See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/280255410

adrenaline in cardiac arrest

Article · March 2015

CITATION READS

1 695

1 author:

Michael Anthony Smyth

The University of Warwick
48 PUBLICATIONS   1,033 CITATIONS   

SEE PROFILE

All content following this page was uploaded by Michael Anthony Smyth on 26 October 2016.

The user has requested enhancement of the downloaded file.


Adrenaline
and
cardiac arrest
Historically, cardiac arrest research has focussed extensively on increasing the number of patients with
return of spontaneous circulation (ROSC) and survival to hospital discharge, with fewer studies focussing
on improving quality of life post cardiac arrest. However, over the last decade or so researchers have
been striving to improve neurologic outcomes for survivors of cardiac arrest.Therapeutic hypothermia is
one example of a recent intervention that may help improve this important parameter, whilst the use of
adrenaline has been attracting increasing attention for its effect on neurologically intact survival.
What is adrenaline?
Adrenaline is a hormone, produced
principally in the medulla of the adrenal
glands, that stimulates the sympathetic
nervous system. It is the body’s primary ‘fight
or flight’ hormone. Adrenaline secretion
increases heart rate and cardiac output,
dilates bronchioles and pupils, increases
blood supply to skeletal muscle, and elevates
available blood glucose.
Normal circulating adrenaline levels are
around 10 ng/L, but these may rise up to
50 fold in times of stress (Baumgartner
et al 1985). In cases of cardiac arrest, we
administer 1mg boluses that raise the
plasma concentration to 10000-100000
ng/L – at least a 1000 times higher than the
normal circulating amount.
History of adrenaline use in cardiac
arrest
Routine use of adrenaline for cardiac arrest
was first proposed in the 1960’s and has
remained entrenched in clinical practice
ever since (Callaway et al 2012). Its inclusion
within cardiac arrest management was based
upon an understanding of the physiological
role of adrenaline, and experimental data
from animal research which showed that
ROSC was more likely when the drug was
used (Pearson & Reading 1963). It was not
included on the basis of evidence of benefit
in humans, but has remained a significant
component of advanced life support despite
minimal human data indicating beneficial
effect (Callaway et al 2012).
How might adrenaline benefit the
cardiac arrest patient?
In cardiac arrest, adrenaline’s primary
beneficial effect is to increase coronary
artery perfusion pressure.
Administration of large quantities of
adrenaline (relative to the body’s normal
production) causes vasoconstriction leading
to increased venous return. Increased
Spring 2015 | Ambulancetoday
Focus on Adrenaline & Cardiac Arrest
venous return fills the heart with blood, vasoconstriction. The consequence of this
whilst external chest compressions generate reduced perfusion is widespread ischaemia
forward flow of blood through the arterial which precipitates an inflammatory
system (valves in the heart and veins response following ROSC (Gaussorgues
minimise backward flow through the venous et al 1988, Adrie et al 2002). In addition
system). Vasoconstriction is not limited to there is evidence that adrenaline may
veins, arteries are also affected; therefore induce hypokalaemia (Roffey et al 2003),
the forward flow of blood generated by platelet aggregation (Poulis et al 2000), and
chest compressions is impeded as a result cause oxidative damage (Bindoli et al 1992,
of increased aortic tone. As aortic pressure Behonick et al 2001).
rises blood flow is encouraged toward lower
pressure areas, consequently blood flow into Of particular concern is the fact that
the coronary arteries is increased leading adrenaline has been shown to reduce
to improved coronary artery perfusion cerebral microvascular blood flow in animal
pressure. studies (Ristagno et al 2009); these minute
vessels are the vessels in which gaseous
Experimental studies have shown that exchange takes place. If blood flow in these
ROSC is related to coronary perfusion vessels is reduced then so too is the ability
pressure. When coronary perfusion to deliver oxygen and remove metabolic
pressure is below 15 mmHg the likelihood waste.
