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." 

You gave adensoine for THAT? (part 3)

To recap - the paramedic had a patient who was throwing off long segments of both narrow-complex tachycardias, and wide-complex tachycardias. An initial dose of adenosine managed to transiently establish a sinus rhythm.

Sinus rhythm for 3 whole beats! *Pumps fist in air*

So what was converted; SVT or VT?
It's tempting to think that, beacause it was converted by adenosine, it must have been a SVT with aberrant conduction. A few things suggest that this was, instead, true VT.

Playing the odds...
First, a wide-complex rhythm in an older patient is far more likely to be VT than SVT - if you're betting, that's where yo should put your money. 

Your instructor was right - axis is important!
Second, you could be tempted to call this a left bundle branch block, but the axis is unusual. A LBBB usually points off towards the left.

Note the large R waves in I and aVL (Source)

Our patient, on the other hand, shows an axis oriented a bit to the right.

Note the large R waves in II, III, and aVF

Fusion beats
Third, the patient keeps kicking out fusion beats, or QRS complexes that show features of both a supraventricular beat, and a simultaneous ventricular beat. They usually look like an "average" of a PAC and a PVC. Here's an example from Life in the Fast Lane:

Not wide, not narrow, just ... average.
(source)

 When we look at the initial rhythm strip we see a bunch of sorta wide/sorta narrow beats.

Another ECG, done in the ED, also shows multiple fusion beats, indicated by the arrows.

Such a finding strongly suggests that this patient had ventricular tachycardia that was converted by adenosine. Crazy, right?

Well, it turns out that not everything that converts with adenosine is SVT!  One infrequent kind of VT can convert with adenosine - right ventricular outflow tachycardia.

RVOT
A fairly uncommon kind of VT is know as RVOT, named for the location of the problem. It basically looks like a LBBB, but with an inferior, rather than a left-oriented axis. A great example comes courtesy of Dr. Ken Grauer. Compare it with the initial 12-lead we have.

RVOT - from Dr Gauer's collection.

I'm not going to go on further about this rhythm, since it's pretty uncommon, but if you want to know more go check out Dr Grauer's blog.

(I'll note again that my cardiology education started when I read the 1993 edition of his ACLS textbook. He has a 2014 update, available on a variety of e-readers. Buy it!)

Uh, so there's this rare RVOT thing. Why should I care?
As I mentioned in Part 2, there are two important things to know about giving adenosine for a WCT:

1. Adenosine is relatively safe in regular, monomorphic WCT.
2. However, it can convert certain types of VT.

Since the publication of the 2010 ACLS Guidelines, a large number of EMS agencies have adopted adenosine as the first agent to administer in the treatment of a stable, regular, and monomorphic wide-complex tachycardia. I don't have any hard numbers on how common this protocol is, but instead of a study, I can give you a collage! 

I makes it for u.

Despite the popularity of this protocol, many clinicians have reservations about the wisdom
of this approach, since there are a number of potential pitfalls. One of the big ones would be to assume that adenosine is a reliable test for supraventricular rhythms. Keep in mind that he ACLS guidelines only state that "adenosine is relatively safe for both treatment and diagnosis."  

Safe, not accurate!

The Bottom Line
The SHCGB protocols allow for the use adenosine when the etiology of a WCT isn't clear. Keep in mind that, even if adenosine is successful, the etiology may still be unclear!

You gave adenosine for THAT?! (part 2)

In a prior post, I looked at whether you could give adenosine to a patient with a history of WPW (see "Can you give adenosine to a patient with WPW"). The answer was "Yes, but..."

I want to look at another adenosine issue today - can (or should) you give adenosine to a patient with a wide-complex tachycardia (WCT)?  

Spoiler: The answer to this questions is...

Or, more specifically:

1. Adenosine is relatively safe in regular, monomorphic WCT.
2. However, it can convert certain types of VT.

A case of WCT treated with adenosine by EMS
Our paramedic was just "minding his own business" when he was called for a patient with palpitations. He was an older person, with no history of any cardiac problems, and was hemodynamically stable. His rhythm strip, however, looked like:

Wut.

Okay, that's a data-rich ECG!  Taking a closer look at two different segments, we see evidence of both a regular monomorphic WCT...

So it's VT, right?
... as well as a regular narrow-complex tachycardia.

Tell me if you see P waves. I didn't.

