July 19, 2018

expert reaction to trial looking at adrenaline for cardiac arrests

Scientists publishing in the NEJM report that using adrenaline in cardiac arrests results in less than 1% more people leaving hospital alive – but nearly doubles the survivors’ risk of severe brain damage.

A briefing accompanied this roundup.

Prof Sir Nilesh Samani, Medical Director, British Heart Foundation (BHF), said:

“These results will have a major impact on the way cardiac arrests are treated around the world.

“Using adrenaline to treat people after a cardiac arrest was based on sound reasoning, but not on robust evidence.  It’s incredibly hard to carry out research on people whose life is hanging in the balance, but these new findings emphasise the importance of such research in identifying both benefits and harms.

“There are over 30,000 out of hospital cardiac arrests every year in the UK, but sadly less than 1 in 10 people survive.”

Prof Sam Parnia, Associate Professor of Medicine, Director of Critical Care & Resuscitation Research, Division of Pulmonary, Critical Care and Sleep Medicine, New York University Langone Medical Center, said:

“This is a fascinating study that highlights a number of key challenges in resuscitation science.

“Firstly, without the use of adrenaline it is clear that there is almost no chance of survival. Therefore, this study clearly supports the need for the use of adrenaline. Only 8% of those without adrenaline had their hearts restarted, compared to 36%. This illustrates the main beneficial effect of adrenaline – ie to allow clinicians to increase the chance of successfully restarting the heart, without which death is certain. Adrenaline use was also associated with almost 50% chance of survival compared to it not being used.

“Adrenaline is not the treatment choice for preservation of brain function after cardiac arrest. The ability to keep people alive and without brain damage after the heart has been restarted falls on the care received in the intensive care units and not so much the adrenaline given before the heart had been restarted. The effect of a single standard 1mg dose of adrenaline is largely lost from the human body within 3-5 minutes, and considering that the median dose of  adrenaline was 5 mg – which equates to 5 doses – then this suggests any observed brain injury is occurring not from the adrenaline (which would have been washed out) but actually from events that had occurred after patients had arrived in the hospitals. Studies have shown that brain damage largely occurs in the first 24-72 hours after the heart has been restarted and patients taken to hospitals.  This is largely due to the effects of reperfusion injury, which takes place when oxygen is added back to the brain after it has been deprived of this.  Although many therapies have been recommended by national and international medical bodies to limit this injury process, they are often not adhered to and are not regulated or standardized. Therefore among those who initially survive and have their hearts restated, 2/3 routinely die subsequently in the hospital. Many also end up with brain damage. This could be improved greatly with higher adherence to medical recommendations.

“The main limitation of this study was that it did not take into account differences in what is now termed post-resuscitation treatment in the two groups. This relates to the treatments received during the first 24-72 hours after the heart has been restarted. This is the main factor that leads to the ability to save the brain and limit brain injuries. Since adrenaline leads to more initial survivors, then without adequate post-Resuscitation treatment it may be possible to see a slightly higher rate of brain injuries in those initial survivors. However, without a study that incorporates the effects of post Resuscitation treatments, it is hard to agree with the assumption that adrenaline itself is leading to increased brain injuries.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“The study seems well conducted and analysed.  Adrenaline saves a small number of people who survive relatively well (possibly about 6 per thousand, although this was not statistically different from those who survived well without adrenaline, but the study may not have been sufficiently powered to detect that).  However, the improvement in survival also occurs among a group who survive with major disability, possibly because brain damage has occurred prior to resuscitation.  This latter group would die, probably before reaching hospital, without adrenaline.  So in my view it isn’t that adrenaline increases the risk of disability, it just improves survival in both groups and so among the survivors there is an excess of disability.  Would I want adrenaline?  Yes if I am in the group with no disability, but probably not if I am in the group with disability.  Perhaps one day it will be possible to predict the disability but it doesn’t seem possible now.”

Dr David Nunan, Senior Researcher at the Centre for Evidence Based Medicine, University of Oxford, said:

“Every now and then scientific research produces landmark findings.  This is one of those occasions.

“At the core of evidence-based practice is ensuring the treatments we give to patients provide more benefit than harm.  It may come as a surprise that for many treatments we simply do not know whether they do more good than harm.  One such treatment is the practice of giving adrenaline to patients whose hearts have stopped.

“The need to do this research was underpinned by a serious concern that although using adrenaline might help restart the heart in the short term, it may cause severe brain damage leading to death a few hours or days later.

“There are challenging ethical issues in performing a clinical trial of this nature because patients in cardiac arrest are unable to consent to participating before being enrolled.  However, given the uncertainty of the evidence and the life-threatening nature of the condition being treated, it is important that we have the best evidence we can to provide the best treatment possible.

