Every year in the UK, around 30,000 people receive treatment from NHS Ambulance Services for cardiac arrest. In 1 in 4 cases, the heart can be re-started, but over half of these patients die in intensive care due to severe brain damage. However, compared to other conditions such as cancer or heart disease, there is relatively little information out there that gives medical professionals an idea of the best way to treat these patients. One commonly-used treatment for cardiac arrest is a hormone called adrenaline, which increases blood flow to the heart. It has been used for over 50 years, but has not been extensively tested to determine whether it is helpful or harmful as a treatment. Recent studies raised questions about whether it can reduce blood supply to the brain, causing severe damage. However, none of these tests are conclusive, so the International Liaison Committee for Resuscitation called for a definitive study to give medical professionals the information they need. This study has been funded by the National Institute for Health Research.

We have taken particular care to ensure that the project meets all legal and regulatory requirements. It is normal for a patient to be asked for their consent before being enrolled in a trial, but it was not possible to ask for consent in cardiac arrest as the patients were unconscious. Emergency treatments must be given without delay which makes it impractical to obtain consent from the patient's next of kin without introducing harmful delays to treatment.

Once the the initial emergency had passed a member of the research team asked the patient or their legal representative for consent to participate in the study at the earliest opportunity. People who did not want to be part of the trial also had the option to notify the trial team of their wishes in advance, by requesting a ‘No study’ bracelet and having their address flagged by the ambulance service.

The legal basis for entering a patient into the trial prior to informed consent in an emergency situation is set out in Statutory Instrument 2006 No. 2984, The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006. The trial protocol and supporting documents have been reviewed and approved by the funding body, the National Institute for Health Research (NIHR); by a Research Ethics Committee (REC) who consider the need for the research and weigh up the risk and benefit for patients; the Medicines and Healthcare Regulatory Authority (MHRA) who review the application with regard to Good Clinical Practice and the Confidentiality Advisory Group (CAG) who review applications for research where consent from the patient cannot be obtained.

Until now, adrenaline had never been formally tested as a treatment for cardiac arrest. Recent studies have created substantial concern amongst doctors, nurses, paramedics and patients that adrenaline may be harmful when used as a treatment for cardiac arrest. We want the best possible outcomes for all people who have a cardiac arrest, both now and in the future.

The PARAMEDIC-2 trial was reviewed and approved by the South Central Oxford C Research Ethics Committee. All research studies run in the NHS are conducted in accordance with the Research Governance Framework and relevant legislation. The Health Research Authority provides robust, ethical review of proposed research via independent Research Ethics Committees (RECs) who scrutinise applications and put the rights, safety, dignity and well-being of research participants at the centre of their decision making.

Studies based on which treatments people have received (known as observational studies) are at risk of giving biased or misleading results. The only reliable way to assess the effects of treatments in cardiac arrest is to create two groups of patients where one group receives the active treatment (in this case adrenaline) and another group which receive the placebo (salt water). Which treatment the patient received is determined by chance (a process known as randomisation). This ensures half the patients treated receive adrenaline and half receive placebo and allows an unbiased assessment of the effects of treatment.

We are aware of the sensitive nature of the circumstances in which patients will be part of the trial, and of distress that relatives will be in at such a difficult time. We have given careful consideration to the need for a compassionate approach to relatives, to reduce further distress, and have discussed this in detail with both the Ethics Committee and with our patient/service user advisers for the trial. The trial has been designed and conducted according to the legal and ethical requirements, and has been independently monitored to ensure that patients’ rights, dignity and safety are paramount.

When a person is unconscious due to their cardiac arrest we can’t ask permission about their treatment. Due to the urgent need for treatment we are not able to ask a relative or friend, should there be anyone else on scene. Research like this is considered lawful and ethical, provided it has been scrutinised and rigorously reviewed by several regulatory organisations including an ethics committee (which is a panel of medical, scientific and legal experts as well as representatives of the public) who review the research in terms of its importance to clinical practice and assess the risk and benefits of doing such a trial. The trial has been reviewed regularly by two independent monitoring committees, made up of representatives of the public and very experienced medical and scientific experts in the field.

The research team included experienced doctors, nurses, paramedics and scientists. The team were required to keep the research ethics committee and regulatory authorities informed of progress with the trial, and to report to an independent monitoring committee who had the authority to stop the research if there were major concerns about patient safety. Without research like this we would not be able to make improvements in patient care in the emergency setting.

