The end of adrenaline? The results of PARAMEDIC2.
Adenaline was the first drug I ever gave as a doctor. I remember starting my house jobs with a "week of nights" and on the first evening found myself at the bedside of a man who'd had a cardiac arrest. Stunned by the drama of the event, all I could do was follow the orders of my registrar and give the adrenaline. But even then I remember thinking "how does this enormous dose of adrenaline help a dying heart?" The textbook answer is that it limits flow to the peripheries and redirects blood through the arteries and towards the injured muscle. But at what cost? In those who've suffered cardiac arrest, adrenaline has been shown to trigger dysrhythmias and further episodes of cardiac arrest. Nevertheless, adrenaline is believed to reduce mortality and is widely used. But is this assumption correct?
The PARAMEDIC2 study, published this year in the New England Journal of Medicine, sought to determine whether adrenaline was of benefit to more than 8000 patients who suffered an "out of hospital" cardiac arrest. Patients were randomised to receive either a dose of adrenaline (1mg) or placebo every three to five minutes until, "a sustained pulse was achieved, resuscitation was discontinued or care was handed over to a clinician". Irrespective of the treatment, the results weren't good. In those given adrenaline only 130/4012 (3.2%) survived to 30 days compared to 94/3995 (2.4%) who received placebo. A similar difference was seen at three months.
From these results it would appear that adrenaline might offer a small, but significant benefit. However when you look closer at the results there's a risk too...
Severe neurological impairment was commoner in survivors given adrenaline. 39/126 (31%) compared to 16/90 (18%) scored 4 or 5 on the Modified Rankin Score. When a 4 is, "unable to walk without assistance or attend to own bodily needs" and 5 is, "bed ridden, incontinent and requiring constant nursing care and attention", it is clear that many survivors (and their carers) are often faced with a devastating future. This was confirmed in preliminary work by the researchers who found that the public, "identified survival with a favourable neurologic outcome to be a higher priority than survival alone".
Put in purely numerical terms, Justin Morganstern draws these results together and writes,
"For every 1000 out of hospital cardiac arrests, the use of adrenaline will result in 246 extra cases of ROSC (return of spontaneous circulation), 158 extra admissions to hospital and eight extra survivors at 30 days. Of these eight extra survivors, 3 will have a good neurological outcome and 5 will have a bad neurological outcome"*
Should this study alter our practise?
We asked some mountain medics for their thoughts...
"Would this change my practice?
It's a timely study throwing light on a practice which needed examination.
As health professionals we are expected to save lives but the cost in this situation seems exorbitant. We are also charged with doing no harm by our interventions. Of the few lives saved the high likelihood of severe disability for most of them poses the following questions:
Is the subsequent burden on the patient, the family and the health system acceptable?
Are we allowed to make such judgements?
Are we in a position to defend a decision not to use the drug?
During an arrest there is no time to consult with the relatives, informing them of the pros and cons of this intervention. Asking them to decide is neither realistic nor humane. So the decision must be ours alone.
Being retired it's not going to change my practice but if I wasn't it would."
Dr Jim Duff
"My thoughts on the Paramedic 2 trial, having recently chaired a Clinical Governance meeting where it was presented, were that the overall meaningful survival was so shockingly poor that frankly adrenaline or no adrenaline why are we spending literally millions of pounds of tax payers money on training people to treat out of hospital cardiac arrest (bystander CPR courses, ALS courses the list goes on and on) not to mention the money spent treating them in hospital on ITU if they get ROSC? If someone presents for surgery and their NELA score was 97% then I'd be having a VERY hard think and chat about whether it was the right thing to do and that person is alive! In those who've suffered a cardiac arrest we're spending the money on those who are already dead!
On the flip side - if I had an out of hospital cardiac arrest tomorrow would I want people to turn up and try to resuscitate me? Err ... YES! Would I want those people to have had training and do as good a job as possible? Err ...YES! So I think we need to be VERY careful about where we spend our resources in the NHS and do some more trials that provide better subgroup analysis in order to find out who's outcomes are better than 3% and possibly draw some lines in the sand on who we resuscitate - That might be quite controversial!"
Dr Emma Lloyd Davies
"As a Core Medical Trainee my experience of cardiac arrest has been solely in the hospital setting. Here, the presence of ward staff plus a dedicated arrest team allows initiation of CPR, early defibrillation and provision of adrenaline within minutes (when indicated by ALS guidelines). These times differ dramatically from those experienced by patients in the PARAMEDIC2 study (median time for ambulance to arrive - 6 minutes, median time to adrenaline - 22 minutes).
This difference is important in cardiac arrest, which has been described as having three time phases - electrical (<4mins), circulatory (4-10 mins) and metabolic (>10 mins) where the impact of different treatments vary. It follows that we cannot generalise the results of the PARAMEDIC2 study to an in-hospital setting, since adrenaline delivery occurs at a very different phase of the arrest, and could result in a very different outcome.
As an aside, whilst reading around this subject I was reminded that the only two interventions in cardiac arrest that have been shown to improve survival with good neurologic outcomes continue to be high-quality CPR and early defibrillation. In my future practice I will aim to prioritise these two simple interventions - which can easily be disrupted by the difficulties of less critical tasks such as obtaining arterial blood gases or administrating intravenous drugs."
Dr Sophie Mohun Kemp
"Drugs aside, it's all about early CPR and defibrillation where an AED is available. In an event where a patient has arrested and I've witnessed it, I have managed to get a high percentage back with no drug support and maintained until handover. It is the lay person at an incident with basic training and no drugs which keep people 'alive' until the ambulance etc gets to them. It has been a debate for years as to whether or not filling these people with drugs is appropriate especially in an environment where we would be working. Me thinks ... keep it simple ... do simple well ..."
Dave Gregory (Paramedic)
"This paper addresses an important topic. We have discussed it extensively at our Devon BASICS meetings.
Importantly, doctors are now asking their patients to advise on research and this takes into account patient wishes for quality of life after resuscitation. We are filling up too many ICU's with old vegetables past their sell by dates because doctors do not have the courage to make decisions as they used to. The pendulum will swing. I hope. This paper takes into account outcome. What a step forward.
I am sure eventually we will see medical (as opposed to trauma) resuscitation guidelines reduced to simple good quality BLS then ALS which will only be airway and CPR and defibrillation and no drugs to mess up our physiology.
An important part of personal care for your own resuscitation is to discuss with family, consider organ donation and make sure somebody you know well has power of attorney.
Is there a place for ALS on the hill? I can think of worse places to die than on a hillside looking at the view or the rain. Think further when it comes to avalanche or hypothermia or lightening.
An important paper since it stimulates real thought and questions dogma."
Dr David Hillebrandt
Many of the comments made by contributors to STDZ are echoed in the PARAMEDIC2 discussion,
"The benefit of epinephrine for survival that we found in our trial should be considered in comparison with other treatments in the chain of survival. The number of patients who would need to be treated with epinephrine to prevent one death after cardiac arrest was 112, as compared with early recognition of cardiac arrest (number needed to treat - 11), CPR performed by a bystander (number needed to treat - 15), and early defibrillation (number needed to treat - 5)."
Let's focus upon the need to recognise a cardiac arrest quickly, perform effective CPR and defibrillate as soon as possible. Meanwhile, the role of adrenaline in out of hospital cardiac arrest clearly needs closer scrutiny!
The abstract of the study can be found here:
If you'd like a copy of the study please contact us.
*For a thorough critique of the study take a look at: