No difference in epi survival.

[Melclin]

RCT from Australia showing no statistically significant improvement in survival to discharge.

This is pretty damning right? So what now? The adrenaline still showed a pretty considerable improvement in ROSC. Will this be enough to save its place in the arrest algorithm?


http://www.resuscitationjournal.com/article/S0300-9572(11)00405-9/fulltext

 

[MrBrown]

A very well designed study and even if the numbers of patients actually enrolled was small (slightly more than 500) Brown thinks the results extrapolate very well.

This basically proves what we have known for the last twenty years - that adrenaline is sort of helpful sort of not because it increases ROSC but doesn't have a significant impact on survival to hospital discharge.

Without significant compelling negative evidence Brown thinks adrenaline will be around untill at least 2015 as its proven ability to increase ROSC seems to infer an emperical benefit.

It is interesting to note that WA Intensive Care Paramedics still like to intubate their cardiac arrests in the majority of cases over using the laryngeal mask airway. Brown would say the opposite is true here, well maybe somewhere left of opposite but becoming moreso.

 

[systemet]

There's a similar study out of Norway as well.

-------------------------------------------------------------------------




Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L.
Source

Institute for Experimental Medical Research, Oslo University Hospital, Ullevaal, N-0407 Oslo, Norway. t.m.olasveengen@medisin.uio.no
Abstract
CONTEXT:

Intravenous access and drug administration are included in advanced cardiac life support (ACLS) guidelines despite a lack of evidence for improved outcomes. Epinephrine was an independent predictor of poor outcome in a large epidemiological study, possibly due to toxicity of the drug or cardiopulmonary resuscitation (CPR) interruptions secondary to establishing an intravenous line and drug administration.
OBJECTIVE:

To determine whether removing intravenous drug administration from an ACLS protocol would improve survival to hospital discharge after out-of-hospital cardiac arrest.
DESIGN, SETTING, AND PATIENTS:

Prospective, randomized controlled trial of consecutive adult patients with out-of-hospital nontraumatic cardiac arrest treated within the emergency medical service system in Oslo, Norway, between May 1, 2003, and April 28, 2008.
INTERVENTIONS:

Advanced cardiac life support with intravenous drug administration or ACLS without access to intravenous drug administration.
MAIN OUTCOME MEASURES:

The primary outcome was survival to hospital discharge. The secondary outcomes were 1-year survival, survival with favorable neurological outcome, hospital admission with return of spontaneous circulation, and quality of CPR (chest compression rate, pauses, and ventilation rate).
RESULTS:

Of 1183 patients for whom resuscitation was attempted, 851 were included; 418 patients were in the ACLS with intravenous drug administration group and 433 were in the ACLS with no access to intravenous drug administration group. The rate of survival to hospital discharge was 10.5% for the intravenous drug administration group and 9.2% for the no intravenous drug administration group (P = .61), 32% vs 21%, respectively, (P<.001) for hospital admission with return of spontaneous circulation, 9.8% vs 8.1% (P = .45) for survival with favorable neurological outcome, and 10% vs 8% (P = .53) for survival at 1 year. The quality of CPR was comparable and within guideline recommendations for both groups. After adjustment for ventricular fibrillation, response interval, witnessed arrest, or arrest in a public location, there was no significant difference in survival to hospital discharge for the intravenous group vs the no intravenous group (adjusted odds ratio, 1.15; 95% confidence interval, 0.69-1.91).
CONCLUSION:

Compared with patients who received ACLS without intravenous drug administration following out-of-hospital cardiac arrest, patients with intravenous access and drug administration had higher rates of short-term survival with no statistically significant improvement in survival to hospital discharge, quality of CPR, or long-term survival.
TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00121524.

 

[medicsb]

i don't think there is actually enough to debunk the idea that epi is beneficial for cardiac arrest.

Of course, it is pretty much definitive that epi increases ROSC and hospital admission. No one has been able to show a statistically significant increase in survival to discharge, BUT in both studies, survival to discharge DID increase. Unfortunately, both studies were underpowered.