If you decide you do want to know about the treatment your relative received we can tell you this. There is an online enquiry form available here (www.warwick.ac.uk/paramedic2) to find out whether a relative was enrolled into the trial. Alternatively enquiries can be sent to paramedictrial@warwick.ac.uk. Once your relative's involvement in the trial has been confirmed, an information leaflet will be sent with a form to be completed. Once this has been received, a member of the team will be in touch to confirm which treatment was given as part of the trial.

We respect the wishes of members of the public who do not wish to be enrolled in the PARAMEDIC 2 trial. Members of the public who did not wish to be enrolled in the PARAMEDIC 2 trial, in the event that they had cardiac arrest, had the option of requesting a stainless steel bracelet which has the words ‘NO STUDY’ engraved on it. Local paramedics were trained to look for these bracelets in the same way they do for other medical ID bands. This means that, in the event that they had a cardiac arrest, they will have received the standard treatment which may have included adrenaline. This system has also been used successfully in North America for a number of trials.

• Request a no study bracelet

We have carefully considered the benefits and burdens of different approaches to informing the relatives of the deceased, to inform them about the trial. The trial sought specific advice on this question from the “Resuscitation Council (UK) Patient Advisory Group”, an advisory group made up of actual patients and their families. Their advice was very clear on this point and some specific anonymised comments from that group now follow:

“Given all the benefits and disadvantages outlined for both the passive and active communication channels, I think and feel that the decision to use the passive methods outlined will cause the least distress at what is already a very difficult time for the relatives whilst still being transparent and open."

“I have read this through carefully and would greatly favour the passive communication approach. I had a cardiac arrest myself and know that my XXXspecific family information redacted from here XXXXX, had enough emotion to contend with without receiving additional paperwork. I commend this approach.”

“People receive and process information very differently at the best of times, and since there's no way of telling in advance how an individual will react in a situation like this, there are good reasons for trying to avoid distress both for the relative/friend of the CA victim AND for those having to deal with them at the time”

“I don't think there's any way I could have dealt with any extra issues on the spot. The days after are full of frantic activity, there's so much to be done with arranging funerals etc., and receiving something through the post during that period would have felt much more like an intrusion than anything else”

We recognise that the opinions of different people in our community will vary. After very careful consideration and discussion with the research ethics committee, our assessment was that the overall burden of writing to the families of patients who had recently died would have outweighed the potential benefit. This is based on what most of the people we spoke to told us. We realise that this approach will not have suited all families but we tried to approach this difficult subject in as sensitive a manner as possible. We made general information about the trial throughout the time the trial was running. We have responded to families who have chosen to contact us and ambulance teams have met with families if they wished to discuss the trial.

Warwick Medical School, University of Warwick are data controllers for this trial and all the information that is collected. The information will be used to find out whether giving adrenaline during treatment for cardiac arrest helps to improve long-term survival and recovery.

If you received treatment that forms part of this study at the time of your cardiac arrest, information about your cardiac arrest will have been collected. A member of the research team will then make contact with you to discuss what other information we would like to collect, in order for us to follow how well you recover in the 12 months following your cardiac arrest.

We plan to do this in two ways. Firstly we will ask the doctors / nurses / paramedics who cared for you to look at your NHS records to let us know how you are getting on. This will include information about how long you spent in hospital, what treatments you needed and how well you recovered. We will also get information about you from the following organisations:

• NHS Digital (previously the Health and Social Care Information Centre)

• the Patient Episode Database for Wales (PEDW)

• ICNARC (Intensive Care National Audit and Research Centre)

• NICOR (National Institute for Cardiovascular Outcomes Research)

This will tell us about your stay in hospital after your cardiac arrest, as well as any A&E and outpatient attendances since your cardiac arrest. We will also get information on survival rates from the Office for National Statistics, provided through NHS Digital. In order to do this, information identifying you, such as your date of birth and NHS number, will be shared with the organisations listed above. This data will be shared in a secure manner and only for the purposes of the study.

Secondly, we will invite you to answer some short questions around 3 and 6 months after you had the cardiac arrest. This can be done over the telephone, by post or in-person with a member of the research team, whichever option is more convenient to you.

When the research team contact you, you will be given the choice to opt-out of any of the above information collections. If you choose not to take part in any aspect of the study any further, it will not affect the treatment or care you receive in any way.