of achieving ROSC is reduced (Paradis
et al 1990); therefore raising coronary Although external chest compressions
perfusion pressure is a key objective generate arterial flow, the cardiac output
generated by them is at best 1/3 of normal
during resuscitation (Callaway et al 2012).
Our understanding of the physiology of
adrenaline and experimental data relating Biography: Mike Smythe
to coronary perfusion pressure and ROSC
indicates that adrenaline should be of Mike Smythe
benefit to patients in cardiac arrest by its Biography.
pressure generating effects.
Are there any potentially adverse
effects of adrenaline use in cardiac
arrest?
There are several potentially adverse effects
associated with adrenaline use during
resuscitation. It increases myocardial oxygen
consumption (Ditchey & Lindenfeld 1988),
increases post-resuscitation myocardial
dysfunction (Tang et al 1995) and may
induce ventricular arrhythmias (Tovar &
Jones 1997). It has also been argued that
the widespread vasoconstriction caused by
high doses of adrenaline impairs perfusion of
vital organs. Lindberg et al (2000) argue that
adrenaline reduces overall cardiac output as
blood flow to non-vital organs is reduced
to almost zero as a result of the widespread
1
3
Focus on Adrenaline & Cardiac Arrest
(Babbs et al 1983). Perfusion of major
organs, including the brain, is therefore
markedly impaired when external chest
compressions are required to maintain
blood flow. A further reduction in cerebral
blood flow secondary to adrenaline
administration risks exacerbating ischaemic/
hypoxic injury. Although the half-life of
adrenaline, is relatively short, the cerebral
microvasculature will also remain constricted
for some minutes post ROSC, extending the
potential for cerebral insult beyond when
ROSC has been achieved.
What does the available evidence
tell us about outcomes following
adrenaline use in cardiac arrest?
Several clinical studies have been published
in the medical literature relating to the
effects of adrenaline in cardiac arrest, but
the picture presented by the evidence is not
yet clear.
Uncertainty regarding the optimal dose
of adrenaline has existed for a number
of years. Historically very high doses of
adrenaline were routinely administered
during resuscitation. In 1995 Woodhouse
and colleagues showed that there was
no difference in survival when the dose
was reduced from 10mg (practice at that
time) to 1mg (dose currently used). That
same year Herlitz et al (1995) published an
observational study involving 1,203 patients
in ventricular fibrillation (VF) reporting that
patients who received adrenaline were
more likely to achieve ROSC and arrive
at hospital with a pulse, but they were no
more likely to survive to hospital discharge.
The authors concluded that adrenaline does
not increase survival from out-of-hospital
2 Spring 2015 | Ambulancetoday
cardiac arrest (Herlitz et al 1995).
The research group OPALS published an
observational study based on results before
and after the introduction of Advanced Life
Support by paramedics in Ontario, Canada.
Following the change patients were 33.9%
more likely to achieve ROSC (10.9% BLS vs
14.6% ALS), but they were no more likely to
survive to hospital discharge. 95.8% of ALS
patients had received adrenaline (Steill et al
1995).
In 2002, Holmberg and colleagues published
data from an analysis of 10,966 out-of-
hospital resuscitation attempts showing that
patients who had received adrenaline were
half as likely to survive as patients who did
not, while patients who were intubated
were 40% less likely to survive. They also
reported a further subgroup analysis of
patients who had received 3 or more shocks
(the group of patients most likely to benefit
from adrenaline and require intubation)
indicating that there was no improvement
to survival if adrenaline or intubation were
used.
In 2007 Marcus Ong and his group
undertook a similar ‘before and after’ study
involving 1,296 out-of-hospital cardiac
arrest victims and showed that prehospital
adrenaline did not increase ROSC, survival
to admission or survival to discharge. It did,
however, cause a small increase in on-scene
time.
In 2009 Teresa Olasveengen conducted
a trial comparing outcomes for out-of-
hospital cardiac arrest patients (in Norway)