But, what is the probability that epi/acls would would trend better on survival to discharge in both studies for all rhythms combined, VF/VT, and non-VF/VT? Because, if it was really up to "chance", one would expect the frequency of epi being better to be roughly 50/50. But, with the exception of non-VF/VT in the norwegian study, epi was better. The chance of epi being better by chance for the all rhythms combined, VF/VT, and non-VF/VT for both studies is 3.125%, according to my calculations.

If the percentages in the WA study were to have stayed the same, the differences would have been statistically significant around 4-500 patients in each arm.

More research is needed, but I think it might actually work.

 

[systemet]

We could do a crude meta-analysis for survival to discharge

Study Drugs No drugs

Jacobs 11 / 272 5 / 262
Olasveengen 44 / 418 40 / 433

Meta 55/690 (7.97%) 45/695 (6.47%)

I get P = 0.25 (uncorrected), with a chi-squared but I might have messed up the math. Possibly hilariously.

 

[medicsb]

I did 2x2 chi-square analysis and found a similar p value, so I don't think you are far off.

 

[Smash]

It's a pity that political BS stopped this from being a proper multi-centre trial as it was intended. It also would have been interesting to see what would have happened if the trial had enrolled some more numbers to power it better. Personally I still think that epi as a blanket drug per ACLS is a waste of time. There may be some sub-groups who it will provide some benefit to, but unless they are identified there is no point in keeping the earthworms up at night.

 

[Smash]

Actually, I have to change my tune there. Epi is a very useful drug. It makes me look busy at an arrest, and saves me from having to do to much CPR - "You just carry on there, make sure you swap every two minutes. I just have to draw up some more of this very important drug to give... somebody get me a chair please. And a flat white, one sugar."

 

[silver]

Doubtful that epi will be removed, rather more agressive post-arrest therapies will probably arise in the future.

 

[Shishkabob]

Huge increase in ROSC (nearly 3x as many), which, hate to sound like a broken record in all these, but you can't have survival without ROSC. Just need to find out how to maintain the pulse after it's regained. Many pieces to the puzzle, and we're gaining ground on it.

The missing link, I believe, is post arrest management. Hypothermia is pushing us in that direction, but obviously have further to go.




As far as CPC goes, I'm willing to bet if we found something that caused systemic constriction, but not cerebral constriction, you'd see a better CPC rate on discharges.

 

[mycrofft]

This thread is motivating me to get a DNR tattoo

Speaking allegorically of the state of the art right now, the "leaving the scene with a pulse" curve has overtaken the "got enough residual myocardium, or brain, left to bother with" curve. This can indicate a breakthrough in after-scene care is necessary (even if it is to discover something different to do on scene that will facilitate after-scene care), or it can indicate that there is an absolute statistical barrier where a percentage of total arrests are not going to survive no matter what. Finger of Diety and all that.

 

[Melclin]

Huge increase in ROSC (nearly 3x as many), which, hate to sound like a broken record in all these, but you can't have survival without ROSC. Just need to find out how to maintain the pulse after it's regained. Many pieces to the puzzle, and we're gaining ground on it.

The missing link, I believe, is post arrest management. Hypothermia is pushing us in that direction, but obviously have further to go.




As far as CPC goes, I'm willing to bet if we found something that caused systemic constriction, but not cerebral constriction, you'd see a better CPC rate on discharges.

I've made a similar point before discussing adrenaline.

The question of whether or not adrenaline can be used to temporise a pt until we fix them with good post ROSC care is not an unreasonable one in my mind. If we improved our post ROSC care, would it turn into improved ROSC into improved survival to discharge?

Or are we just reanimating corpses?

Is there a sub group of people who will really benefit from adrenaline but they get lost in the mix of a study that has decent numbers but is ultimately underpowered because it includes too many corpses to notice the difference?


I think we need a lot more information about sub groups of cardiac arrest patients. Who is a viable arrest and who isn't. Who would benefit from what therapies and when, rather than sledge hammer therapies like epi for all. Might be a long time in the making though.

 

[systemet]

The trouble with ROSC as an indicator of anything is we've known for years that we can increase it with very high doses of epinephrine. It just doesn't translate into survival to discharge.

We have clear evidence that CPR, defibrillation, early recognition, etc. work.

I agree that there's definitely a possibility that a subgroup of patients exist who might benefit from epinephrine or antiarrhythmics. We may just be hiding them by throwing in a bunch of no-hopers in the analysis.