All information that is collected about you during the trial will be kept strictly confidential, and will only be seen by authorised staff involved in the research, organisations such as NHS Digital who are providing data, and people from government regulatory authorities who ensure that research studies are carried out correctly. All of them have a duty of confidentiality to you as a research participant and you can be assured that all information will be handled securely and in line with relevant laws such as the Data Protection Act.

Any personal information about you will only be used for this research study. Anonymised data may be used for future research. No information that can identify you will be used for other research or in any published reports.

You have the right to see your personal health information relating to the research trial, but you will not be able to look at some parts of the information until after the trial has finished. Contact details for the study team can be found on the ‘Contacts’ page.

You can change your mind about taking part in any aspect of the trial follow-up at any point, without having to give a reason and without your care or legal rights being affected.

If you change your mind about completing follow-up questionnaires, and/or would like the research team to stop collecting further data about your health status, please contact your trial team using the contact details provided on the Participant Information Sheet. Alternatively, you can call 02476151164 or email paramedictrial@warwick.ac.uk.

While adrenaline has been used to treat cardiac arrest for decades, recent evidence suggesting that it may be harmful has led to calls for a large trial to assess whether adrenaline improves outcomes for our patients. Resolution of this uncertainty is urgent, as adrenaline is used widely to treat cardiac arrests, and if harmful, may be responsible for many avoidable deaths.

Adrenaline has never been formally tested in humans with sufficient numbers to inform us reliably whether it is helpful or harmful.

There are several precedents where ‘established’ treatments have been evaluated after years or even decades of use and have been found to be ineffective or harmful - well-known examples include pulmonary artery catheters in intensive care; beta agonists for acute respiratory distress syndrome (ARDS), and corticosteroids for head injury. It is possible that adrenaline for out of hospital cardiac arrest (OHCA) may be a similar case.

The International Liaison Committee on Resuscitation appraised the evidence surrounding adrenaline in OHCA in 2010 and again in Oct 2012. They concluded there is an urgent need for randomised, placebo-controlled trials of adrenaline. The Resuscitation Council (UK) issued a statement in May 2013, supporting the need for a randomised, controlled trial of adrenaline versus placebo in adults sustaining out-of-hospital cardiac arrest, and stated that, in the context of such a trial, comparing adrenaline with placebo is considered ethically justified.

Particular care has been taken to ensure this project meets all legal and regulatory requirements.

This type of research, where a drug is being investigated, is called a CTIMP (Clinical Trial of an Investigational Medicinal Product) and falls under legislation known as the UK Clinical Trials Regulations 2004 and 2006, which are subsidiary to the EU regulations 2001.

The legal basis for entering a patient into the trial prior to informed consent in an emergency situation is set out in Statutory Instrument 2006 No. 2984, The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006.

The trial protocol and supporting documents have been reviewed and approved by the National Institute for Health Research (NIHR), who are funding the trial, by a Research Ethics Committee (REC) which considers the need for the research and weighs up the risk and benefit for patients; the Medicines and Healthcare Regulatory Authority (MHRA) which reviews the application with regard to Good Clinical Practice and the Confidentiality Advisory Group (CAG) which reviews applications for research where consent from the patient cannot be obtained.

As a clinician working in emergency care you may have had experience where you administered adrenaline and the patient had a return of spontaneous circulation (ROSC) and survived to reach hospital.

Several studies have reported an association between adrenaline administration and short term survival (minutes and hours), but there is no evidence so far that shows any long term survival benefit (i.e survival to hospital discharge and beyond with good neurological outcome) from adrenaline use, and importantly there is some evidence that patients who received adrenaline had worse neurological outcomes compared to a similar group of patients who received the same treatments (e.g. basic life support and defibrillation) but no adrenaline.

The only way (and the ‘gold standard’) to undertake a ‘fair test’ of a treatment is to undertake a randomised trial: create two arms where patients are assigned randomly to receive either the ‘active’ drug (adrenaline) or a placebo; the outcomes from patients in the two treatment arms with similar characteristics (e.g. age, sex, co-morbidities, presenting ECG rhythm) are then compared. This approach reduces the chance of bias, which is a serious limitation of other kinds of research.

The suppliers of the (purple) Aurum adrenaline were not able to also supply the equivalent placebo, and do not have the relevant clinical trial experience required to meet the strict regulatory requirements to carry out a clinical trial. We have therefore arrangements with a supplier who is able to meet the regulatory requirements.

It is the dose (1mg) not the volume that is important. As soon as the drug is injected it becomes mixed with a large volume of blood in the vascular compartment so the concentration reaching the heart will be the same whether injected from 3ml or 10ml.

Small volumes will not make any difference (3 versus 10ml) to generalisability (some EMS systems still give it in 1ml). Some people also give 20ml flushes. The key thing is that the placebo and active drug are in the same volume.

Research is recognised as ‘core business’ in the NHS Constitution. Your Ambulance Service NHS Trust is committed to this trial and will support you in your participation. Without your participation we cannot carry out the trial. It is essential to the success of the trial (so that we can answer definitively the question about the safety and effectiveness of adrenaline) that we include all eligible patients. While as a clinician you are entitled to make –and be accountable for- decisions in relation to individual patients, we will provide training and ongoing support so that you feel confident in undertaking the trial procedures.

If we do not include all eligible patients into the trial we will not be getting an accurate picture of the survival across the two arms of the trial because lots of patients will be missed from the data collection. An example would be where prehospital clinicians decide to use the trial drug pack only in patients they consider ‘more likely to die’ and give regular adrenaline to patients they consider to have a higher chance of survival. This would result in a group of patients with very low probability of survival being recruited to the trial and it may not be possible to detect a difference at all; the trial would therefore be a waste of time, money and hard work by all involved, and not be fair to the patients and families involved.

If you have any concerns about any aspect of the trial please contact your local Research Fellow in the first instance.

We will endeavour to provide feedback from time to time to ambulance staff on how recruitment is going (and to say thank you!), and of course when the trial is completed we will share the findings with those who have been involved. Please bear in mind this process can be very slow: the trial is planned to run for several years before we get the final results.

It’s important that we don’t ‘second guess’ the results of the study. There must not be any selection about which groups of patients get regular adrenaline and who gets the trial drug pack; it is therefore important to adhere to the trial protocol, for which we will provide training and support.

You should continue to treat the patient and deal with any questions when you are able to, providing reassurance and compassionate care to patient and relatives as you would normally do. The trial team will make contact with the patient or their relative in hospital (for those patients who reach hospital) to explain the trial at the appropriate time, with due care and attention to the sensitivities at what will be a difficult time for them.

If anyone wants to know more information then you should direct them to the local Research Fellow who can take the time to explain fully what the trial is about. We will provide contact details for the Research Fellow and further information for patients and relatives in trial documentation.

Because the concerns are about the effects and safety of adrenaline in patients with out of hospital cardiac arrest, our focus is on patients treated by the ambulance service before reaching hospital. This is because the first treatments given to patients are the most important in determining survival. We will, however, be collecting some data on treatments given in hospital so that we can ensure that we make a fair comparison of patients in each arm of the trial.

The trial drug pack should be used in any patient in whom you are performing advanced life support, except for those with anaphylaxis, pregnant women and children*

• * Patient presumed 16 or over; and women not known to be pregnant

The trial pack must only be used on eligible patients. The trial is not approved for children (under 16s) or pregnant women as explained below.

If patients who have already received adrenaline (e.g. from another health professional before you arrive on scene) are included and given the drug in a trial pack, this will ‘muddy the water’ when it comes to analysing trial data and we will be unable to answer the research question about the safety and effectiveness of adrenaline.

We have designed the trial to include the vast majority of patients with out-of-hospital cardiac arrest. However, we are unable to include pregnant women or children (<16years). It is common practice to exclude pregnant women (or women suspected of being pregnant) from clinical trials where the drug is not intended for use in pregnancy. We are excluding children because it is best practice not to enrol a child in a clinical trial unless the trial is of particular relevance to children.

No.

No.

Yes. If your intention is to attempt resuscitation with advanced life support, and the patient is not known to be pregnant, aged under 16 years or in anaphylaxis (see above), you should use the trial pack.

The trial drug pack should be used if all the inclusion criteria are met (as above). Only if another vehicle has arrived first and regular adrenaline has already been used should you not open the trial pack.

If the patient is eligible, please use the trial drug pack regardless of who arrived first on scene.

If resuscitation has already started the trial drug pack can still be used as long as the patient is eligible and adrenaline has not already been given.

