of hazmat or chemical plating company, will have cyanide released as a product of combustion when there's a fire. So, it's fairly ubiquitous.

The challenge with recognizing cyanide as a problem with smoke inhalation is unlike carbon monoxide, where now we have noninvasive CO detectors like pulse-oximetry devices, we're used to getting co-oximetry as part of the arterial blood gas (ABG) or venous blood gas (VBG) analysis in the emergency department (ED), very few of us have the availability of a rapidly available diagnostic test for cyanide (CN) poisoning. Very few hospitals in this country can get quantifiable lab tests for cyanide. Dr Borron will talk a little bit more how to make that diagnosis in the ED, but it's been very challenging. Even if you thought about cyanide poisoning, therein lies the challenge -- how do I confirm the diagnosis because I don't want to pull the trigger and go ahead and give somebody treatment for cyanide when in fact the cyanide may not be there, or maybe in fairly low level amounts that's not going to significantly harm or kill my patient? The other part of this is carbon monoxide (CO),and CN will work synergistically and make the patient worse off than if they were exposed to either one of these individually.

In terms of some well known fires in the past, when they've actually measured cyanide levels, and these are usually done postmortem or perimortem, they found that some very well known fires resulted in some large numbers of fatalities over the last several decades.

Indeed, like the ones I mentioned shown on this slide here, cyanide was actually a larger component, or was present in higher levels of the fatalities than carbon monoxide.

This really has led to this whole push now to think about cyanide whenever you think about carbon monoxide in patients who are exposed to smoke. Any time somebody is exposed to serious smoke inhalation, cyanide is going to be omnipresent. The challenge is it's a difficult diagnosis to make because we don't have readily available blood tests.

Because cyanide is disabling so quickly when someone is exposed to cyanide, it makes their ability to remove themselves from the fire, to run out of their burning home, much more difficult because it incapacitates them so quickly. So, the question is if someone has cyanide poisoning from smoke inhalation, why is there an urgency to treat them so quickly, vis-à-vis prehospital setting, let alone the ED? The problem is we all recognize, we're all trained to recognize, whether you're a paramedic, a nurse, a physician, a surgeon, or whatever your role in emergency health care, we always think about ABCs. We recognize airway difficultly, airway compromise, hypoxemia. We have ways to measure it. There are classic signs and symptoms, and we treat that in our primary survey right off the bat. The problem is cyanide is a cellular poison. That's kind of the cruel irony here. If I recognize or if I think about someone being a potential cyanide poisoning victim, I can give them allthe oxygen available, I can put them on continuous positive airway pressure (CPAP), I can put them on a nonrebreather mask, I can go ahead and intubate them, with 100% FIO₂, but it's not going to work because the cells are still poisoned by the cyanide, and it's not going to help us. That's the cruel irony. I can oxygenate their blood, but the cells are still going to starve from lack of oxygen and ultimately die. So, what happens of course, the cells, because cyanide poisoning is a cytochrome oxidase in the mitochondria, can't utilize the oxygen no matter how much oxygen we're giving the patient. The cells shift over to an anaerobic metabolism, and you have a huge build up of lactic acidosis, and eventually the cells start to die. Not surprisingly, which organ systems are most sensitive to hypoxemia? The brain and the heart, so the signs and symptoms relate to hypoxemia of the brain.

The classic signs and symptoms we've all learned about as part of our normal education, and/or as part of training in terms of weapons of mass destruction, cyanide poisoning, maybe the patient looks cherry red, there may be this bitter almond odor, cyanosis, those are all unreliable, very, very unreliable, and you can't hang your hat on any one of those things. Cyanosis can be very, very late, and normal to pink skin color, again based on patients' different skin pigmentation and different metabolism. It's very, very unreliable. So, the first that you're going to note that someone may be a victim of smoke inhalation, of course, obviously is the history. If it's a large building like an office building, if you think about the first time the World Trade Center was bombed in 1993 -- people forget it was bombed not once, but twice -- when there were only about a dozen fatalities, thousands and thousands of office workers were streaming out of the World Trade Center, and most of thosefolks had soot around their nose and mouths. That's the first indicator that patients have potential smoke inhalation. Because they're breathing in that environment, they have soot around their nose and mouth.

The signs and symptoms obviously run the spectrum from minor to severe, and again they all make sense because the brain's starved from lack of oxygen because the cyanide is a cellular poison. Based on the concentration of cyanide you're exposed to, and the duration of exposure through inhalation, eventually you go from mild symptoms of anxiety, and headache, and nausea, to dyspnea, eventually to respiratory arrest, seizures, and ultimately hemodynamic collapse, and cardiac arrest.

Again, this may present very, very rapidly if the concentration of exposure is very, very high, or it's a prolonged exposure.

The problem is CO and CN poisoning in a smoke inhalation patient are virtually indistinguishable. Again, the end result is hypoxia, signs and symptoms are very, very nonspecific, and now we have some ways to diagnose CO poisoning noninvasively. How do we diagnose CN poisoning, and can we give an antidote perhaps safely? The challenge is, of course, the adverse effects if I'm wrong.

