www.bmj.com/cgi/content/full/327/7427/1332
BMJ 2003;327:1332-1335 (6 December), doi:10.1136/bmj.327.7427.1332
Andrew P C McLean-Tooke, specialist registrar1, Claire A Bethune, specialist registrar1, Ann C Fay, consultant immunologist1, Gavin P Spickett, consultant immunologist1
1 Regional Department of Immunology and Allergy, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP
Correspondence to: A P C McLean-Tooke [email protected]
Adrenaline (epinephrine) is the recommended first line treatment for patients with anaphylaxis. This review discusses the safety and efficacy of adrenaline in the treatment of anaphylaxis in the light of currently available evidence. A pragmatic approach to use of adrenaline auto-injectors is suggested.
Anaphylaxis is the clinical syndrome representing the most severe systemic allergic reactions. Mediator release results in smooth muscle contraction, vasodilation, increased vascular permeability, and activation of vagal pathways, leading to the classic features of anaphylaxis, including urticaria and angioedema, bronchoconstriction and hypotension. Owing to the nature of anaphylaxis there are few controlled clinical trials, and therapeutic recommendations are based on clinical observation and animal models. We look at the current evidence for the use of adrenaline (epinephrine) in anaphylaxis, including its safety and route and timing of administration. We also discuss adrenaline auto-injectors and their role in patients with anaphylaxis.
We searched Medline using the key words adrenaline, anaphylaxis,epinephrine, and Epipen, and articles from the authors' personal collection. When necessary we accessed cross references and related articles. Evidence has been graded, where possible (see bmj.com). Only studies with clinical outcomes have been classified (see table on bmj.com); those showing in vitro improvements have not been graded.
Anaphylaxis is a severe, life threatening systemic reaction that can affect all ages. The clinical syndrome may involve multiple target organs, including skin, respiratory, gastrointestinal, and cardiovascular systems. The essential underlying mechanism is the presence of biologically active chemical mediators released from mast cells or basophils.1 If this occurs in the contextof a classic IgE mediated reaction from previously sensitised mast cells or basophils then anaphylactic reaction is the preferred term. Degranulation of mast cells or basophils may also occur in non-IgE mediated mechanisms, and these reactions are termed anaphylactoid reactions. Clinically it is not possible to distinguish the two, and treatments for both mechanisms are identical. Invalid assumptions of an anaphylactoid cause have led to fatal re-exposure.2
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Anaphylaxis occurs in an acute and unexpected manner. The true incidence is unknown. Epidemiological studies have shown differing results owing to differences in both definitions of anaphylaxis and the population groups studied. A retrospective population based study in Olmsted County, United States showed an incidence of 21 cases per 100 000 person years.3 A retrospective study in a UK accident and emergency department suggested an incidence of between 1 in 2300 and 1 in 1500 attendances, and retrospectiveanalysis in a US emergency room has shown an incidence of 1 in 1100 attendances.4 5 Most data for the incidence have been derived from hospital databases, and it is widely believed anaphylaxis is under-recognised and under-reported.5-7 Anaphylaxis remains an important cause of mortality. Of 164 fatal reactions identified between 1992 and 1998 in the United Kingdom, around half were iatrogenic.8 Of the non-iatrogenic causes, half were relatedto venom (for example, wasp sting) and most of the remainder to food.
Adrenaline has physiological benefits in the treatment of
anaphylaxis:stimulation of 
adrenoceptors increases
peripheral vascular resistance thus improving blood pressure
and coronary perfusion, reversing peripheral vasodilation, and
decreasing angioedema. Stimulation of 
1 adrenoceptors has
both positive inotropic and chronotropic cardiac effects. Stimulation
of 2receptors causes bronchodilation as well as increasing
intracellular cyclic adenosine monophosphate production in mast cells
and basophils, reducingrelease of inflammatory mediators.9 However,
given the speed of onset, the often unexpected occurrence
and rapid response to treatment, there are few controlled
clinical trials in acute anaphylaxis, and this is unlikely to
change. Most treatment recommendations have therefore been based
on clinical observation, interpretation of the pathophysiology
and, to an extent, animalmodels.9 w1
Is adrenaline safe?
