Part 2: Does Cyanokit save lives in cardiac arrest?

In the last post I reviewed some key facts about hydroxocobalamin (HCB), otherwise known by its brand name Cyanokit. However, paramedics and firefighters aren't really concerned with the animal studies - they want to know if it saves human lives! 

And according to some flashy headlines, many people believe this stuff works when nothing else can.

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But these are news reports and press releases - what does the medical evidence show? 


Does HCB help in cardiac arrest due to smoke?
This is the tough hurdle for studying any toxicologic antidote, and it's especially hard to do research in this area. The events are rare, and it's usually an emergency when these poisoning occur. For these reasons, and more, there have only been a few studies of HCB in humans.

Four studies have looked at the use of HCB in smoke-exposed patients. Interestingly, 3 of them were done in France, mostly in Paris.

Just for fun, Google "Paris" and "burning."

Study #1 - All smoke exposure patients who got HCB  
The authors of the first study looked at all the patients treated with HCB over an 8-year period  for "suspected cyanide poisoning" after a smoke inhalation, usually from a house fire. It's important to understand that there was no comparison group so it is impossible to know whether the drug helped, hurt, or did nothing.

With that in mind, all 101 patients got HCB, and all were from residential house fires; about 1/3 of those were in cardiac arrest. Forty two patients died, 30 survived, and the status of 29 patients was "unknown." 

How about patients found in cardiac arrest? Of the 38 patients who where found in arrest, 21 of those had prehospital ROSC - pretty encouraging. Unfortunately,  the majority of those (19/21) subsequently died in the ICU.

This might be encouraging if we were givne some data about those 2 out of 38 patients who survived. For instance, did they get the HCB before, during, or after their cardiac arrest? Unfortunately, there are no further details. 

Study #2 - All cyanide exposures who got HCB
Just like the study above, the authors of study #2 included patients with smoke inhalation or cyanide ingestion who were treated with HCB by EMS. Since this was written by the same authors as study #1 above,  and covers mostly the same period (1995-2008), it is likely that many of these patients overlap with those in the prior study.
Out of the 161 patients studied, 61 were found in cardiac arrest. Most of these died in the field, or ended up dying in the hospital, but 5 patients lived after getting HCB from EMS!

 
That's an 8% save rate, which seems very promising, but the authors note that most of these "saves" didn't actually get HCB before they had ROSC. As they point out (my emphasis):

"Among the 61 patients in [cardiac] arrest, 5 survived without sequelae and, in particular, without neurological sequelae. Four of the 5 patients were ... discovered in cardiac arrest by the fire brigade, and spontaneous cardiac activity was obtained after cardiac massage and oxygen therapy. ...

[H]ydroxocobalamin was not responsible for the recovery of spontaneous cardiac activity in these patients."

I'll point out that the 5th cardiac arrest survivor had his age only listed as "adult," suggesting that the EMS records were incomplete, at the least... 


Study #3 - All smoke exposures, who got HCB, and who made it alive to the ICU
The last study adopted a slightly different approach. The authors performed a retrospective "observational case series" of all of the patients who who had smoke exposure, received HCB in the field, and were subsequently admitted to the ICU. 

A total of 69 patients were enrolled. Of these, 15 patients had been in cardiac arrest when EMS found them. Of these 15 patients, only 2 survived.

Hey, 2/15 is a 13% save rate, which might be really promising. Or might not be - we can't tell from the study design.

Study #4 - All smoke exposure patients who got HCB - in Texas! 
You might not have thought that Paris and Houston would have a lot in common!

You can skip Googling "Paris" and "Houston"

As it turns out, both Parisians and Texans have been using HCB for years, and a just-published abstract describes the experience of the FD in Houston. Unfortunately, the study wasn't "Texas-sized," and was actually smaller than those done in Paris.

Like the French studies, the Houston authors looked retrospectively at all the patients who had received HCB for "possible cyanide poisoning." Over a period of 4 years, 22 patients got the drug. Half of those were found in cardiac arrest, and 8/11 had ROSC "after administration of HCB."

So, awesome, right? Unlike study #2 above, the patients in cardiac arrest actually got HCB before ROSC, not after. Is this proof that HCB, given in arrest, can produce ROSC rates in almost 75% of cases? 