VT with episodes of PSVT?
The full 12-lead ECG looked wide and scarey:

So, what to do?
Our intrepid medic decided that adenosine would be appropriate, and gave a slug, right as the patient was going through a spell of WCT.

At first it seemed to work ....

... aaaand right back into the WCT, after a brief period of apparent sinus rhythm.

Wait, what the heck - the adenosine converted a VT? Or was it aberrant SVT? What should the next drug be? How much does the response to adenosine change our impression?

To be continued...
Tell me what you think, and I'll be back with the follow-up, as well as how lessons from this case should affect your assessment and treatment in the field.

"We had a LUCAS save!" - No, you didn't.

I don't get it.

More and more, I'm seeing Facebook posts, newspaper articles, and personal testimony that excitedly describe a "LUCAS save." That is, a successful resuscitation is credited to the use of a mechanical compression device made by Physio-Control. For example:

"Saves man's life!"

Source

"More residents survived thanks to LUCAS!"

Source

"Life-saving CPR technology!"

Source

"Life-saving technology!" "Saves local man!" "Thanks to LUCAS!" Why hasn't this news of Lazarus-like success swept the country? Why are we still doing CPR with our hands?

Doing CPR with our muscles... like a sucker!

 Well, there is one teensy fact that the press releases leave out...

The LUCAS doesn't save lives.
And no, I don't mean this in the clever "guns don't kill people..." sense. 
I mean this in the "proven by science" sense.

Source

This study, published in January, describes the use of the LUCAS in out-of-hospital cardiac arrest. 

 - Methods
The study looked at patients who had a cardiac arrest treated by EMS. They enrolled adults, who had suffered a non-traumatic arrest, and were neither too small, nor too large, to fit in the LUCAS. They randomized patients to either get manual CPR according to 2005 European ACLS guidelines, or to get chest compressions delivered by a LUCAS device.

The teams were well-trained - not only was there initial preparation for the teams with both usual and mechanical techniques, but team members had twice-yearly re-training, as well as random "spot checks" of individual participants using a manikin. Pretty rigorous!

The primary outcome was maintaining survival for 4 hours after ROSC. You can quibble that this isn't as important as, say, neurologically-intact discharge from the hospital, but it's a reasonable goal, and likely easier to achieve.

 - Results
This should have been a slam-dunk for the machine. Mechanical CPR is consistently high-quality, does not fatigue, and frees up EMS workers for other tasks. One more bonus for the machine - the protocol called for defibrillations to be given during the mechanical compressions, something that humans are not usually able to do! In theory, this elimination of the peri-shock pause should have increased survival in the LUCAS-treated patients.

LINC trial protocol

However, after 2500 patients were enrolled, they found squat for differences between manual CPR and the LUCAS. Nothing. No matter what outcome you picked, there was no advantage to using the LUCAS. None.

LINC trial results

 - Interpretation
So that's the end of the LUCAS for routine management of cardiac arrest by EMS, right? We did the research, it was negative, and we took the expensive machines off the rigs. The EMS services that haven't bought them have expressed relief that they didn't lay out the cheddar.

"But the LUCAS..."

But regardless of these completely negative results, people are protesting. They point out that, yeah, maybe this study didn't show a difference. "But the LUCAS..., " they point out...

• "...delivers better CPR!" 
• "...can shock during CPR!"
• "...can do better CPR during transport!"
• "...doesn't get tired!"

Despite all that, which is likely true, no difference was found in a high-quality trial where the researchers has every opportunity to demonstrate these . This is how clinical research goes - the slaying of appealing theories by means of ugly facts.

The graph is explained HERE, if you're into that sort of thing.

Don't give credit to a piece of plastic!
A recent article over at JEMS describes a successful cardiac arrest resuscitation. The authors write about the myriad contributing factors:

The integrated training between EMS responders and the CPR/AED-equipped police officers; the multilayered, coordinated response and resuscitation effort by police and EMS familiar with the pit-crew approach to resuscitation and use of a mechanical CPR device; and the rapid response and time-to-care by the rescuers—particularly at such a large gathering—were all key factors in this successful resuscitation.

But the authors then go on to emphasize in the last paragraph that the LUCAS "was clearly a part of this successful resuscitation," and that "they’d never seen this type of response in all of their years of managing cardiac arrest cases." 