based upon on whether or not patients
received IV drugs, or not (the drugs were
not limited to adrenaline and included
atropine and an anti-arrhythmic). She
found that patients who received vascular
access and drug administration had better
short-term survival (40% vs 25%) but no
significant improvement in survival to
hospital discharge, or long-term survival
(10.5% vs 9.2%, p not significant). When
outcomes were analysed by presenting
rhythm i.e. shockable vs non-shockable,
survival rates appeared to be slightly higher
in shockable rhythms, and lower in non-
shockable rhythms however these findings
were not statistically significant (i.e. they
could have occurred by chance). Her group
also undertook a post-hoc analysis of the
same patients depending upon whether or
not they received adrenaline; this analysis
showed that patients receiving adrenaline
were no more likely to achieve ROSC
than those not receiving adrenaline, and
furthermore that patients who received
adrenaline had worse long term survival
outcomes than those who did not.
The first, and thus far only, randomised
controlled trial comparing outcomes
between cardiac arrest patients receiving
adrenaline versus saline placebo was
undertaken by Jacobs et al in Australia.
Their results, published in 2011, indicated
that patients receiving adrenaline were
3.4 times more likely to achieve ROSC,
but no more likely to be discharged alive.
Two patients in the adrenaline arm of the
study had poor neurologic outcome, while
none in the placebo arm did. This trial also
showed the same trend when comparing
patients presenting with shockable vs non-
shockable rhythms. Unfortunately this trial
only recruited 535 patients, and a significant
number of patients were excluded from
analysis, this trial does not therefore provide
adequate evidence to change current
practice.
There has been a recent increase in the
number of studies addressing the use of
adrenaline in cardiac arrest. In 2012, Glover
et al reported that survival was inversely
related to the amount of adrenaline
administered i.e. the more doses of
adrenaline administered, the less likely the
patient is to survive. This information should
not necessarily be interpreted to suggest
adrenaline is harmful, but may instead
reflect that patients who receive prolonged
resuscitation attempts are less likely to
survive, and will receive more adrenaline
in the course of an extended resuscitation
attempt.
That same year Hayashi et al published a
study comparing no adrenaline with early
(within 10 minutes) and late adrenaline
administration. Their observational study
included 3,161 patients and they found that
patients who received adrenaline were 33%
less likely to survive neurologically intact
at 1 month. Additionally, those patients
who presented in ventricular fibrillation
(VF) and received adrenaline early were
almost 3 times more likely to suffer adverse
neurologic outcomes (Hayashi et al 2012).
In another small study Machida et al
(2012) studied 644 out-of-hospital cardiac
arrest patients and compared survival and
neurologic status among patients who had
and had not received adrenaline before
arriving at hospital. They did not identify
any significant differences between the
adrenaline and non-adrenaline groups with
regard to return of spontaneous circulation,
survival to hospital admission, survival to
hospital discharge, or good neurologic
recovery at hospital discharge. They
concluded that adrenaline administration
before arrival at the hospital for the
treatment of out-of-hospital cardiac arrest
did not improve the clinical outcome.
A major analysis of registry data comparing
cardiac arrest outcomes before and after
the introduction of advanced life support
paramedics was published by Hagihara et al
in 2012. This observational study reported
outcomes for 417,188 patients and the
results repeated a pattern similar to those
observed in the previously reported studies
- patients receiving adrenaline were more
likely to achieve ROSC, but were less likely
to survive to discharge. The pattern was the
same for both shockable and non-shockable
rhythms. A second study utilising the same
Japanese cardiac arrest database, using
slightly different methods to the Hagihara
study, was published by Nakahara et al
 Focus on Adrenaline & Cardiac Arrest