The indication criteria to think about treating a patient with potential cyanide poisoning, again, is the fact that they're going to be a smoke inhalation victim, as evidenced by soot around their nose and mouth, and altered mental status, and hypotension. In terms of recognizing these folks are sick, it makes sense.

The source, severity, duration of exposure, and concentration.

The antidote has to be safe if I'm going to give it empirically. We've been saying that we don't have a noninvasive test to confirm cyanide poisoning, unlike some new modalities available for CO poisoning, we don't have rapid access to co-oximetry through ABG or VBG sampling, which is usually a very rapid turn around time in most EDs. Most hospitals we work at, mine included, if I want to get a cyanide level, it's a send out. I'll probably never get it back in a timely manner, and obviously I have to make a treatment decision very, very quickly. So, an antidote in this realm has to be safe to be given empirically because if I'm wrong, and it's ultimately shown the patient does not have a significant cyanide exposure, I don't want to hurt the patient with my treatment if the treatment is worse than the disease. Therein lies the challenge.

Everybody here is familiar with the long-standing cyanide antidote kit that's been available in this country for many, many years. You see the cyanide antidote kit here on the slide. This has gone under a variety of names throughout the last several decades. It's been sold to different manufacturing pharmaceutical companies, Lilly Kit, Taylor Kit, Pasadena Kit, or just CAK for cyanide antidote kit. The components have been the same, but the names have changed, and what's new on the market now is the Cyanokit, which we'll talk about in a moment.

The classic cyanide antidote kit, or Lilly Kit, has 3 components; 2 of which are nitrites, one's a thiosulfate. How do these work? The nitrites convert the iron in hemoglobin from the ferrous to the ferric form and, therefore, creates methemoglobinemia, which cyanide has a high affinity to. In fact we're creating cyanomethemoglobin, The cyanide comes off the mitochondria that's poisoned, and we have methemoglobinemia, converted to cyanomethemoglobin, thereby releasing the cyanide from the cells. The third component is a thiosulfate, which is a sulfur donor, so an enzyme in the body called rhodanese, now has more sulfur to eventually excrete the cyanide renally. The amyl nitrite is given as a pearl, much like you would give an ammonia inhalant for noxious stimuli. It's given through inhalation under an oxygen mask, or through BVM, and the sodium nitride is given intravenously. So, there are 3 components. The amyl nitrite causes very, very low levels of methemoglobinemia, probably nomore than 1% or 2%, which is probably clinically not helpful shall we say. The amount of methemoglobin created by amyl nitrite pearls is really clinically irrelevant. It's more of a feel good thing, and it's part of the kit to try to temporize the patient until you get an IV started, again the sodium nitrite and then also hang the thiosulfate.

What are the side effects? Of course, everything has some side effects. We all know that all nitrites have similar side effects as nitrates, which is hypotension. The other problem is, aside from hypotension because it's a potent vasodilator, is that the nitrites, the way they work to treat cyanide poisoning, as we mentioned. They convert hemoglobin to methemoglobin. As you know, if you have too much methemoglobin you're going to get more and more hypoxic. So, we have a patient who has moderate-to-severe cyanide poisoning through smoke inhalation. They may have also a component of carbon monoxide poisoning, so the body's hypoxic. The cells are poisoned, so, it's a cellular poison, and if it's a severe enough poisoning they're also hypotensive. Of course I can't give them a drug that's going to make them more hypotensive and may make them more hypoxic. Clearly, nobody's going to give the classic components of the cyanide antidote kit to a smoke inhalation victim empirically becauseyou're likely to make them much, much worse, meaning the patient may survive their injuries and die from the therapy, and that's not a good thing.

What is Cyanokit? Cyanokit is hydroxocobalamin. For those of you that have not heard the term hydroxocobalamin, it's just a vitamin B₁₂ precursor. That's all it is. It's a naturally occurring substance, vitamin B_12A. It's based on cobalt, and in its form of hydroxocobalamin, for smoke inhalation it's been used in France for about 10 years. Some folks have asked, haven't we had hydroxocobalamin available, ie, Food and Drug Administration (FDA) approved in this country for many years for treatment of pernicious anemia? That of course is correct, but the problem is given the concentration of it for pernicious anemia, if you were to use that for smoke inhalation patient, the volumes you'd need, multiliters of the drug, couldn't be therapeutic. It would not be amenable to this setting. So, they reformulated the concentration of vitamin B_12A to use in cyanide patients, and that formulation known as Cyanokit has been used in France asempiric treatment for smoke inhalation patients, based purely on signs and symptoms, and that same formulation got FDA approval in the United States almost a year ago.