I think, though, that there's a certain reality that if you're investing time and effort in cardiac arrest survival it's better used providing more bystander CPR, greater PAD coverage, quicker first response, etc.

Regarding cerebral vasoconstriction -- if we were able to somehow prevent this, or perhaps inject an alpha-antagonist into the CNS, it might help. But a lot of the problem with epinephrine is probably related to increased cardiac irritability, increased afterload, post resuscitation myocardial dysfunction, and infarct extension. So, these concerns also have to be addressed.

I guess the good thing that comes from these studies is we now have some evidence supporting epinephrine not being particularly harmful. It would have been embarrassing if the no-drugs cohort came out showing a significantly better survival, and we had to face that decades of resuscitation medicine had been making the problem worse.

[Of course, just as we're sitting here saying there's a subgroup that might benefit from epinephrine, so exists the potential that we're concealing a negative effect for a subgroup that might be harmed.]

I would be interested in seeing if lower doses of epinephrine were beneficial. I mean, when you look at what we're doing, an epinephrine infusion is 2-10ug/min. We're giving epinephrine (even 1mg q5) at 20-100 X that dose. Granted the distribution of epinephrine is much slower in an arrest state, and with acidosis it's less effective. But it's not hard to see how this could be dangerous. We wouldn't typically take a 70kg pre-arrest patient and bolus inject 70 mg of dopamine, for example, and expect good things to happen.

I wonder if the barrier for ALS now isn't just technology. Our issue seems to be supporting the circulation. We know we can improve outcomes with good CPR. We know that pharamcology does very little. Perhaps we just need some rocket surgeon to build some form of portable circulatory support device that can be used to augment CPR?

While I'm rambling wildly -- I seem to remember hearing about a study in Australia around 2000, where the paramedics were going to insert some sort of plunger device to directly compress the heart, and do direct defibrillation. Obviously this didn't turn out well, or we'd have heard about it -- but does anyone have any information or citations for it?

---------------------------------------





N Engl J Med. 1998 Nov 26;339(22):1595-601.
A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group.
Gueugniaud PY, Mols P, Goldstein P, Pham E, Dubien PY, Deweerdt C, Vergnion M, Petit P, Carli P.
Source

Department of Anesthesiology and Emergency Medical System, Edouard Herriot Hospital, Claude Bernard University, Lyons, France.
Abstract
BACKGROUND:

Clinical trials have not shown a benefit of high doses of epinephrine in the management of cardiac arrest. We conducted a prospective, multicenter, randomized study comparing repeated high doses of epinephrine with repeated standard doses in cases of out-of-hospital cardiac arrest.
METHODS:

Adult patients who had cardiac arrest outside the hospital were enrolled if the cardiac rhythm continued to be ventricular fibrillation despite the administration of external electrical shocks, or if they had asystole or pulseless electrical activity at the time epinephrine was administered. We randomly assigned 3327 patients to receive up to 15 high doses (5 mg each) or standard doses (1 mg each) of epinephrine according to the current protocol for advanced cardiac life support.
RESULTS:

In the high-dose group, 40.4 percent of 1677 patients had a return of spontaneous circulation, as compared with 36.4 percent of 1650 patients in the standard-dose group (P=0.02); 26.5 percent of the patients in the high-dose group and 23.6 percent of those in the standard-dose group survived to be admitted to the hospital (P=0.05); 2.3 percent of the patients in the high-dose group and 2.8 percent in the standard-dose group survived to be discharged from the hospital (P=0.34). There was no significant difference in neurologic status according to treatment among those discharged. High-dose epinephrine improved the rate of successful resuscitation in patients with asystole, but not in those with ventricular fibrillation.
CONCLUSIONS:

In our study, long-term survival after cardiac arrest outside the hospital was no better with repeated high doses of epinephrine than with repeated standard doses.
Comment in

N Engl J Med. 1999 Jun 3;340(22):1763-4; author reply 1765.
N Engl J Med. 1999 Jun 3;340(22):1764; author reply 1765.