Whilst there is equipoise about the use of IV adrenaline for cardiac arrest due to asthma, there is evidence that it may be beneficial for patients with anaphylaxis as it attenuates the severity of the IgE mediated reaction. The rationale for the change was that during the pilot study ambulance staff were concerned about potential overlap between the presentation of asthma and anaphylaxis (both may present with severe bronchospasm). We felt the safest option was to extend the exclusion for anaphylaxis to include cardiac arrests suspected to have been caused by life threatening asthma.

Yes. The definition of ROSC according to Utstein requires a palpable pulse: “ROSC is defined for all rhythms as the restoration of a spontaneous perfusing rhythm that results in more than an occasional gasp, fleeting palpated pulse, or arterial waveform”. We recognise that some advanced paramedics are now equipped with focussed echocardiography equipment, which may be valuable in supporting decision making in some patients provided its use does not result in interruptions in effective chest compressions. Echocardiographic evidence of cardiac wall movement during ongoing CPR is not considered to meet the definition of ROSC, such patients should continue to be treated according to the trial protocol.

It should be noted that in the absence of a “No Study” bracelet, if an individual(s) makes representation to the attending ambulance clinician(s) that the patient in cardiac arrest does not wish to take part in the trial, these wishes should always be respected and the patient should not be recruited as a study participant.

If the crew find out part way through a resuscitation attempt that an exclusion criteria has been met then the trial should be terminated and the resuscitation attempt should be continued with standard adrenaline where indicated. The call details should still be sent through in the normal manner to the research fellows within Trusts. The incident should be reported via your incident reporting system so that your trust research team can report the incident to Warwick Clinical Trials Unit for recording.

Prior to recruitment you will have taken reasonable steps to ensure the patient was not excluded. If you later find out that the patient was excluded this should be reported to your local research paramedic as soon as possible and reported through your local incident reporting system.

Yes.

The use of adrenaline for a previous cardiac arrest is not an exclusion to the trial.

Resuscitation given by the ambulance team and not by the hospital resuscitation team.

Yes, standard (JRCALC) guidelines for terminating resuscitation on scene apply. You do not have to take each patient to hospital if you wouldn’t normally just because you used the trial drug pack. But it is vital that you return the trial pack and documentation is completed accordingly.

Please send any unused syringes from the pack with the patient to hospital, but at handover the unused syringes must be returned and treatment as per hospital standard practice takes over. Place them in the bag near the patient so they can be used during the transport if needed.

Please make sure following handover of the patient to hospital staff that the drug pack is brought back to the ambulance and document on the PRF that the patient is in the trial. Please see local procedures on what to do with the unused syringes.

Yes, if ambulance staff are called to resuscitate the patient (e.g. in the hospital grounds, car park or away from a clinical area), but not if the hospital resuscitation team are called (e.g. in a clinical area).

This does not impact on the trial. Please note which hospital the patient goes to on the PRF as you would normally. The trial team will then follow up the patient in that hospital.

Yes. If the ECA or technician would usually fetch and open the adrenaline for the paramedic.

This is for each ambulance service to determine, not the Trial Team.

Stop giving adrenaline. This has been agreed with your Ambulance Service NHS Trust.

Please do not open another trial pack or use standard adrenaline as this could lead to contamination of the treatment arm.

A recent study of over 3,000 OHCA patients in London reported that were no survivors amongst patients requiring 10 or more doses of adrenaline. This will be covered during your training.

If a patient rearrests, continue to use any remaining study drug but do not open a new pack or use standard adrenaline.

Research undertaken by London Ambulance Service reported that no patient survived after 10 or more doses of adrenaline.

Please do not open more than 1 trial pack as this could lead to contamination of the treatment arm.

We need to ensure that a patient in the trial receives only one of the trial treatments – if a patient gets drugs from two trial packs we will not be able to answer the research question about the safety and effectiveness of adrenaline.

The procedure for disposing of unused syringes will be determined by local procedures, which will be provided for you by your local Research Fellow.

We need to keep a close track on which patients receive which treatment in this trial to ensure that the trial results are as scientifically valid as possible. Without this, we will be unable to answer the research question.

Careful documentation is essential in high quality research such as our trial. We need to be able to track which patients have had which drug pack in order to undertake the statistical analyses necessary to answer the research question about adrenaline, and also to ensure we fulfil our legal obligations in relation to a drug trial.