Adrenaline is the recommended first line treatment in anaphylaxis (fig
1).10Confusion
arises because systemic allergic reactions can be mild,
moderate, or severe. For example, generalised angioedema and
urticaria without airway involvement would not be described as
anaphylaxis. A good working definition is that an anaphylactic reaction
involves one or both of the two severe features: respiratory difficulty
(which may be due to laryngeal oedema or asthma) and
hypotension (which may present as fainting, collapse, or loss of
consciousness). Inappropriate use of adrenaline may be
dangerous. Most adverse events with adrenaline usage occur when it is
given in overdose or intravenously. Those particularly at risk
include elderly patients and patients with hypertension, arteriopathies, or known ischaemic heart
disease.7 8 10 w2
w3 As there are no controlled trials there
is no way to estimate the risk in relation to benefit. Based on
the current evidence, the benefit of using appropriate doses of
intramuscular adrenaline far exceeds the risk (grade C). It should
be stressed that adrenaline is not contraindicated in individuals
with underlying ischaemic heart disease, as the decrease in filling
pressure due to anaphylaxis is likely to result in further coronary
ischaemia (grade C).1 Careful
monitoring and avoidance of adrenaline overdose is necessary in these
patients.
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What is the best route for administering adrenaline?
Subcutaneous and intramuscular routes
The correct route of administration and dose of adrenaline has been under
debate. One study showed that subcutaneous administration of
adrenaline was associated with a striking difference in the time of
maximum plasma adrenaline concentrations of children compared
with the intramuscular route (average time: intramuscular group, 8
minutes; subcutaneous group, 34 minutes).11 The
average maximum plasma concentration was also
significantly higher for the intramuscular group than for the
subcutaneous group, and this has been shown elsewhere (grade
B).11 12
Inhaled adrenaline
Studies using inhaled adrenaline by way of a pressurised aerosol have given
conflicting results.w4-w6 One report showed that adrenaline
was present systemically after an inhaled 3 mg dose but not
after 1.5 mg and that the clinical effect was less pronounced and shorter
lasting than by subcutaneous injection.w4 Other studies have shown the
reverse.w6 No direct comparisons have been made
between the inhaled and intramuscular route. Such findings
have only been shown in healthy volunteers and have, as yet, not
been confirmed in patients during anaphylaxis.
Intravenous route
Intravenous adrenaline has been associated with the induction of fatal
cardiac arrythmias and myocardial infarction. Major adverse
effects usually occur when adrenaline has been given too rapidly,
inadequately diluted, or in excessive dose (grade C).1 2 8 9 Such
published reports often fail to state clearly that other
factors, including hypoxia, acidosis, or the direct action of
inflammatory mediators, may be, at least in part, responsible
for the cardiovascular complications. Given all of this, the
intravenous route should be reserved for those with
unresponsive anaphylaxis. This includes any patient whodeteriorates despite
receiving intramuscular adrenaline or those in whom
there is doubt about the circulation. It should only be given in
a resuscitation area during electrocardiography by medical
staff who are trained in its use (grade C).7
What dose of adrenaline is appropriate?
Some disagreement exists about the recommended dose of adrenaline.Although
almost all of the literature agrees on 0.01 mg/kg in infants and
children, North American guidelines suggest a dose in adults of
0.3-0.5 ml of adrenaline diluted 1:1000 (0.3-0.5 mg), whereas
European literature suggests 0.5-1.0 mg.13 w1
w7 No comparative trials have been
conducted. For most patients only one dose is needed, although repeat
doses may be given at five minute intervals until symptoms
improve.
Does adrenaline have any important drug interactions?
Anaphylaxis may be made worse by blockers, and these drugs decrease the
effectiveness of adrenaline (grade C).14 Paradoxically the
dose of adrenaline should be halved owing to the increased risks
associated with unopposed stimulation of adrenoceptors and reflex
vagotonic effects, including bradycardia, hypertension, coronary
artery constriction, and bronchoconstriction.15 Blockers, including
eye drops containing them, should therefore be withdrawn and
substituted in any patient who is considered at risk of anaphylaxis.16 Tricyclic
antidepressants and monoamine oxidase inhibitors potentiate adrenaline and
increase the risk of cardiacarrhythmias. The dose of adrenaline should be
halved in these patients (grade C). Cocaine sensitises
the heart to catecholamines (as does uncontrolled hyperthyroidism),
and adrenaline is therefore relatively contraindicated (grade
C).10
When should adrenaline be given?