“Despite some limitations, this is a well-conducted study providing the highest-quality evidence about a long standing yet untested treatment in medical practice.  The study found that if we give adrenaline to 1000 people whose hearts have stopped, 9 more people will be alive after 30 days.  However, the risk of serious brain damage in people who are able to return home is almost doubled if they are given adrenaline.  We now have a decision to make about the small survival benefit versus the large increased risk of debilitating brain damage when giving adrenaline.

“The funders, researchers, health professionals and participants (and their families) who gave consent should all be praised for their roles in this important research.  The practice of giving adrenaline to someone in cardiac arrest has been the standard of care for nearly 60 years.  Make no mistake, the results of this landmark trial will change the way people are treated if, unfortunately, their heart should stop.”

Prof Mark Wilson, Clinical Professor specialising in Brain Injury at Imperial College London, said:

“This is a landmark paper investigating the long held practice of giving adrenaline in cardiac arrest.  It demonstrates that whilst it helps restore cardiac function, it may be doing this at the expense of neurones.  As highlighted by the authors, other elements of the chain of survival (early recognition of cardiac arrest, early CPR, early AED use) are more effectual at restoring cardiac output whilst maintaining good neurological outcome.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This is a good, carefully conducted and analysed clinical trial.

“This trial considered only patients whose hearts had stopped beating, not in a hospital, and for whom initial attempts at resuscitation (CPR, defibrillation with electric shocks) had not succeeded.  Such patients are certainly very ill.  The trial results make it clear that adrenaline is far from a wonder cure for such patients.  The report points out that interventions that the general public can learn to carry out, like recognising cardiac arrest, performing CPR or using a defibrillator can have much bigger effects on the patient’s chances of surviving than giving them adrenaline.  That’s important to know.

“It might clarify the trial’s findings to look at some numbers.  Suppose there are 200 patients whose hearts have stopped and for whom initial resuscitation effects have failed.  If they all are treated with adrenaline, and respond as in the trial, about 6 of the 200 would survive until they left hospital.  Of these 6, about 4 would leave hospital with what the trial defines as a ‘favourable neurological outcome’, and the other 2 survivors would have ‘severe neurological impairment’, that is, severe brain damage.  If the 200 had not been treated with adrenaline, about 5 would survive until they left hospital, again about 4 would leave with a favourable neurological outcome, and 1 of the survivors would have severe brain damage.  The trial can’t tell us whether the 4 who would survive without severe brain damage if they get adrenaline are the same people as the 4 who would survive without severe brain damage if they don’t get adrenaline, but the point is that the numbers are about the same.  (I’ve had to calculate these as numbers out of 200 patients rather than the more usual 100, because, unfortunately, the chances of survival of people this ill are very low.)

“Do these results mean that the question of whether adrenaline should be used has been answered by this trial, and that it should simply not be used in these circumstances?  It’s still not entirely clear, I’d say, and that’s in line with the statement by the lead author that the findings “will require careful consideration” by those concerned, including the wider community.  The trial did find that more patients survived if they were given adrenaline, and that difference was statistically significant.  But the difference was small – less than one percentage point.  (Relative to the survival rate in patients receiving a saline solution placebo, the survival rate in patients who had adrenaline was more than one third higher, but that’s not really the issue – a third of a low survival rate is still a very small difference.)  The chance of surviving without severe brain damage was statistically indistinguishable between patients who had adrenaline and patients who received a placebo, and that’s why it’s particularly important to look at the chances of severe brain damage in survivors.  It would be a bit less important, in my view, if the survival rates in people who received adrenaline had been much higher than those in people getting placebo.  The researchers explain how there can be a small difference in survival rates overall, but no difference for survival without severe brain damage, by pointing to the higher proportion of patients who survive with severe brain damage in the group who received adrenaline.

“However, is it clear what potential patients and their relatives would feel about surviving a cardiac arrest with what is described in this trial as ‘severe neurological impairment’?  Obviously the patients can’t be asked at the time of treatment.  ‘Severe neurological impairment’ does include being in a state where one is bedridden and incontinent, requiring constant nursing care, though people like that aren’t all in a ‘vegetative’ state.  I’m pretty sure that I wouldn’t want to survive a cardiac arrest in that condition – some others would have a different view.  But ‘severe neurological impairment’ also includes what is described on the scale used by the researchers as ‘moderately severe disability’, where the patient cannot attend to their own bodily needs without help, and cannot walk unassisted, but is not bedridden or incontinent or requiring constant care.  I’m not so sure what I feel about ending up in that state.  Is it worth being treated with adrenaline if it slightly increases one’s chances of surviving, even if one might only survive in a state of considerable disability?  I think that’s a bit difficult to say, overall.  Definitely a case for consideration by a wide range of people.  The researchers did involve members of the public who were interested in first aid in designing their study, and, not surprisingly, they thought that long term survival without brain damage was the most important outcome.  But most patients like those in the trial simply can’t have that outcome, so the question of whether it’s preferable to survive with considerable brain damage, or alternatively not to survive at all, remains crucial.”

