NIHR DC Discover

Paramedic giving injection to patient at the scene.

NIHR Signal Adrenaline can restart the heart but is no good for the brain

Published on 4 September 2018

doi: 10.3310/signal-000639

Treating cardiac arrests with adrenaline during resuscitation by paramedics slightly increases survival compared with placebo. Though adrenaline initially helped restore circulation in a third of cases, 3.2% of people survived to 30 days compared to 2.4% of people in the placebo group. Severe brain damage was nearly twice as likely in those who survived after adrenaline injections.

Cardiac arrest occurs when the heart no longer pumps blood around the body, usually due to an irregular heart rhythm which can have a variety of causes including coronary heart disease.

This NIHR-funded trial of 8,014 people who had a cardiac arrest outside hospital provides high-quality UK-based evidence on the benefits and harms of adrenaline use during advanced cardiopulmonary resuscitation (CPR).  

Due to the low overall survival rate, the jury is still out on whether adrenaline should be reserved for use in certain heart rhythms or within a particular time period and not for others. Early bystander recognition and CPR, plus early defibrillation probably have a greater impact on survival.

Share your views on the research.

Why was this study needed?

Adrenaline injections have been commonly used during CPR for cardiac arrest for more than 60 years, without clear evidence if it is helpful or harmful. Adrenaline can increase the likelihood that the heart will regain a normal rhythm as it directs blood flow to the heart. However, it also causes constriction of small blood vessels which can reduce blood flow to other organs, including the brain, and may lead to neurological damage.

Use of adrenaline has been linked to better short-term survival in observational studies, so it has remained in the cardiac arrest guidelines. Randomised controlled trials have been needed to determine if the benefits outweigh the potential harms. This study assessed routine adrenaline use in cardiac arrests occurring outside hospital.

What did this study do?

The PARAMEDIC2 randomised controlled trial allocated 8,014 people with cardiac arrest to receive either 1mg adrenaline or placebo saline injections as part of advanced CPR treatment by paramedics at the scene. On average people in the adrenaline, group received a total dose of 4.9mg.

The average age was 70. Bystander CPR was also performed in 59% of each group. The ambulances took just over six minutes to arrive and gave the injections on average 21 minutes after emergency services were first called. Major outcomes were adjusted for variations in these factors.

Over a third of cases had unwitnessed cardiac arrest, over half had no heart electrical activity (asystole), and only 19% had a shockable rhythm. This may have contributed to the low survival rates.

Overall this large, well-designed trial provides much-needed UK-based, high-quality evidence to inform practice.

What did it find?

  • People who received adrenaline had a slightly higher rate of survival at 30 days, 130/4,105 (3.2%) compare to 94/3,999 (2.4%) who received the saline placebo (adjusted odds ratio [OR] 1.47, 95% confidence interval [CI] 1.09 to 1.97).
  • Return of spontaneous circulation was much more likely with adrenaline, occurring in 1,457 (36.3%) people in the adrenaline group versus 468 (11.7%) people in the placebo group. A substantially higher number of people given adrenaline survived until hospital admission, 947 (23.8%) compared with 319 (8%) of the placebo group.
  • Although the overall rate of survival at 30 days was slightly better with adrenaline, 39/126 (31%) people had severe neurological disability in the adrenaline group, compared with 16/90 (17.8%) in the placebo group. Severe neurological disability was defined as a score of 4 or 5 on the modified Rankin scale.
  • Only 27 people in total had no neurological symptoms at discharge. There were a similar number of people in each group when combining those with no symptoms, mild or moderate neurological disability, modified Rankin scale 0 to 3 (OR 1.19, 95% CI 0.85 to 1.68).

What does current guidance say on this issue?

The 2015 Resuscitation Council UK guideline recommends giving adrenaline every three to five minutes during CPR if a normal heart rhythm is absent. Guidance on the early management of people who have had a cardiac arrest by the Faculty of Pre-Hospital Care at the Royal College of Surgeons of Edinburgh (2017) emphasises the importance of recognising that the person is having a cardiac arrest and beginning CPR as soon as possible.

What are the implications?

Adrenaline improved the return of spontaneous circulation and likelihood of survival to reach hospital but only slightly increased survival rates at 30 days. More of those survivors had severe neurological problems.