Evidence in the literature suggests that a poor outcome from anaphylaxis
is associated with late administration of adrenaline. In a series
of 13 fatal and near fatal anaphylactic reactions over a 14
month period, only two of the six patients who died received
adrenaline within the first hour compared with sixof the seven survivors (grade
C).17 In
a retrospective study of 27 patients with anaphylaxis occurring
outside hospital, all those treated within 30 minutes
recovered compared with two deaths in those in whom treatment was
delayed by more than 45 minutes (grade C).18 One
study showed that whereas adrenaline was used in the treatment of 62% of fatal
reactions it was used in only 14% before cardiac arrest (grade
C).8 This
may, however, be due in some part to both the speed of
reactions and the availability of treatment. As a result current
guidelines suggest adrenaline should be given as soon as
possible.19
Which patients have the worst outcomes?
The severity of previous reactions does not determine the severity of future
reactions, and subsequent reactions could be the same, better, or
worse. The unpredictability depends on the degree of allergy
and the dose of allergen.8 20A
series of paediatric anaphylaxis showed that in two of the
three fatal reactions and five of the six near fatal reactions,
the previous allergic event had not required urgent hospital
intervention (grade C).19 Studies
have also shown a significant increased risk of near fatal and
fatal reactions in patients with coexistent asthma.17 19 In
one study, 13 of the 14 fatal or near fatal reactions occurred in patients
with known asthma (grade C). It is not clear if this is
related to the severity of the underlying asthma.
Who should be prescribed adrenaline auto-injectors?
Studies have shown that only 50-75% of patients prescribed
auto-injectors for self administration of adrenaline
carry them around at all times.21-24 w8 Of
these, only 30-40% were able to correctly demonstrate
how they would administer adrenaline to themselves. A
retrospective analysis showed that only 29% of children with recurrent
anaphylaxis were treated with their adrenaline auto-injector.25 The
subsequent need for adrenaline and admission to hospital was reduced
in those patients who did receive the appropriate dose by
auto-injector (grade C).25 Adrenaline
auto-injectorsproved unsuccessful in nine of 14 patients with severe
reactions, either due to unavailability (n = 4),
rapidity of reaction (n = 1), incorrect dose (n = 1), or despite
correct treatment (n = 2) (grade C).8 In
another study, 23% (n = 22) of adult patients admitted
that they would probably not be brave enough to selfadminister adrenaline—half
would seek medical assistance and the other half would ask another
person.22
Studies in primary and secondary care have shown that most doctors are themselves uncertain about the correct method for use of auto-injectors.24 w8Only instruction provided by an allergy specialist has been shown to have any effect on proper injection technique (grade C).23 24 Patients need to be aware about expiry dates for their auto-injectors, although studies have shownadrenaline content and bioavailabilty in outdated auto-injectors.w9 Instruction by a physician familiar with auto-injectors and regular review of technique and reinforcement of the issues surrounding their use is therefore vital for these patients (fig 2). Current opinion on prescription of auto-injectors is divided. American opinion suggests that all patients with an episode of major allergy should be prescribed an auto-injector.13 15 In the United Kingdom some people believe auto-injectors are over-prescribed.22 Current UK paediatric guidelines suggest auto-injectors should be given only to patients with previous severe reaction or reactions involving the airway.21 Given that current evidence supports the relative safety of intramuscular adrenaline, and early administration is associated with an improved survival, any patient with a systemic allergic reaction should be a candidate for adrenaline by auto-injector. The prescription of auto-injectors, however, needs to be targeted to those most likely to use the adrenaline and in whom the benefit outweighs the risk. We propose an algorithm for identifying patients who may benefit from an adrenaline auto-injector (fig 3). Further careful epidemiological research is needed to clarify who benefits most from such treatment.
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See also Primary care p 1328
Grades of evidence, details of
studies with clinical outcomes, and web
references w1-w9 appear on bmj.com
We thank the reviewer for his comments.
Contributors: APCMcL-T is the primary author. All authors contributed to all aspects of this review. GSP will act as guarantor for the paper.
Funding: None.
Competing interests: AF and GS have received funding from ALK-Abelló to attend academic meetings.
(Accepted September 22, 2003)
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