Last week various newspapers (see here and here) reported on a planned research study of adrenaline for patients suffering a cardiac arrest outside hospital. The PARAMEDIC 2 trial (full protocol here) involves ambulance officers randomly giving patients either the traditional resuscitation drug adrenaline, or a salt-water solution (placebo). The trial has been strongly criticized by Ruth and Lindsay Stirton, writing in the Journal of Medical Ethics.

There are two main controversial elements to the trial design. The first involves the lack of consent for involvement in the trial, the second involves the researchers’ plan not to inform families of patients who died that their loved one had been in a research trial.

First, it is important to appreciate the context of this trial. 50,000 people in the UK each year have a cardiac arrest outside hospital. Contrary to public perception, the chance of survival if this happens is extremely low – less than one in ten patients leave hospital alive. Adrenaline is a naturally occurring stress hormone that has been used for a long time for patients whose hearts have stopped. But there is actually very little good evidence that adrenaline is helpful in this situation. There has only been one relatively small trial, which didn’t show a definite benefit. And there is some reason to think that adrenaline may be harmful. Very large studies (not randomized trials) that compared patients who had received adrenaline to those who had not received adrenaline suggest that adrenaline may increase the chance of patients’ hearts being restarted. But these studies also suggest that those patients who received adrenaline had a lower chance of surviving to leave hospital, and may have a higher rate of long term disability.

Is it ethical for a trial like this one to take place without consent? Normally research studies ask patients (or their surrogates) beforehand whether they would like to take part. But the nature of this sort of emergency treatment study is that consent beforehand is impossible. There is no way to predict which patients are going to have a cardiac arrest out of hospital, and no time to ask family members. Either the trial takes place without consent, or it does not take place at all.

The PARAMEDIC2 trial is a very good example of a study where it is ethically justifiable to perform research without consent. Research ethics guidelines (eg see here or here) allow research studies to go ahead without consent for emergency , life-threatening conditions like cardiac arrest. The question addressed by the study must be important, with no other way to answer it. There must be enough available evidence from animal studies and other types of research to suggest that a trial is needed. (In this case, the large international consensus group that provides guidelines for resuscitation (ILCOR) have reviewed available evidence and recommended that a trial take place urgently). And the trial must be carefully reviewed by relevant research ethics committees.

All of those conditions are met by the PARAMEDIC2 trial. And if I were to have a cardiac arrest out of hospital I would want paramedics to include me in the trial, to randomize me to receive adrenaline or not. This is not a self-less altruistic choice, wanting to contribute to science or the wellbeing of future patients. Given the existing uncertainty about whether or not adrenaline is beneficial or harmful, it would be in my best interests to be in the trial. It would be a rational way to manage the risks of resuscitation – adrenaline might be better at restarting my heart or it might not, it might give me a better chance of leaving hospital alive, or it might not, it might leave me in a more disabled condition if I survive, or it might not. The uncomfortable fact is that no one knows whether or not adrenaline is the right treatment. In that situation it is better to be in a trial where you have a 50% chance of receiving one of two treatments that might be helpful.

It is ethical to involve patients in the trial without consent. (Indeed, given the existing uncertainty, it is arguably unethical not to do the trial, and not to randomize). The second question is what to do afterwards. Should the patient or their family be told that they were in a trial? For survivors, the answer is straightforward. The patient or their family should be told – this respects that patient’s autonomy in a way that is possible and meaningful. It means that the patient/family can decide whether or not to take part in ongoing follow-up that is an important part of the study. Some patients may choose to discontinue involvement in the research at that point.

The more difficult question is what to do where the patient has died. Sadly, most trial participants will be in this category. As noted above, 9 out of 10 patients who are enrolled in the trial are likely to die before leaving hospital. In this situation, informing family members that the patient was involved in a trial cannot benefit the patient, nor respect his/her autonomy. At that point they cannot decide not to take part in the study – the die is already cast, and no further follow-up is required. It does not give them any meaningful choices. Furthermore, informing families at this stage, grieving and distressed, is likely to be harmful to them. Although it is (as argued above) completely rational to be randomized to receive adrenaline or placebo in this situation, grieving is not by its nature a rational process. Families may well blame the research study or the researchers for the death of their family member. Guilt, denial and anger are normal parts of grieving. No matter how carefully explained by researchers, it would be difficult to avoid exacerbating some families’ distress and loss. David Hunter has argued that it is a “a matter of respect that you inform people”. But the key issue is how much weight we give to that respect compared with the risk of harming and distressing families by informing them about the trial.

If families are not informed, there is another risk – that down the track some families will discover about the trial anyway, and that delayed discovery of this fact would be even more distressing. This might lead to significant negative media attention, and could lead to the trial being stopped. It is possible that this would threaten future, important research studies of emergency treatments, and mean that they do not take place. These risks are important to consider too. One way of mitigating them is to have open discussion about the trial in the media, and information about the study widely disseminated within the press, internet and the community. That would help to avoid any perception that the trial was being done secretly or that there was an attempt to unethically experiment on vulnerable patients.

For myself, I would not want my family to be informed if I had been in the PARAMEDIC2 trial. It cannot help them, and it cannot help me. The researchers have chosen this path after carefully reflecting on the risks and benefits of various alternative approaches. The ethics committees that have reviewed the studies have presumably judged that most patients would feel as I do. It is important to reflect on the ethical questions around studies raised by trials like this. But it is even more important that the studies go ahead.

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