In other words; "We did okay, but we're pretty sure that this inanimate object should get the lion's share of the glory." 

You know, I think I've seen this before...

"Simpsons already did it!"

The Bottom Line: 
You know what saves lives? 

You. 

You, and your well-trained team, utilizing the proven techniques that save lives. Believe me, if the LUCAS was able to generate these sorts of results...

 Source

... you would have heard about it by now!

(For another analysis of this trial, plus some interesting comments, read the post Man vs Machine: A CPR Battle to the... over at Ryan Radecki's excellent blog.)

Sudden Cardiac Death Among Firefighters ≤45 Years of Age

I want to talk about a new study that looks at heart attacks in younger firefighters, so no jokes or funny picture today. It’s hard to come up with a humorous spin for a graph like this: 

From a 2012 FEMA report

The chart above comes from the 2012 USFA report of firefighter fatalities, and it’s shocking. Over half the fatalities in that year had nothing to do with burns, entrapment, falls from ladders, or other traumatic dangers. Instead, MI and stroke, in general, were the biggest danger firefighters faced. 

Now, this is partly a function of age, but 15% of the deaths from MI were in firefighters younger than 45 years old. A recent study focused on this group, and found some surprising results.

The Study
The authors of Sudden Cardiac Death Among Firefighters ≤45 Years of Age in the United States wanted to take a closer look at these younger firefighters who died of cardiac causes, and see if there were any risk factors that could explain those deaths. 

To do this, they used the database maintained by NIOSH (http://www.cdc.gov/niosh/fire/) to find all cases of firefighters < 45 years of age who had a sudden cardiac death. They looked at the period from 1996 to 2012, and examined autopsies and other reports.

They then selected a bunch of age-matched, healthy, “occupationally active” control firefighters to compare them to. Additionally, they looked at noncardiac traumatic fatalities (deaths due to blunt trauma, burns, or asphyxiation) to serve as a second comparison group.

1. The FFs with sudden cardiac death 
They found 87 FFs under the age of 45 who had a sudden cardiac death during that time. 

A few results stand out:

• Almost all were men.
• Over 1/4 of them smoked 
• (Only 18% of Americans smoke). 
• Almost 2/3 (63%) of them had a BMI ≥ 30. 
• (Versus about 36% of American males)
• Over 1/4 of them had a BMI over 35. 
• Over 1/2 had evidence of both cardiac disease and cardiomegaly. 
• (Only 40% of men age 40-59 have CAD, HTN, CVA, or CHF)

At first glance, it looks like these firefighters had much worse health than the general public. But maybe this is due to the unique stresses of the job. For example, disruption of normal sleep patterns could encourage sleep apnea, leading to hypertension and obesity.

So in order to clarify the issue, they compared the FFs who had sudden cardiac death with the people most like them - other firefighters!

2. Compared with occupationally active FFs
When they compared these FFs to the “occupationally active" FFs, however, they found concerning results, suggesting that the FFs who had cardiac arrests were indeed unhealthier than their own peers.

Obesity, smoking, and hypertension were significant predictors of cardiac death while at work. Not unexpectedly, a history of cardiac problems was a huge risk factor as well.

3. Compared with FFs who had a traumatic death
When they then compared the FFs who died from sudden cardiac death to those that had a traumatic death, they found significant difference in both age, and in the size of their hearts. FFs who suffered a cardiac death had higher rates of cardiomegaly, or enlarged hearts, suggesting that they had had longstanding problems with hypertension or obesity (or both).

So what do we do with these results?
First off, prevention (i.e. lifestyle) trumps everything. Quitting smoking, keeping a healthy weight, and maintaining a vigorous exercise routine, amongst other things, may have gone a long way towards preventing many of these deaths. Although firefighting presents many unique challenges to staying healthy (e.g. schedules that disrupt sleep patterns, exposure to heat stress), the comparisons to healthy FFs, as well as those who died from trauma, show that smoking and hypertension play a huge role in raising the risk of cardiac death.

Second, we need to prepare for cardiac arrest in firefighters. The unique nature of the fireground, as well as the obstacles that the clothing and equipment present, mean that departments need to practice their response to a "fallen" firefighter, aiming to start CPR and assess for a shockable rhythm as soon as possible. This requires special procedures, teamwork and practice. Watch these guys from Hilton Head FD run through a drill.

 


Be safe, and take care of your heart!