Prof Sian Harding, Professor of Cardiac Pharmacology, Imperial College London, said:

“Adrenaline has always been a double edged sword in cardiac resuscitation because of its known potential for cardiovascular damage.  This study confirms the marginal benefit and possible harms from emergency treatment, giving a basis for future guidelines.”

Prof Steve Goodacre, Professor of Emergency Medicine, University of Sheffield, said:

“For decades doctors and paramedics have wanted to know, what are the benefits and risks of giving adrenaline in cardiac arrest?  The PARAMEDIC2 trial gives us clear answers.  It is a large, robust, carefully undertaken study that randomly allocated patients to adrenaline or placebo.  This means that we can reasonably assume that any differences in outcome between patients receiving adrenaline and patients receiving placebo was due to the adrenaline rather than any other factors.

“The trial showed that patients have a very low chance of survival if their cardiac arrest hasn’t responded to initial treatment.  Adrenaline slightly increases their chance of survival but also increases the risk of surviving with brain damage.  The challenge now is how we use this information, since we can’t discuss risks and benefits with a patient who has had a cardiac arrest.  We need to consult the public to work out what most people would want in these dire circumstances.”

Prof Tim Chico, Professor of Cardiovascular Medicine and Honorary Consultant Cardiologist, University of Sheffield, said:

“This is a very important study in an area that is very challenging to research, and the team and the patients and their families involved should be congratulated.

“Many forms of cardiac arrest, if recognised and treated immediately are completely treatable; cardiology nurses in the UK save the lives of thousands of patients each year by immediately defibrillating patients with abnormal heart rhythms.

“Unfortunately, when a cardiac arrest happens to someone not in hospital, it can take too long for life saving treatment.  For every second such treatment is delayed, there is a lower chance of survival.  In this study of people who had a cardiac arrest when not in hospital, only around 2-3% of patients survived, mostly because it took so long for them to receive treatment.  Even if patients do survive, the interruption of blood flow to the brain often leaves them with brain damage that can be permanent and disabling.

“This study shows that a drug called Adrenaline (also called Epinephrine) given intravenously improves the chance of survival when given to patients who suffer a cardiac arrest when not in hospital.  Unfortunately, although it seems to stop some people dying, there was no evidence that it reduced brain damage in the survivors.  The numbers of people who suffered severe brain damage were higher in the adrenaline group although the chance of surviving to three months after the cardiac arrest with only a small amount of brain damage was not worsened by adrenaline.

“This is an important finding which suggests although adrenaline helps restart the heart it may not help protect the brain.  The study highlights the need to find ways to get CPR and defibrillation to cardiac arrest patients as quickly as possible.  I hope people reading about this study are inspired to learn how to do CPR (it’s very easy) because it is clear that bystander CPR is more effective than Adrenaline in saving lives.”

Prof David Spiegelhalter, Winton Professor for the Public Understanding of Risk, University of Cambridge, said:

“Very roughly, these results mean that out of every 250 patients given adrenaline, 8 survived, of which 2 had brain damage, whereas out of 250 not treated, 6 survived, and 1 had brain damage.  So there were two extra survivors per 250 people treated, but one of these had brain damage.  This seems very important when considering this treatment.”

* ‘A randomized trial of epinephrine in out-of-hospital cardiac arrest’ by G. D. Perkins et al. published in the New England Journal of Medicine on Thursday 19 July 2018.  

Declared interests

Prof Stephen Evans: “No conflicts.”

Prof Mark Wilson: “None to declare.”

Prof Kevin McConway: “I am a member of the SMC advisory committee.”

Prof Sian Harding: “No interests to declare.”

Prof Steve Goodacre: “I am chair of the NIHR Health Technology Assessment (HTA) Programme Clinical Evaluation and Trials (CET) Board.  The HTA programme funded this trial and the CET board made the decision to provide funding, although I was not involved in the decision.  I am currently collaborating with the Chief Investigator of the PARAMEDIC2 trial, Gavin Perkins, on a trial of a different ambulance service intervention.”

Prof Tim Chico: “No conflicts.”

Prof David Spiegelhalter: “No conflicts of interest.”

None others received.