Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.

Also posted over at Paramedicine 101. Go check out the rest of what is there.

This study has received a lot of attention. I will interchangeably use the terms the IV (IntraVenous) group and the epinephrine group depending on the terminology I think is more relevant at the time. The distinction is not one that I believe is important. This is a study of IV medication in cardiac arrest. Epinephrine is the stated focus of the study.

There has never been any evidence to suggest that medication leads improved resuscitation outcomes. Unless your idea of an improved resuscitation outcome has nothing to do with quality of life.

Beneficial short-term effects of epinephrine have been shown in animal studies,3-5 but there is increasing concern for increased myocardial dysfunction6,7 and disturbed cerebral microcirculation after cardiac arrest.8[1]

Some people argue that the short-term effects are important. If we do not get a pulse back, we will not resuscitate anyone. This is true, but the problem is how much long-term damage do we inflict just to obtain that short-term improvement?

High-dose epinephrine is no longer recommended, even though it was better than standard-dose epinephrine at producing ROSC (Return Of Spontaneous Circulation). The current recommendation for epinephrine is based on this same misconception. More ROSC = better outcomes – except that the dogma is not supported by any evidence.

CONCLUSIONS–High-dose epinephrine (HDE) significantly improves the rate of return of spontaneous circulation and hospital admission in patients who are in prehospital cardiac arrest without increasing complications. However, the increase in hospital discharge rate is not statistically significant, and no significant trend could be determined for neurological outcome. No benefit of NE compared with HDE was identified. Further study is needed to determine the optimal role of epinephrine in prehospital cardiac arrest.[2]

That study was 17 years ago. That was far from the first study of epinephrine. There has been many studies of epinephrine in cardiac arrest since then.

We still do not have any research to show improved outcomes with any dose of epinephrine to treat cardiac arrest, but rather than admit that epinephrine should only be used in well controlled studies, we continue to make excuses. We are practicing alternative medicine, not real medicine.

Absence of evidence of benefit does not mean an absence of benefit, but when does it become enough evidence to insist that we stop using this ineffective and potentially harmful drug as the standard treatment?

Back to the current study.

Because there are no randomized controlled studies showing improved survival to hospital discharge with any drugs routinely administered during CPR, we concluded such a study was warranted.[1]

This study is possible because these researchers are outside of the US. In the US, the IRBs (Institutional Review Boards) seem to have concluded that it is unethical to deviate from the standard treatment, even if the standard treatment is harmful. Of course, we can never learn if the standard treatment is harmful, or even if it is beneficial, if we are prohibited from studying the treatment. However, the IRBs’ definition of ethics seems to have been arrived at while consuming hallucinogens and reading Lewis Carroll.

Epinephrine in cardiac arrest is also firmly established outside of the US. Here is a part of their explanation of the study design.

In this prospective, randomized controlled trial of intravenous drug administration during out-of-hospital cardiac arrest, we compared outcomes for patients receiving standard ACLS with intravenous drug administration (control) and patients receiving ACLS without intravenous drug administration (intervention).[1]

ACLS is Advanced Cardiac Life Support – almost all of the treatments that would be given in the ED (Emergency Department). Not giving the drug is the intervention. Giving the drug is considered the non-intervention – the control against the effects of the treatment, which is the non-treatment.

Defibrillation was attempted in more patients in the intravenous group compared with the no intravenous group (47% vs 37%, respectively; OR, 1.16 [95% CI, 0.74-1.82]). More defibrillation shocks were delivered to those who received defibrillation in the intravenous group compared with the no intravenous group (median, 3 [range, 1-22] vs 2 [range, 1-26], respectively; P = .008). Both groups had adequate and similar CPR quality with few chest compression pauses (median hands-off ratio, 0.15 for the intravenous group and 0.14 for the no intravenous group) and the compression and ventilation rates were within the guideline recommendations (Table1).[1]

While there were no apparent differences in the quality of CPR, the more frequent defibrillations might be worth looking at. One of the important aspects of this study, as opposed to most prehospital research, is the recognition of a need to control for quality.

The explanation for the more frequent defibrillations that seems most likely is that the epinephrine produced a shockable rhythm more often than CPR alone produced a shockable rhythm. Since a shockable rhythm appears to be the next best thing to ROSC, this would not be a surprise. Many patients will change from a shockable rhythm to asystole when defibrillated. Defibrillation is a profound vagal stimulus and asystole is the ultimate vagal state. Even with similar initial rates of shockable rhythms, some of both groups would be expected to be shocked into asystole. The epinephrine, being a huge cardiac stimulus, would be expected to lead to a return of a shockable rhythm more often than just CPR. In other words, if the epinephrine is expected to produce ROSC more often, it should also produce a shockable rhythm more often. The authors came to a similar conclusion.