(2013) who matched equivalent pairs measure of perfusion, when elevated it Conclusion
of patients who had received adrenaline suggests poor or inadequate perfusion). The evidence for adrenaline administration
with who had not i.e. paired two patients in cardiac arrest does not demonstrate
of similar age, co-morbidities, presenting While earlier papers have indicated that
there is no difference in survival to discharge improved patient centred outcomes despite
rhythm, presence of bystander CPR, its routine use. The International Liaison
duration of resuscitation attempt, one of when adrenaline is administered, recent
papers begin to suggest that adrenaline Committee for Resuscitation (ILCOR),
whom received adrenaline and one who European Resuscitation Council and the
did not. They studied 1,990 pairs of patients may be harmful. Observational studies
using propensity matching attempt to adjust United Kingdom Resuscitation Council have
presenting in shockable rhythms and 9,058 identified that there is a lack of evidence
pairs of patients presenting with non- for time as a variable and suggest that we
should question the value of adrenaline to support the routine use of adrenaline
shockable rhythms. They reported that, for in the management of cardiac arrest. Both
patients who presented with a shockable in cardiac arrest. However, because these
studies are observational in nature we ILCOR and the UK Resuscitation Council
rhythm, those who received adrenaline have stated there is a need for a large
were more likely to survive, but there cannot be certain.
randomised controlled trial to determine
was no improvement in neurologic status. The above represents a summary of the if adrenaline should be used in cardiac
Patients who presented in non-shockable evidence surrounding adrenaline use in arrest. The need is being addressed.
rhythms had an increase in both survival cardiac arrest. The weight of evidence PARAMEDIC2 is a randomised controlled
and improved neurologic status. However, a suggests that adrenaline does increase short trial that will attempt to answer this
re-analysis of the same data by Olasveengen term survival (i.e. adrenaline improves ROSC question. The West Midlands, South Central,
published in the BMJ indicated that patients rates), but it is uncertain that it benefits North East, Welsh and London Ambulance
who were in a shockable rhythm and long term survival. Some observational data Services will be participating in this trial.
received adrenaline were, in fact, more suggest that adrenaline may be associated The first patient entered into the trial was
likely to have worse neurologic outcomes with adverse neurologic outcomes however recruited by London Ambulance Service in
(Olasveengen 2013). there may be some neurologic and survival December 2014.
The most recent study addressing the use of benefit for the subset of patients presenting
in non-shockable rhythms. Unfortunately To find out more about PARAMEDIC
adrenaline for out-of-hospital cardiac arrest 2 visit the trial website:
is a small retrospective study that aimed to observational studies are not able to
provide a definitive answer to the question http://www2.warwick.ac.uk/fac/med/
identify factors associated with a favourable research/hscience/ctu/trials/critical/
neurologic recovery (defined as survival “is adrenaline beneficial in cardiac arrest?”
– this should be evident when considering paramedic2/
to hospital discharge with a GCS of 14 or
15). Kaji and colleagues (2014) reported that the same Japanese cardiac arrest Disclaimer
that survival to hospital admission and a database has been used to produce differing This project is funded by the National Institute for Health
results. The only randomised controlled Research’s Health Technology Assessment programme
good neurologic outcome was associated (project number 12/127/126). The views and opinions
with having received less than 1.5mg of trail designed to address adrenaline use in expressed therein are those of the authors and do
adrenaline and having a lactate level of less cardiac arrest suggests there is no benefit; not necessarily reflect those of the Health Technology
than 5 mmol/L. (Lactate can be a useful however the trial was too small to provide a Assessment Programme, NIHR, NHS or the Department
conclusive answer. of Health.
References
Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, Fraisse F, Dinh- Lindberg L, Liao Q, Steen S. (2000) The effects of epinephrine/norepinephrine on end-tidal
Xuan AT, Carli P, Spaulding C, Dhainaut JF, Cavaillon JM. (2002) Successful cardiopulmonary carbon dioxide concentration, coronary perfusion pressure and pulmonary arterial blood
resuscitation after cardiac arrest as a ‘sepsis-like’ syndrome. Circulation 106(5), 562–568. flow during cardiopulmonary resuscitation. Resuscitation 43(2), 129–140.
Babbs CF, Voorhees WD, Fitzgerald KR, Holmes HR, Geddes LA. (1983) Relationship of blood Machida M. Miura S. Matsuo K. Ishikura H. Saku K. (2012) Effect of intravenous adrenaline
pressure and flow during CPR to chest compression amplitude: evidence for an effective before arrival at the hospital in out-of-hospital cardiac arrest. Journal of Cardiology.