It remains unclear if out of hospital protocols should change as a result of this trial. The findings are also not able to inform hospital cardiac arrest protocols, as use of adrenaline typically occurs within three minutes of cardiac arrest.

Other studies of out of hospital cardiac arrest have shown better outcomes from prompt recognition, bystander CPR and defibrillation. Strategies to increase public training in CPR and make more defibrillators available may increase the number of people surviving out of hospital cardiac arrest.

Citation and Funding

Perkins GD, Ji C, Deakin CD, et al. PARAMEDIC2 Collaborators. A randomized trial of adrenaline in out-of-hospital cardiac arrest. N Engl J Med. 2018; 379(8):711-21.

This project was funded by the National Institute for Health Research HTA Programme (project number 12/127/126).

Bibliography

Deakin C, Brown S, Jewkes F, et al. Prehospital resuscitation. London: Resuscitation Council (UK); 2015.

Monsieurs KG, Nolan JP, Bossaert LL, et al. European Resuscitation Council Guidelines for Resuscitation 2015 Section 1. Executive summary. Resuscitation. 2015;95:1-80.

Resuscitation Council (UK). Resuscitation to recovery. London: Resuscitation Council (UK); 2017.

Soar J, Deakin C, Lockey A, et al. Adult advanced life support. London: Resuscitation Council (UK); 2015.

Why was this study needed?

Adrenaline injections have been commonly used during CPR for cardiac arrest for more than 60 years, without clear evidence if it is helpful or harmful. Adrenaline can increase the likelihood that the heart will regain a normal rhythm as it directs blood flow to the heart. However, it also causes constriction of small blood vessels which can reduce blood flow to other organs, including the brain, and may lead to neurological damage.

Use of adrenaline has been linked to better short-term survival in observational studies, so it has remained in the cardiac arrest guidelines. Randomised controlled trials have been needed to determine if the benefits outweigh the potential harms. This study assessed routine adrenaline use in cardiac arrests occurring outside hospital.

What did this study do?

The PARAMEDIC2 randomised controlled trial allocated 8,014 people with cardiac arrest to receive either 1mg adrenaline or placebo saline injections as part of advanced CPR treatment by paramedics at the scene. On average people in the adrenaline, group received a total dose of 4.9mg.

The average age was 70. Bystander CPR was also performed in 59% of each group. The ambulances took just over six minutes to arrive and gave the injections on average 21 minutes after emergency services were first called. Major outcomes were adjusted for variations in these factors.

Over a third of cases had unwitnessed cardiac arrest, over half had no heart electrical activity (asystole), and only 19% had a shockable rhythm. This may have contributed to the low survival rates.

Overall this large, well-designed trial provides much-needed UK-based, high-quality evidence to inform practice.

What did it find?

  • People who received adrenaline had a slightly higher rate of survival at 30 days, 130/4,105 (3.2%) compare to 94/3,999 (2.4%) who received the saline placebo (adjusted odds ratio [OR] 1.47, 95% confidence interval [CI] 1.09 to 1.97).
  • Return of spontaneous circulation was much more likely with adrenaline, occurring in 1,457 (36.3%) people in the adrenaline group versus 468 (11.7%) people in the placebo group. A substantially higher number of people given adrenaline survived until hospital admission, 947 (23.8%) compared with 319 (8%) of the placebo group.
  • Although the overall rate of survival at 30 days was slightly better with adrenaline, 39/126 (31%) people had severe neurological disability in the adrenaline group, compared with 16/90 (17.8%) in the placebo group. Severe neurological disability was defined as a score of 4 or 5 on the modified Rankin scale.
  • Only 27 people in total had no neurological symptoms at discharge. There were a similar number of people in each group when combining those with no symptoms, mild or moderate neurological disability, modified Rankin scale 0 to 3 (OR 1.19, 95% CI 0.85 to 1.68).

What does current guidance say on this issue?

The 2015 Resuscitation Council UK guideline recommends giving adrenaline every three to five minutes during CPR if a normal heart rhythm is absent. Guidance on the early management of people who have had a cardiac arrest by the Faculty of Pre-Hospital Care at the Royal College of Surgeons of Edinburgh (2017) emphasises the importance of recognising that the person is having a cardiac arrest and beginning CPR as soon as possible.

What are the implications?