Without differences in the predefined primary outcome, patients in the intravenous group received more defibrillations, were resuscitated for a longer period, and more frequently had ROSC. With similar and adequate CPR quality, this is likely due to the pharmacological effects of the drugs used (epinephrine, atropine, and/or amiodarone). This finding is consistent with previous animal studies with epinephrine,6,7 and clinical studies evaluating the effects of amiodarone,23 atropine,24 and even high-dose epinephrine,25 all of which documented improved short-term effects without improving long-term outcomes.[1]

One major criticism of the methods is that they did not have a placebo to be given to keep the EMS crews blinded to the actual treatment. The authors do admit that this is a limitation. Of course, this placebo would probably not be called a placebo, since the epinephrine arm is the placebo arm, while the non-treatment arm is the active intervention arm, but that is really only an amusing problem of terminology and attitude. When the epinephrine group is the group with an IV line in place during resuscitation and the no epinephrine group is the one that does not have an IV until after return of pulses, there is not even an attempt at blinding. Did this lead to any detectable difference in the way patients were treated by EMS, other than other than the differences intended by the study design?

Our study has several limitations. First, ambulance personnel could not be blinded to the randomization. Closely related to this, only patients who were randomized to the no intravenous group could be monitored with regard to protocol compliance. If intravenous drugs were administered to a patient in the no intravenous group, violation of the study protocol could be documented. If intravenous drugs were not administered to a patient in the intravenous group, several valid reasons could exist, such as rapid ROSC. We have no reason to believe that personnel refrained from establishing intravenous access under the pretense that the procedure was unsuccessful. The ambulance personnel involved were strongly committed to testing the hypothesis presented, but we cannot totally rule out possible bias toward procedures such as intravenous access and administration of drugs, which have been important in Norwegian culture for decades.[1]

This is a reason for creating a sham drug to use for the study. Without knowledge of the contents of the syringes being used, any bias of the treating medics should not affect the results. That is the purpose of blinding.

Analysis was performed on an intention-to-treat basis regardless of which treatment was actually given.[1]

In the No IV group, 10% received IV drugs. 9% of patients received epinephrine.

In the IV group, 82% received IV drugs. 79% of patients received epinephrine.

Why did some of the No IV patients receive epinephrine, or any drug? Clearly a protocol violation. I tripped and the IV landed in the patient, is not a valid explanation.

Why did 21% of the IV group not receive epinephrine? That is not clearly explained by the authors. Were these patients resuscitated prior to initiation of an IV and administration of epinephrine?

CPR and defibrillation are indicated before drugs. Since both CPR and defibrillation have research showing that they improve the long-term outcome from cardiac arrest, it is not unreasonable to expect that cases of ROSC with only CPR and defibrillation will be the reason for some patients not receiving epinephrine.

One of the perversions of a requirement that epinephrine be given in cardiac arrest is that the 1 mg bolus dose of epinephrine, repeated every 3 to 5 minutes, is never to be given to a patient with a pulse – Never. The reason is that epinephrine is so toxic to the heart, that it could be expected to produce cardiac arrest.

There are people criticizing this study because not all of the patients in the IV group received epinephrine. They see this as a bias. Contrariwise, I see their objection as just looking for any excuse to complain about research results they do not like, even though the study’s results are consistent with all of the other research that has been done. The critics fail to consider that some patients will be resuscitated prior to the point in the algorithms where drug administration is indicated. Their apparent demand that patients resuscitated prior to epinephrine administration be given epinephrine, even though the patient is no longer in cardiac arrest, is silly.

This would also not be likely to do anything to improve outcomes in the epinephrine group. The patients resuscitated prior to epinephrine administration are likely to be the patients with the briefest periods of cardiac arrest and therefore maybe the patients with the best potential for good outcomes. Returning them to a cardiac arrest, by means of epinephrine, just to follow an algorithm, would not be a good thing and it would probably have a dramatic negative effect on the survival of the patients in the epinephrine group.

The standard dose of epinephrine for a patient with a pulse, but not in cardiac arrest, is 2 mcg/minute to 10 mcg/minute. The standard dose of epinephrine for a patient without a pulse, but in cardiac arrest, is 1,000 mcg fast push every 3 to 5 minutes. I do not know of any medical professional, or any medical organization, or any medical reference, that recommends giving a living human being the dose of epinephrine that we only give to dead patients, and repeating it every 3 to 5 minutes. I would not be surprised at murder charges if the patient were to die soon after receiving this treatment that is given indiscriminately to dead patients.

Unless we can predict which patients, if any, will benefit from epinephrine, we need to find a better way to prevent giving epinephrine to the patients who will be harmed by epinephrine. If we cannot do that, we need to admit that we do not have any basis for using epinephrine in cardiac arrest.

Until there is research to show any benefit from epinephrine in cardiac arrest, we should eliminate epinephrine from all cardiac arrest treatment algorithms that are not part of well controlled studies.

Correction posted 3/07/2010 in Correction on Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.


^ 1 Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L.
JAMA. 2009 Nov 25;302(20):2222-9.
PMID: 19934423 [PubMed – in process]

If you want to read the entire study, this link opens it in PDF.

^ 2 A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest.
Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J.
JAMA. 1992 Nov 18;268(19):2667-72.
PMID: 1433686 [PubMed – indexed for MEDLINE]

Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, & Wik L (2009). Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA : the journal of the American Medical Association, 302 (20), 2222-9 PMID: 19934423



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