 Limitations of these "case series"studies
Unfortunately, we still can't say.  All of these studies were basically case series. It is very low-quality evidence, ranking just above expert opinion. You can think of such a study design as just a fancy doctor phrase meaning "a bunch of cool stories."

Why? Because there is no comparison group in any of them. Since the drug was never actually tested against another drug, let alone a placebo, we don't know if HCB helped, or did nothing. 

Heck, for all we know, it may have even hurt patients. We just don't know.

 So, what can we do with this data?
By itself, not much. HCB is a new therapy, with potential, but no solid human evidence to support when we should use it. Of course, we don't always wait for perfect evidence to come along before using drugs and therapies.

With that in mind, what should you and your teammates do the next time FD drags a patient in cardiac arrest out of a fire? Or what if one of your firefighter teammates collapses next to you during a fire?

The next post will offer some suggestions, based on better evidence, of techniques and therapies that have been shown to lives.

Cyanokit: What's the evidence? (Part 1)

Cyanide is a very, very potent toxin. I'm not sure this needs more emphasis, especially after two recent examples in the news (from upstate NY, and from a little closer to home). 

Just a quiet suburb? (source)

Hydroxocobalamin (HCB) is an FDA-approved antidote for cyanide poisoning (brand name Cyanokit). It isn't new, having been used for years in France, but there has been lots of talk about it in the U.S., especially for treating patients who have inhaled smoke; e.g. in a house fire.

First step in treating smoke inhalation:
Do not park ambulance in the fire! (source)

There are other antidotes for cyanide, such as sodium nitrite or sodium thiosulfate, that have been available for years. The appeal of the "new" drug, HCB, is that the dosing is somewhat simpler, and there are perhaps fewer adverse effects (at least compared to sodium nitrite).
 

Second step in treating smoke inhalation:
Remove patient from a burning ambulance! (source)

But the interest in HCB doesn't just have to do with dosing or side effects, but also a number of well-publicized and exciting accounts of miraculously revived patients. However,  there are still questions about when to use it, and what the evidence is.

In this 3-part series, I'll review the basic and clinical evidence for HCB. In order to get a fuller picture, I also spoke with a number of paramedics, firefighters, and physicians. I also was able to discuss the evidence with EMS physicians around the country, as well as a number of toxicologists. This group included, of note, not one but three dual-trained firefighter/MDs. 

Okay, five things you should know about HCB...

1. It's pretty effective - if you're a dog.
The field of toxicology, in general, relies on a lot of basic science and animal studies. It's just too hard to conduct the controlled human trials that would be expected in other fields.

HCB has been studied in a number of animals - pigs, dogs, and even rabbits. I'll just give one example. In a study of beagles getting intravenous cyanide, researchers gave either HCB or placebo. They waited to give the drugs until the dogs had been apneic for 3 minutes. Despite this "head-start" for cyanide, none of the dogs who got the high-dose HCB died, whereas 80% of the untreated dogs died. 

This suggests suggests a strong benefit for HCB, (at least for dogs who are shooting up cyanide).

2. Then again, so is epinephrine (if you're a pig).
Another group of researchers took three groups of pigs, and gave them IV cyanide infusions, up until the point of cardiac arrest. Group #1 of pigs got one dose of HCB, group #2 got epinephrine, and group #3 got nada.

The nada group (#3) didn't do well - all of those pigs died, despite CPR. On the other hand, almost 3/4 of the pigs in both the HCB (#2)and the epi (#2) groups survived.

The authors noted that other measures, like lactate, troponin, and pH, all showed benefit for HCB. Nonetheless, HCB and epi looked just about the same for survival, and both were literally better than nothing!

Okay - anybody want to read more animal data?

"We would prefer to see the human data, if it's all the same to you."

Moving on then - How does this work in people?

3. It appears safe in human volunteers.
When HCB was given to human volunteers, not much happened. There was a small bump in the systolic BP, about 20 mm Hg, and a few minor allergic reactions. The most dramatic reaction was a "skin redness" seen in almost all the subjects who got HCB.

This rash took up to 2 weeks to resolve in some cases! Not dangerous, but certainly something to be ready for. It also turned the urine and tears the same color.

4. It's expensive!
This much is clear - it costs $$$.

Source

Whew! Over a thousand bucks. 

By contrast,  IV amiodarone costs about $20 per code, while a ResQPOD will set you back about $100.  On the other hand, tenecteplase, a fibrinolytic drug that is proven to save lives in STEMI, costs about $1500 a shot.

By contrast, the older drug, antidote sodium thiosulfate is relatively cheap.

Source

5. HCB might save human lives...
$1000 might be worth it, or even cheap, if this drug can save lives. With that in mind, we'll take a look in the next post at the evidence "from the field."


To be continued...

Checking firefighters for carbon monoxide - recent studies, persistent concerns.

Carbon monoxide (CO), we can all agree, is bad. The symptoms are vague, the patients sometimes can't give a good history, and definitive diagnosis requires a needle stick. 

"Do I have to? I can't stand having my blood drawn!" (source)

Of particular concern, firefighters can be exposed to high levels of CO in the course of their duties. For example, one small study suggested that FFs can double their CO levels during overhaul, a period when many personnel are not using SCBA (see abstract #4).

In response, many fire departments have started to screen for elevated carbon monoxide during the rehab phase of a fire. For the most part, EMS agencies and FDs use devices made by Masimo Corporation that monitor CO levels noninvasively, and are quite portable, whether as a stand-alone device (in the picture below), or available as an option in some monitor-defibrillators. 

Name 4 things done incorrectly in this ad.
Answers below!

Sounds great! What's the problem?
They may not be accurate enough to screen FFs.

A large study done by Touger et al. in 2010, conducted in an ED in the Bronx, looked at the ability of these devices to diagnose high CO levels. They compared the CO values obtained by the traditional blood draw method with the painless finger probe on the RAD-57.

They checked out a bunch of patients who came to the ED with suspected CO poisoning, and found that the RAD-57 was usually correct if it predicted a high level, but ...

... it missed a lot of cases too.

In fact, it missed about half of the cases where the CO level was ≥ 15%. In 3 cases where the patients had CO levels over 15%, the RAD-57 gave a value of "zero." The authors concluded that 

"Our results do not support use of this device to replace standard laboratory measurement or as an out-of-hospital triage tool."

Why did they choose 15% CO as the cutoff?
Most toxicologists will tell you that they don't care as much about the specific CO level, as they do about the symptoms. A patient with a level of 17%, but only feels some mild dizziness, is less concerning than a patient who passed out for 10 minutes, but has a "lower" level of 11%.

Instead, the 15% threshold comes from the National Fire Protection Association (NFPA) guidelines. Here's an example of what their training curriculum says about using CO levels.

Rehabilitation and Medical Monitoring: A Guide for Best Practices : an Introduction to NFPA 1584

The implication of the Touger study is that half of CO-poisoned firefighters might not be identified during screening in the rehab sector. Not good.

Can we use a different cut-off?
Sure! A few studies have looked at this, but the results show that there is a trade-off.

How about a CO level of 1o%?
A 2012 Candian study (Zaouter) used human volunteers, instead of ED patients. This study was conducted in a lab setting, where the researchers were able to precisely deliver CO to the volunteers, and then test them using both the RAD-57 and the standard blood test.

• The Good Part: They were able to look at the performance of the RAD-57 over a range of well-controlled CO levels.  
• The Bad Part: You can't really give human volunteers more than 15% CO blood levels - too dangerous.

The subjects breathed in CO until they reached levels of 10 - 15%, and then the researchers measured the CO level, simultaneously using the finger probe and a blood draw. How did the RAD match up?

Not so hot. Using a cut-off of ≥ 10%, they found that (like Touger), that it missed about half of the cases. Of the 24 patients who had CO levels of 10 - 14%, only 13 were identified by the RAD-57. The authors note that:

"In light of this low sensitivity, it has been advocated that the RAD-57 cannot be used to exclude CO poisoning in any patient with an appreciable risk of being intoxicated."