Please record drugs administered on the PRF as you would do normally. You may notice the batch number of the pack has more numbers than usual, this includes the trial pack number and it is essential that this is recorded on the PRF so we can match each pack used, back to a specific patient.

If you notice anything unusual about the patient which you suspect may be due to the administration of the trial drug you must report this immediately as per normal procedure but also let the Research Fellow and or Principal Investigator for your ambulance service know immediately – contact details below – they will then complete a trial Serious Adverse Event form and inform the Warwick Clinical Trials Unit.

Yes. It is acceptable to initiate Advanced Life Support by giving drug therapy before securing an advanced airway providing the attending clinician is happy with the airway management currently in use.

We have received advice from a senior coroner who has asked that the coroners within the trial areas be informed. To facilitate this a letter has been sent to all coroners within the trial areas along with public information leaflets.

If they are eligible for the trial (based on the inclusion/exclusion criteria), please enrol them into the trial and administer the trial drugs. It is really important that all eligible patients are enrolled, including the ones that have a crew-witnessed arrest. In fact, excluding patients who arrest in front of you could actually create bias in the data, as those patients are often the ones who receive early effective CPR and defibrillation, and therefore potentially better outcomes.

In the first 950 patients enrolled, equivalent to 9500 syringes, we have had reports of 18 broken syringes which equates to 0.18%, thus the risk of this is considered very low.

Adrenaline has been in use to treat cardiac arrest for around half a century. It was introduced before the scientific methods (randomised controlled trials) to test new medicines were used routinely.

Recent studies have created substantial concern amongst doctors, nurses, paramedics and patients that adrenaline may be harmful when used as a treatment for cardiac arrest. Specifically, recent research has shown that adrenaline reduces blood supply to the brain which can lead to severe brain damage and death. This concern led the International Liaison Committee on Resuscitation, a worldwide collaboration of resuscitation experts and scientists, to call for urgent studies to find out the effects of adrenaline in cardiac arrest.

Although adrenaline has been part of advanced resuscitation guidelines for over 50 years, until now there have been no well-designed trials looking at whether it improves, worsens or has no effect on outcomes in those who have an out-of-hospital cardiac arrest. It was included in initial guidelines in the 1960s. The existing evidence supporting its use is limited, and some recent studies have actually suggested that it may cause harm and result in worse outcomes in those who receive adrenaline. It is because of this conflicting evidence, that the PARAMEDIC2 study is needed. As the use of adrenaline is engrained into resuscitation practice, any changes in whether it is used or not used need to be informed by a well-designed study.

Indeed, many drugs thought to be beneficial initially have been withdrawn following clinical trials. Examples include rosiglitazone (a diabetes drug which increased risk of heart attacks), and Vioxx (a pain killer which increased heart attacks).

The PARAMEDIC-2 trial was reviewed and approved by the South Central Oxford C Research Ethics Committee.

All research studies run in the NHS are conducted in accordance with the Research Governance Framework and relevant legislation. The Health Research Authority provides robust, ethical review of proposed research via independent Research Ethics Committees (RECs) who scrutinise applications and put the rights, safety, dignity and well-being of research participants at the centre of their decision making.

NHS Research Ethics Committees consist of up to 18 members, a third of whom are lay (broadly, this means their main professional interest is not in a research area, nor are they a registered healthcare professional). They safeguard the rights, safety, dignity and well-being of research participants, independently of research sponsors. They review applications for research and give an opinion about the proposed participant involvement and whether the research is ethical. RECs are entirely independent of research sponsors (that is, the organisations which are responsible for the management and conduct of the research), funders and investigators.

This study has been approved by an Ethics Committee, and has been conducted according to strict ethical and methods protocols. It’s design and ethical scrutiny has included experts in resuscitation, those involved in frontline resuscitation work, and lay people. The trial has had oversight from a steering committee and data-monitoring committee to ensure best practice was followed at all times.

Medical trials in such areas of sudden immediate medical intervention face many more challenges in establishing patient consent to participate in the trial. Nevertheless such trials are not new and the ethical regulators of the trial have been assured of the need for the trial, and that the trial team have worked with health professionals to put in place a system for individuals to register their wish not to participate in the trial.