PMID:
9828247
[PubMed - indexed for MEDLINE]

Free full text

 

[Melclin]

Regarding cerebral vasoconstriction -- if we were able to somehow prevent this, or perhaps inject an alpha-antagonist into the CNS, it might help. But a lot of the problem with epinephrine is probably related to increased cardiac irritability, increased afterload, post resuscitation myocardial dysfunction, and infarct extension. So, these concerns also have to be addressed.

I guess the good thing that comes from these studies is we now have some evidence supporting epinephrine not being particularly harmful. It would have been embarrassing if the no-drugs cohort came out showing a significantly better survival, and we had to face that decades of resuscitation medicine had been making the problem worse.

[Of course, just as we're sitting here saying there's a subgroup that might benefit from epinephrine, so exists the potential that we're concealing a negative effect for a subgroup that might be harmed.]

I would be interested in seeing if lower doses of epinephrine were beneficial. I mean, when you look at what we're doing, an epinephrine infusion is 2-10ug/min. We're giving epinephrine (even 1mg q5) at 20-100 X that dose. Granted the distribution of epinephrine is much slower in an arrest state, and with acidosis it's less effective. But it's not hard to see how this could be dangerous. We wouldn't typically take a 70kg pre-arrest patient and bolus inject 70 mg of dopamine, for example, and expect good things to happen.

I wonder if the barrier for ALS now isn't just technology. Our issue seems to be supporting the circulation. We know we can improve outcomes with good CPR. We know that pharamcology does very little. Perhaps we just need some rocket surgeon to build some form of portable circulatory support device that can be used to augment CPR?

While I'm rambling wildly -- I seem to remember hearing about a study in Australia around 2000, where the paramedics were going to insert some sort of plunger device to directly compress the heart, and do direct defibrillation. Obviously this didn't turn out well, or we'd have heard about it -- but does anyone have any information or citations for it?

When I was writing an essay on this at uni, I began to wonder why we didn't use norad. I've since heard they tried it and it didn't work or some such, but in any case the question still remains as to why there hasn't been more work done with selective adrenergic agents or beta blockers. On consultation with the cardiac arrest bible, "cardiac arrest: science of practice" (I love this book), it tells me that they had some success with alpha methylnoradrenaline in animal models in the way that you would expect, all the benefits of peripheral constriction, without the myocardial dysfuntion and subsequent arrythmias. That paper (1) was from 2001 and I've not be able to find anything published subsequently and alpha-MNE is not commercially available.



Portable ECLS? A recent paper in resuscitation provided a case study (2), two I think, but I can't seem to find the second one. I don't have full text access because I am a uni student no more, but it sounds like they had a remarkable recovery in every other aspect other than profound hypoxic brain injury. Maybe some massively simplified version will have a place in 20 yrs. I sure would like to be the guy trialling that. It sounds like fun.

1. http://content.onlinejacc.org/cgi/content/figsonly/37/3/951
2. http://www.sciencedirect.com/science/article/pii/S0300957211002334

 

[systemet]

When I was writing an essay on this at uni, I began to wonder why we didn't use norad. I've since heard they tried it and it didn't work or some such, but in any case the question still remains as to why there hasn't been more work done with selective adrenergic agents or beta blockers. On consultation with the cardiac arrest bible, "cardiac arrest: science of practice" (I love this book), it tells me that they had some success with alpha methylnoradrenaline in animal models in the way that you would expect, all the benefits of peripheral constriction, without the myocardial dysfuntion and subsequent arrythmias. That paper (1) was from 2001 and I've not be able to find anything published subsequently and alpha-MNE is not commercially available.

There's these two papers, one also in rat [1] and another in pig [2], from the same group. Obviously not a good LOE. Especially consider the rat heart had substantially different electrophysiology with a heart rate of 400, and a very short phase 2. It doesn't look like anyone's done human trials.

I think part of the proposed mechanism of epinephrine is that it increases SVR via alpha-1 agonism, and improves coronary perfusion pressures. So alpha-2 action would oppose this. [Although I guess it could be argued that alpha-1 receptors in the coronary vasculature cause unwanted coronary vasoconstriction].

There's also been comparison of norepinephrine (high dose) versus epinephrine (also high dose), to see if the beta-1 action is more or less important. No difference [3].

It sounds like a good book. I almost had an MI when I saw how much a new copy costs on amazon.