How about a CO level of 6.6%?
However, an Austrian study from 2011, (Roth) seemed to show that the RAD-57 could pick up almost all the cases of CO poisoning. Like the studies done by Touger et al. and by Sabbane et al., it was done in an ED, and involved simultaneous blood draws and use of the RAD-57.  So why the difference?

Because they ended up using a lower CO level of 6.6%, not 15%. They calculated this level after running the tests, and then calculating receiver operating curves, statistics, etc. What this table also says, is that, if you ran 100 FFs with CO levels above 6.6% through rehab, and checked them with the RAD, you would catch 94 of them.

So, is the answer to use a cut-off of 7% instead of 15%? We don't really know. Problem was, almost no one in this study had CO poisoning - only 1.1% of the patients. With so few "positives," the researchers couldn't say much about the rate of "false-positives." As the authors noted:

"The opportunity for false-negative results was limited. Because a false-negative reading could have serious medical consequences, this device should be tested in a much larger number of poisoned patients to confirm the generalizability of our stated cut-off values."

How about a CO level of 9%?
A French team of researchers (Sebbane) was also conducted in the ED, examining suspected CO-poisoned patients. The decided to try using different cut-offs for smokers and non-smokers, and defined CO toxicity as a blood level of ≥ 5% in non-smokers, and ≥ 10% in smokers. 

After studying a bunch of ED patients, and doing the same sort of statistical stuff as the Austrian team above, they found that using RAD-57 levels of ≥ 6% and ≥ 9%, respectively, they still missed a number of folks, all of them non-smokers. It was worse if they use a cut-off of ≥ 9% for everyone.

The researchers concluded that:

"Subjects with suspected CO poisoning and first-line, positive RAD-57 testing (SpCO 9% in smokers, or 6% in non-smokers) could benefit from immediate care. However, a negative RAD-57 test will not exclude standard blood COHb measurement to confirm CO poisoning."

Large study using the RAD-57, with firefighters, in real-life!
Lastly I have to talk about the big study, the one that enrolled a pretty large number of active firefighters.

In this "real-world" test of the RAD-57, the researchers enrolled all firefighters coming through the rehab station at major structure fires. They were able to simultaneously measure the blood levels of CO at the same time as using the RAD-57. Instead of being done in a lab setting, or even in an emergency department, they tested it in the challenging environment of a true fire scene. The firefighters were dirty, their fingers were cold, and the real firefighters (not research staff) checking the RAD-57 measurements didn't have time to obtain multiple measurements - they had to get it right the first time.

So how did the RAD-57 measure up? How many CO-poisoned FFs did the device pick up? How many did it miss, and, as a result, let go back to their duties?

Well, we don't know. Because no such study exists. Despite the heavy marketing to fire departments around the country, telling them this device saves lives, there are no studies showing that the RAD-57 can function accurately in this environment. 

The Bottom Line 

Looking over all of these studies (plus a few more), a few results are found reasonably consistently:

• On average, the RAD-57 is fairly accurate. 
• However, the "average" can hide a lot of variation.
• You can usually trust a "high" reading. 
• A "negative" test, however, can very often be false. 
• Most importantly, you cannot use the RAD-57 to "rule-out" CO toxicity.

Most toxicologists are very skeptical about using RAD-57-type devices to make clinical decisions. A very recent article, written by 3 critical-care physicians, noted that 

"Until well-performed trials demonstrate that these devices provide consistently accurate measurements, we cannot recommend their routine clinical use."

With these results in mind, I'm not sure that fire departments can use this to safely return firefighters to duty.

Answer to picture question

1. The rehab/medical monitoring station is set up right next to the fire and a diesel engine? This seems like a bad place to evaluate the asymptomatic firefighter.
2. Perhaps the FF is suspected to be symptomatic for suspected CO toxicity. In that case, where is the high-flow oxygen?
3. Since the FF is still fully dressed, and his face is covered in soot, we can assume that he hasn't had time to wash up. This could be a problem, since some researchers have found that dirty fingers can lead to false CO measurements (Piatkowski 2009)
4. Lastly, the CO level is being checked in direct sunlight. The operators manual states that "direct sunlight, directed on the sensor, may not allow the Rad-57 to obtain readings."