compression threshold. Annals of Emergency Meicine. 12(9):527–532. 60(6):503-507.
Baumgartner H. Wiedermann CJ. Hörtnagl H. Mühlberger V. (1985) Plasma catecholamines in Nakahara S. Tomio J. Takahashi H. Ichikawa M. Nishida M. Morimura N. Sakamoto T. (2013)
arterial and capillary blood. Archives of Pharmacology. 328(4):461-463. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical
services for patients with out of hospital cardiac arrest in Japan: controlled propensity
Behonick GS, Novak MJ, Nealley EW, Baskin SI (2001) Toxicology update: the cardiotoxicity of matched retrospective cohort study. BMJ. 347:f6829.
the oxidative stress metabolites of catecholamines (aminochromes). J. Appl. Toxicol. 21(Suppl.
1), S15–S22. Ong ME. Tan EH. Ng FS. Panchalingham A. Lim SH. Manning PG. Ong VY. Lim SH. Yap S. Tham
LP. Ng KS. Venkataraman A. (2007) Survival outcomes with the introduction of intravenous
Bindoli A, Rigobello MP, Deeble DJ (1992) Biochemical and toxicological properties of the epinephrine in the management of out-of-hospital cardiac arrest. Annals of Emergency
oxidation products of catecholamines. Free Radic. Biol. Med. 13(4), 391–405. Medicine. 50(6):635-642.
Callaway CW (2012) Questioning the use of epinephrine to treat cardiac arrest. JAMA. Olasveengen TM. Sunde K. Brunborg C. Thowsen J. Steen PA. Wik L. (2009) Intravenous drug
307(11): 1198-1199 administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 302(20):2222-
Ditchey RV, Lindenfeld J (1988) Failure of epinephrine to improve the balance between 2229.
myocardial oxygen supply and demand during closed-chest resuscitation in dogs. Circulation Olasveengen TM. (2013) Adrenaline for out of hospital cardiac arrest? BMJ. 347:f7268.
78(2), 382–389 (1988).
Paradis NA, Martin GB, Rivers EP, Goettng MG, Appleton TJ, Feingold M, Nowak RM.
Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D (1988) (1990) Coronary perfusion pressure and the return of spontaneous circulation in human
Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med. cardiopulmonary resuscitation. JAMA 263(8), 1106–1113.
14(5), 575–577.
Pearson JW, Redding JS (1963) Epinephrine in cardiac resuscitation. American Heart Journal.
Glover BM, Brown SP, Morrison L, Davis D, Kudenchuk PJ, Van Ottingham L, Vaillancourt C, 66(), 210–214.
Cheskes S, Atkins DL, Dorian P (2012) Wide variability in drug use in out-of-hospital cardiac
arrest: a report from the resuscitation outcomes consortium. Resuscitation. 83(11):1324- Poullis DM (2000) Repeated administration of vasopressin but not epinephrine maintains
1330. coronary perfusion pressure after early and late administration during prolonged
cardiopulmonary resuscitation in pigs. Circulation 101(16), E174–E175.
Hagihara A. Hasegawa M. Abe T. Nagata T. Wakata Y. Miyazaki S. (2012) Prehospital epinephrine
use and survival among patients with out-of-hospital cardiac arrest. JAMA. 307(11):1161-1168. Ristagno G, Tang W, Huang L, Fymat A, Chang YT, Sun S, Castillo C, Weil MH. (2009)
Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation. Crit. Care
Hayashi Y. Iwami T. Kitamura T. Nishiuchi T. Kajino K. Sakai T. Nishiyama C. Nitta M. Hiraide A. Med. 37(4), 1408–1415.
Kai T. (2012) Impact of early intravenous epinephrine administration on outcomes following
out-of-hospital cardiac arrest. Circulation Journal. 76(7):1639-1645. Roffey P, Thangathurai D, Mikhail M, Shoemaker W (2003) Implication of epinephrine-induced
hypokalemia during cardiac arrest. Resuscitation 58(2), 231.
Herlitz J. Ekstrom L. Wennerblom B. Axelsson A. Bang A. Holmberg S. (1995) Adrenaline in
out-of-hospital ventricular fibrillation. Does it make any difference? Resuscitation. 29(3):195- Stiell IG. Wells GA. Hebert PC. Laupacis A. Weitzman BN. (1995) Association of drug therapy
201. with survival in cardiac arrest: limited role of advanced cardiac life support drugs. Academic
Emergency Medicine. 2(4):264-273.
Holmberg M. Holmberg S. Herlitz J. (2002) Low chance of survival among patients requiring
adrenaline (epinephrine) or intubation after out-of-hospital cardiac arrest in Sweden. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ (1995) Epinephrine increases the
Resuscitation. 54(1):37-45. severity of postresuscitation myocardial dysfunction. Circulation 92(10), 3089–3093.
Jacobs IG. Finn JC. Jelinek GA. Oxer HF. Thompson PL. (2011) Effect of adrenaline on Tovar OH, Jones JL (1997) Epinephrine facilitates cardiac fibrillation by shortening action
survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. potential refractoriness. J. Mol. Cell. Cardiol. 29(5), 1447–1455.
Resuscitation. 82(9):1138-1143. Woodhouse SP. Cox S. Boyd P. Case C. Weber M. (1995) High dose and standard dose
Kaji AH, Hanif AM, Bosson N, Ostermayer D, Niemann JT. (2014) Predictors of neurologic adrenaline do not alter survival, compared with placebo, in cardiac arrest. Resuscitation.
outcome in patients resuscitated from out-of-hospital cardiac arrest using classification and 30(3):243-249.
regression tree analysis. Am J Cardiol. 114(7):1024-1028.

Spring 2015 | Ambulancetoday 3

View publication stats