How does the hydroxocobalamin work? Unlike going indirectly by having nitrites create methemoglobin and going through that circuitous route, or donating a sulfur group to eventually have the cyanide excreted renally through the body's own clearing systems, the hydroxocobalamin, basically koilocytes as it were, pulls the cyanide off the cells to create vitamin B₁₂. Hydroxocobalamin is converted from vitamin B_12A, to vitamin B₁₂; therefore, it pulls the cyanide off the cells. That poisoning of the mitochondria is reversible, and the cells, unless they've gone too long and they're now dead, that binding is reversible, and the patient can survive. Of course, timing is critical so it directly pulls the cyanide off the cells rather than indirectly causing other problems such as methemoglobinemia and hypotension.

How is this administered? This is given just through a peripheral IV. It comes as a lyophilized freeze dried form. It looks orange to red because of the cobalt, which is the same thing that gives our hemoglobin in our blood a red color. Basically 250 cc of saline or Ringers Lactate is put into the box. It's shaken a little bit and just given as an IV infusion through any peripheral line. The recommended empiric dose for severe smoke inhalation is 5 g over 15 minutes. Once at the hospital, or in the field if it's a long transport time, an additional 5 g can be given as well.

What are the side effects of hydroxocobalamin? We know there are side effects to everything we give. As a matter of fact, I would argue that if someone invented aspirin today, good old generic aspirin, it would never get FDA approval because of all the side effects of aspirin. Never. If you ask any pharmacist, they'll tell you the same thing. Everything has a side effect. What about hydroxocobalamin? Ironically enough, contrary to the traditional cyanide antidote kit, specifically the nitrites, there is actually some temperate transient elevation of blood pressure rather than a decrease of blood pressure. This is transient. Whether it's helpful to the patient or not, we don't know. But it's very, very fleeting so it's not a problem. Overdoses haven't been seen of the patients. There are lots of patients that have been written up and studied in France, again because they have over 10 years' experience with this medication where they've gotten 15 g, they haven't seen any significantserious adverse effects.

Why is it amenable to use empirically in the field or the ED for smoke inhalation patients? Because its side effect profile is very, very minor, no significant serious adverse effects, so it can be given safely. Because if it turns out CO is more the problem than CN, or it's both, or you just can't prove CN's the problem because you'll just have to send out blood tests where using surrogate markers as Dr Borron will talk about, it's safe to be given empirically. I think the analogy, obviously, other than cost issue, is like giving Narcan for the unknown overdose. Because if it doesn't help the patient, it's not going to hurt them.

What are some of the data we have on the prehospital setting on the use of hydroxocobalamin? This is French data. These are patients, again, presumed to have smoke inhalation based upon soot around their nose and mouth, altered mental status, and/or hypotension, and/or evidence of respiratory failure, or hemodynamic instability. They had 69 patients of whom 37 were coma and 14 were cardiac arrest. They all got Cyanokit in the field, in the prehospital setting. Almost three fourths survived, and the majority of those, almost 8 of 10 had no neurologic sequelae. They actually got quantitative cyanide levels at the hospital, and they found that 61% did indeed have cyanide poisoning as defined by a level greater than 1. Most important, there were no significant or serious adverse effects even in the patients who didn't have cyanide poisoning.

Prehospital protocol for smoke inhalation for use of hydroxocobalamin. basically a patient who is suspected to have smoke inhalation, again soot around the nose and mouth, plus altered mental status, and/or any hemodynamic or respiratory compromise. That's your indication criteria. You would obviously remove the patient from the IDLH, or Immediate Danger to Life and Health. They're brought out away from the IDLH. Of course the prehospital providers are using the necessary protective personal equipment, or PPE. The initial ABCs are done. The patient is placed on 100% oxygen, but again 100% oxygen is not going to work because the cells are poisoned by the cyanide, and you go ahead and administer the 5-g dose of Cyanokit in the field. If the patient is still symptomatic or not markedly improved, and you're not at the hospital yet, you go ahead and give a second dose of 5 g in the field. The first 5 g is given through a regular peripheral IV over a 15-minute period of time.

I'll conclude with a brief case study.

A 32-year-old male pulled out of a house fire like you saw in that picture, single family dwelling, well involved with fire on the second floor, heavy smoke. The firefighter finds this gentleman on the primary search of the home. They bring him out, the paramedics. He's unconscious, unresponsive. He has agonal respirations. He does have a gag reflex. They note he has quite a bit of carbonation sputum in his airway. During their ABCs the paramedics immediately assist respiration with a bag-value mask and 100% supplemental oxygen, and they bring him to you in the ED.

What would your differential diagnosis be on this patient? It would be CO toxicity, anoxic encephalopathy, cyanide toxicity, or some combination of those three?

The other issue would be would you consider transferring this patient from your facility to a facility where there's a hyperbaric chamber? Would you consider treatment with hydroxocobalamin? Some combination of the above? Or, would you recommend the paramedics directly transport this patient to a burn center, or a facility with a hyperbaric chamber?

We'll come back to this case. We'll have a couple of others in a moment. Let me now bring up Dr Stephen Borron. He's a professor and a very well known researcher at the University of Texas Health Science Center in San Antonio, whose done a lot of research in this field, in toxicology specifically with cyanide poisoning and hydroxocobalamin. Dr Borron.