Adrenaline administration forms an integral part of the ALS resuscitation protocol.

How does it work in cardiac arrest and what is the evidence for its use?

Dave Slessor

Adrenaline has been recommended for cardiac arrest for over 50 years and was first described in 1906 (1). The theoretical benefits are an increased myocardial and perfusion pressure through alpha mediated vasoconstriction. By increasing coronary blood flow the frequency and amplitude of the ventricular fibrillation waveform are increased. This increases the chances of successful defibrillation. Animal studies have shown an increased short term survival following cardiac arrest with the use of adrenaline (2).

The disadvantages of adrenaline are that in the post-arrest phase the beta mediated affects of adrenaline lead to an increase in myocardial oxygen consumption, as well as an increased risk of arrhythmias (3). Adrenaline has been associated with impaired tissue oxygen utilisation and lactate clearance as well as decreased cortical microcirculatory blood flow leading to increased cerebral ischaemia (3). Adrenaline also activates platelets and coagulation leading to a pro-thrombotic state (4). The task of administrating adrenaline can lead to a break from chest compressions. This is more likely in the pre-hospital environment as there are less staff available to perform all tasks required.

There have been two randomised controlled trials (RCT) investigating the use of adrenaline in out-of-hospital (OOH) cardiac arrest. The first was in 2009 in Norway (5). They randomised 916 cardiac arrest patients to adrenaline or no adrenaline. This was a non-blinded study. They demonstrated an improvement in ROSC (40% vs 25%, P<0.001) but no difference in their primary outcome of survival until discharge with 10.5% vs. 9.2% surviving, P=0.61. They measured the quality of CPR and found it to be similar in both groups. In a post-hoc analysis they carried out a per protocol analysis and demonstrated a significantly improved survival to discharge in those that did not get adrenaline compared with those that did (6). However, this analysis suffers from bias as there are significant differences between the two groups. This includes the fact that in the per-protocol analysis all patients who had a return of spontaneous circulation (ROSC) prior to an opportunity to administer adrenaline were counted as a positive outcome for the no adrenaline group. It is likely that these patients would have survived regardless of whether adrenaline was given or not.

A second RCT was performed in Australia by Jacobs, comparing adrenaline to placebo in OOH arrest (1). They demonstrated a significantly improved rate of ROSC in those that were given adrenaline compared to those that were given placebo. (23.5% vs. 8.4%, P<0.001). However, they did not demonstrate a significant change in survival to discharge (4% vs. 1.9%, p=0.15). The study was underpowered and the actual numbers of patients surviving to discharge was sixteen. This makes it difficult to make any definite conclusions. They also did not report if there were any differences in the number of patients that were treated with therapeutic hypothermia between the intervention and placebo group.

Hagihara recently published a retrospective cohort study with a concurrent control group (7). This included over 400,000 patients with OOH arrest in Japan. When adjusted for baseline characteristics they demonstrated a significantly improved rate of ROSC in those administered adrenaline compared to those that were not. (Odds ratio [OR] 2.36, 95% Confidence Intervals [CI] 2.22-2.5).

However, the probability of survival at one month was significantly worse in the adrenaline group (OR 0.46, 95% CI 0.42-0.51); as was the probability of survival with a good neurological outcome (OR 0.31, 95% CI 0.26-0.36).

In 2012 Hayashi performed a prospective cohort study with a concurrent control group (8). This included some of the same patients as in Hagihara’s study. Hayashi’s study was a non-randomised, non-blinded study comparing adrenaline with no adrenaline in OOH cardiac arrest. They demonstrated an increase in pre-hospital ROSC in those given adrenaline 29.3% vs. 13.4%, P<0.001. However, they also found a significantly poorer neurologically intact 1 month survival rate 4.1% vs. 6.1%, P=0.028. In a pre-defined subgroup they analysed patients with shock resistant ventricular fibrillation that received adrenaline within 10 minutes of the ambulance call out. In this sub-group they had a significantly higher rate of neurologically intact 1-month survival compared to those that did not receive adrenaline at all (66.9% vs. 24.9%, adjusted OR 6.34). However this result suffers from bias. The adrenaline group included only patients that were given adrenaline within 10 minutes of the ambulance being called. This was possible in only nine cases, out of 205 patients who were administered adrenaline. The ‘no adrenaline’ group did not have a limit on the length of time from cardiac arrest to ambulance arrival and therefore are likely to have had longer times without CPR and longer times prior to arrival of medical personnel, compared to those in the adrenaline group. These confounding variables may explain any differences in results.

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References

1. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo- controlled trial. Resuscitation. 2011;82(9):1138-43.
2. Resuscitation Council U. Resuscitation Guidelines. London: Resuscitation Council UK. 2010.
3. Soar J, Perkins GD, Abbas G, Alfonzo A, Barelli A, Bierens JJLM, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation. 2010;81(10):1400.
4. Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost. 2009;102(2):248-57.
5. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest. JAMA: the journal of the American Medical Association. 2009;302(20):2222-9.
6. Olasveengen TM, Wik L, Sunde K, Steen PA. Outcome when adrenaline (epinephrine) was actually given vs. not given-post hoc analysis of a randomized clinical trial. Resuscitation. 2011.
7. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA: the journal of the American Medical Association. 2012;307(11):1161-
8. Hayashi Y, Iwami T, Kitamura T, Nishiuchi T, Kajino K, Sakai T, et al. Impact of Early Intravenous Epinephrine Administration on Outcomes Following Out-of- Hospital Cardiac Arrest. Circulation journal: official journal of the Japanese Circulation Society. 2012.