Cost effectiveness of an intervention is an important part of any study. Although adrenaline is relatively inexpensive, its use may decrease, or increase costs due to unnecessary complications that could be avoided by not using it. We simply do not know, and a study of this size will help answer what costs are associated with the use of adrenaline. Indeed economic analyses help direct funds to those interventions that offer the best chance of survival. However the most important question be answered is whether the use of adrenaline is of real benefit, or no benefit, or actually could in fact cause more harm.

The only way we will know what the right treatment is for a patient with a particular medical condition is to undertake a randomised controlled trial. This is considered the ‘gold standard’ and provides the highest quality evidence to inform future guidelines for patient care. A good explanation of this can be found at the Testing Treatments website.

In emergency situations, such as cardiac arrest, where time is of the essence, there are specific legal requirements to ensure that patients’ rights, dignity and safety are protected. The legal basis for entering a patient into the trial prior to informed consent in an emergency situation is set out in Statutory Instrument 2006 No. 2984, The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006.

The real risk would be to continue to give treatments that may have been used for decades, but have not been properly tested to modern scientific standards. There are several examples in medicine where this has been the case, for example using corticosteroids for head injury was common practice for a long time, but when put to the test in a properly designed trial, was found to be harming patients.

Until now, adrenaline has never been formally tested in humans with sufficient numbers to inform us reliably whether it is helpful or harmful. Recent studies have created substantial concern amongst doctors, nurses, paramedics and patients that adrenaline may be harmful when used as a treatment for cardiac arrest. Specifically, recent research has shown that adrenaline reduces blood supply to the brain which can lead to severe brain damage and death. This concern led the International Liaison Committee on Resuscitation, a worldwide collaboration of resuscitation experts and scientists, to call for urgent studies to find out the effects of adrenaline in cardiac arrest.

The need for this trial has also been recognised by the National Institute for Health Research, which has provided the funding for this study. As part of the funding process they carefully appraised the need for the study.

The need to do this research is underpinned by a serious concern that although using adrenaline might help restart the heart in the short term, it causes severe brain damage leading to death a few hours or days later. We want the best possible outcomes for all people who have a cardiac arrest, both now and in the future.

In addition to the doctors, nurses, paramedics and scientists on the study team, the funding body (National Institute for Health Research) appointed a Trial Steering Group and a Data Monitoring and Ethics Committee to oversee the trial, to ensure it is conducted to the highest standards as set out in the Department of Health’s Research Governance Framework. The Data Monitoring Committee is independent of the trial team and had access to the unblinded study data while the trial was underway. This means that they have been able to monitor the data collected at regular intervals throughout the trial and make sure that patients’ rights, dignity and safety are paramount. If for any reason this committee considered that the patients were being put at risk, or if they considered enough evidence has been accumulated to answer the research question about adrenaline at any point, they would have recommended that the trial be stopped.

The UK figures for survival are from data routinely collected by all UK ambulance services so they are thought to be pretty accurate. The Japanese studies that have raised concerns about adrenaline are large observational studies; this means that people were not randomised to receive adrenaline or no adrenaline; instead the studies compared people who received adrenaline during their normal clinical care with those who did not. It is difficult to tell from this type of study whether the differences in survival are due to differences in the treatment or differences in the patients, hence the need for a randomised trial of this treatment.

All patients will have received treatment that is proven to improve survival from cardiac arrest – for example, cardiopulmonary resuscitation (CPR) and defibrillation (electric shocks). Adrenaline is an unproven treatment for cardiac arrest and may be harmful, which is why there is a need for this study. The salt water formed the ‘placebo’ arm of the trial, which is the comparator. Half the patients will have received a placebo, the other half will have received adrenaline. This is the only scientific means of determining whether adrenaline is good for patients or causes harm.

For people assigned to the placebo (salt water) group - treatment will still have included those treatments that are proven to improve survival - these are high-quality cardiopulmonary resuscitation (CPR) and early defibrillation - either by a paramedic, community first responder or public access defibrillation. Without a placebo as the comparator we cannot say if patients receiving adrenaline will do better than or worse.

We respect the wishes of members of the public who do not wish to be enrolled in the PARAMEDIC2 trial. If a member of the public did not wish to be enrolled in the PARAMEDIC 2 trial, it was possible to request a stainless steel bracelet which has the words ‘NO STUDY’ engraved on it. Local paramedics were trained to look for these bracelets in the same way they do for other medical ID bands. This means that, in the event that they had a cardiac arrest, they will have received standard treatment which may include adrenaline. This system is used successfully in North America for a number of trials.