Adrenaline improved the return of spontaneous circulation and likelihood of survival to reach hospital but only slightly increased survival rates at 30 days. More of those survivors had severe neurological problems.

It remains unclear if out of hospital protocols should change as a result of this trial. The findings are also not able to inform hospital cardiac arrest protocols, as use of adrenaline typically occurs within three minutes of cardiac arrest.

Other studies of out of hospital cardiac arrest have shown better outcomes from prompt recognition, bystander CPR and defibrillation. Strategies to increase public training in CPR and make more defibrillators available may increase the number of people surviving out of hospital cardiac arrest.

Citation and Funding

Perkins GD, Ji C, Deakin CD, et al. PARAMEDIC2 Collaborators. A randomized trial of adrenaline in out-of-hospital cardiac arrest. N Engl J Med. 2018; 379(8):711-21.

This project was funded by the National Institute for Health Research HTA Programme (project number 12/127/126).

Bibliography

Deakin C, Brown S, Jewkes F, et al. Prehospital resuscitation. London: Resuscitation Council (UK); 2015.

Monsieurs KG, Nolan JP, Bossaert LL, et al. European Resuscitation Council Guidelines for Resuscitation 2015 Section 1. Executive summary. Resuscitation. 2015;95:1-80.

Resuscitation Council (UK). Resuscitation to recovery. London: Resuscitation Council (UK); 2017.

Soar J, Deakin C, Lockey A, et al. Adult advanced life support. London: Resuscitation Council (UK); 2015.

A randomized trial of adrenaline in out-of-hospital cardiac arrest

Published on 23 August 2018

Gavin D. Perkins, M.D., Chen Ji, Ph.D., Charles D. Deakin, M.D., Tom Quinn, M.Phil., Jerry P. Nolan, M.B., Ch.B., Charlotte Scomparin, M.Sc., Scott Regan, B.A., John Long, Anne Slowther, Ph.D., Helen Pocock, M.Sc., John J.M. Black, M.B., B.S., Fionna Moore, M.B., B.S., et al., for the PARAMEDIC2 Collaborators*

N Eng J Med Volume 379 , 2018

BACKGROUND Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. METHODS In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). RESULTS At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). CONCLUSIONS In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024.)

The modified Rankin scale scores for disability are defined as:

  • 0 No symptoms
  • 1 No significant  disability despite symptoms
  • 2 Slight disability; unable to perform all previous activities but able to look after own affairs without assistance
  • 3 Moderate disability; requires some help but able to walk unassisted
  • 4 Moderate severe disability; unable to walk and attend to bodily needs without assistance
  • 5 Severe disability; bedridden, incontinent and requiring constant nursing care
  • 6 Death

The number needed to treat (NNT) with adrenaline injections to prevent one death in this trial was, 112 people. Other trials of out of hospital cardiac arrest found much lower numbers for:

  • early recognition, NNT 11 people
  • bystander CPR, NNT 15 people
  • early defibrillation, NNT 5 people.

Expert commentary

This trial shows that adrenaline slightly increases the chances of survival after cardiac arrest but also increases survival with brain damage. Paramedics now know the effect of using adrenaline, but determining practice depends upon patient values, which obviously have to be communicated in advance.

Clinical guideline developers should use the trial results alongside public consultation to determine whether or not adrenaline administration should be standard practice in cases of cardiac arrest.

People who want their treatment to deviate from standard practice will then know that they should make their preference clear in advance.

Steve Goodacre, Professor of Emergency Medicine, The University of Sheffield

Expert commentary

This study addressed the long-recognised need to determine the effectiveness and long-term safety of adrenaline which was previously assumed but not known. Long-term survival to 30 days post-arrest was the primary outcome measure because 95% of public respondents prioritised this over short-term outcomes. The rich data it has produced confirms the short-term effectiveness of adrenaline in achieving return of spontaneous circulation but no longer-term advantage, and a potential for increased harm.

Once fully evaluated, with all previous evidence, by the International Liaison Committee on Resuscitation, it will impact all future guidelines. However, it also highlights two exceptionally important facts: firstly, that early recognition of cardiac arrest, CPR performed by a bystander, and early defibrillation were all far more effective than adrenaline at improving survival. Secondly, that we must look at longer-term outcomes and engage the public and patients to understand what outcomes they and we should really consider as important.

Professor Jonathan Wyllie, President, Resuscitation Council UK