[1]Klouche K, Weil MH, Sun S, Tang W, Zhao DH. A comparison of alpha-methylnorepinephrine, vasopressin and epinephrine for cardiac resuscitation. Resuscitation. 2003 Apr;57(1):93-100. http://www.ncbi.nlm.nih.gov/pubmed/12668305

[2]Klouche K, Weil MH, Tang W, Povoas H, Kamohara T, Bisera J.A selective alpha(2)-adrenergic agonist for cardiac resuscitation.J Lab Clin Med. 2002 Jul;140(1):27-34. http://www.ncbi.nlm.nih.gov/pubmed/12080325

[3] Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J.A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest.JAMA. 1992 Nov 18;268(19):2667-72. http://www.ncbi.nlm.nih.gov/pubmed/11693776

Portable ECLS? A recent paper in resuscitation provided a case study (2), two I think, but I can't seem to find the second one. I don't have full text access because I am a uni student no more, but it sounds like they had a remarkable recovery in every other aspect other than profound hypoxic brain injury. Maybe some massively simplified version will have a place in 20 yrs. I sure would like to be the guy trialling that. It sounds like fun.

Yeah, I realise we have another thread on this elsewhere. But it got me thinking. If drug don't work, but optimising CPR does, then it seems like there's got to be a better way of delivering circulatory support. It doesn't seem like the automated CPR devices are capable of doing that yet.

 

[Smash]

Vasopressin has been tried and found wanting. Ditto with adding beta-blockers to the mix to offset the harmful beta effects of epi. Maybe we just need to throw away the drugs altogether and concentrate on post-arrest care bundles.

I know, then we wouldn't look busy at codes, and we wouldn't be driving to hospital with husks in the back as often, and then where would we be.

The argument that more ROSC is good because it let's us get them to hospital is clearly fundamentally flawed, as it has been shown time and time again that ROSC does not equal survival irrespective of what happens at hospital. And ROSC without survival is not really an outcome at all.

 

[mycrofft]

ROSC and etiological statistical populations/adrenaline puppet strings

What slice of the pie chart for "clinically dead on scene" is due to non-cardio-circulatory-disease events? How about electrocution, poisoning, drowning/suffocation, traumatic shock, brainstem insult, hypothermia, and other etiologies which may present with clinical death but for which the CPR-AED-ACLS treatment pathway is not well-geared, or conversely for which adrenaline and CPR-AED are exactly what is needed until they either sit up, or get to a hospital for some ICU time? (Note the aspect of ageism here, the older you are the less likely your clinical death is to be due to the preceding causes).

(What if you ran across someone with atrial fibrillation or WPW Syndrome who coded who was undetecable via field EKG, how would epineph affect their outcomes? A-Fib is being recognized increasingly since it is now watched for as a potential etiology for embolic CVA).

Adrenaline as puppet strings: Galvan said we could reanimate dead people (and frogs and chickens) through electric stimulation. Later, and you can ask Mrs Hawkins or Ms Henrietta Lacks, we said that properly supported tissues (and, so, organs) could reassume their intrinsic functions. Neither proved strictly correct. It's a good thing to question whether jolting everyone with epi and defib into a semblance of survival will set the stage for definitive resuscitation.

 

[awildstein]

Yes, epi does increase ROSC greatly. However, this doesn't mean we just need better post resuscitation care as the epi may behind the post rescus cardiac dysfunction..

Take a look at the attached article. This one is definitely worth reading in full. It address the clinical pharmacology, studies, all that good stuff

 

[systemet]

Yes, epi does increase ROSC greatly. However, this doesn't mean we just need better post resuscitation care as the epi may behind the post rescus cardiac dysfunction..

Take a look at the attached article. This one is definitely worth reading in full. It address the clinical pharmacology, studies, all that good stuff

Great link! Thanks!

 

[Melclin]

It sounds like a good book. I almost had an MI when I saw how much a new copy costs on amazon.

Its golden. Its a good read too. Well written in that way where you find yourself getting lost in the topics and you check your watch to find you've missed your dentists appointment. I picked up a second hand copy for $60 that was brand new. Stoked.

Yes, epi does increase ROSC greatly. However, this doesn't mean we just need better post resuscitation care as the epi may behind the post rescus cardiac dysfunction..

Nice. Cheers for that.