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| Journal of the New Zealand Medical Association,
05-May-2006, Vol 119 No 1233
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Anaphylaxis management: the essential role of adrenaline
(epinephrine) auto-injectors. Should PHARMAC fund them in New Zealand?
Penny Fitzharris, Marianne Empson, Rohan Ameratunga, Jan
Sinclair, Vincent Crump, Richard Steele, Brian Broom
BackgroundAnaphylaxis is a sudden, severe, and potentially
life-threatening allergic reaction that can affect all ages. The sinister
effects are on the respiratory tract and/or cardiovascular system but the skin
and gut are also frequently involved. Mediator release from mast cells and
basophils results in smooth muscle contraction, vasodilatation, and increased
vascular permeability, leading to the classic features of anaphylaxis, including
hypotension, bronchospasm, angioedema, and urticaria.1,2 Anaphylaxis is
increasingly common3 and is considered to be under-recognised and
under-reported. The prevalence of food allergy is increasing, thus suggesting
that this increase in anaphylaxis is likely to continue.
Signs and symptoms vary from person to person, with onset of
symptoms usually occurring within minutes of exposure, rarely commencing after
more than 60 minutes. There may be rapid progression of symptoms after onset or,
after initial improvement with treatment, there may be delayed deterioration one
or more hours later, producing a “biphasic” reaction. In some
patients, anaphylaxis will run a protracted course. The severity of an initial
reaction does not necessarily predict the severity of future reactions, and the
rapidity with which life-threatening reactions may develop necessitates the
availability of, and early administration of, effective therapy.
Many cases of anaphylaxis are unpredictable. Data from the
UK fatal anaphylaxis register shows that over two-thirds of those dying from
insect sting reactions and over four-fifths of those with drug-induced
anaphylaxis had no previous indication of their allergy.4 However the majority
of those dying from food allergy had usually had previous reactions, although
these had typically not been severe. Many episodes occur in the community, in
the absence of a health care professional. In the UK, foods and insect stings
each make up about one-quarter of deaths, the majority of the remainder being
drug-related, typically anaesthetic agents and antibiotics, or idiopathic in
origin. The pattern is likely to be similar in New Zealand, although detailed
studies are lacking. Epidemiological studies for non-fatal anaphylaxis identify
similar precipitants, but vary in relation to the prevalence of individual
causes. Patients who survive anaphylaxis may be left with significant long-term
disability, related to anoxic cerebral injury.
Clinical featuresSymptoms occurring in fatal anaphylaxis are generally
related to either shock/cardiovascular collapse, which is typically seen in
reactions to intravenous drugs and insect stings, or respiratory arrest caused
by intractable asthma, upper airway angioedema or both.5 Severe bronchospasm is
a more common mode of death in food allergy than cardiovascular collapse.
Additionally, death from food-induced anaphylaxis has been strongly linked with
a history of asthma, though this may be only mild and infrequent.6,7 With foods,
fatal outcome has typically occurred in patients who are aware of their food
allergy and who have made reasonable efforts to avoid eating those foods.
Given the shortage of specialists in the management of
allergic disease, relatively few patients receive expert advice about avoidance.
Commercial catering is a particular risk for those with nut allergy. It is
patients with known food or venom allergy, and those who have experienced
idiopathic anaphylaxis, for whom the availability of effective self-initiated
management is particularly important.
Anaphylaxis should be considered a condition where the
threat of recurrence is chronic, but the event unpredictable.8 Appropriate
management includes accurate identification of the cause, education regarding
effective avoidance strategies, and appropriate medical management. This should
include not only effective training and provision of self treatment, but also
the effective treatment of asthma in those with food allergy and immunotherapy
for those with venom allergy.8 Excellent results have been obtained when an
appropriate management plan is put in place by a regional allergy clinic.9
Treatment of anaphylaxisInjected adrenaline is widely accepted as the first-line
therapy for anaphylaxis, based on its physiological effects, anecdotal evidence
of efficacy, and the morbidity and mortality associated with absent or delayed
administration, as documented in many studies.6,7,10,11 Gold and Sainsbury, for
example, showed that when adrenaline was given in an outpatient setting, only 2
of 13 cases needed additional treatment in hospital, compared to 15 of 32 when
it had not been used.10
It is estimated that no more than 30–40% of
individuals who require adrenaline receive it. Because of lack of controlled
trials, formal estimation of risk-to-benefit ratio for the use of adrenaline is
impossible—but for all major causes of anaphylaxis there is clear evidence
that delays in the use of (or failure to use) adrenaline has contributed to
fatal outcome and increased morbidity. For instance, in the 32 deaths from food
allergy reported by Bock and colleagues, 12 did not receive adrenaline at all,
10 received it late, while 4 received it in a timely fashion.6 In
Pumphrey’s series of deaths from the UK only 14% received adrenaline prior
to cardiac arrest.5
Although there have been concerns regarding the safety of
adrenaline use, current opinion is that the benefit of appropriate doses of
intramuscular (IM) adrenaline far outweighs the risk and that this is the
appropriate management for first medical responders and for patient
self-administration.12,13
Most adverse reactions to adrenaline occur when it is given
in overdose, or intravenously, as a bolus.5,13,14 Patients with known ischaemic
heart disease are at particular risk, but appropriate use of adrenaline is not
contraindicated in these patients.15 Bolus IV adrenaline is not recommended for
the treatment of anaphylaxis, although adrenaline infusions may be appropriate
in severe anaphylaxis in a monitored patient, for example an anaesthetic-induced
reaction.13 Alternative treatments, such as antihistamines, corticosteroids
without the use of adrenaline, or nebulised adrenaline have failed to prevent or
relieve severe anaphylactic reactions.
Route of administrationA randomised, blind study in children showed the time to
peak plasma adrenaline concentration was 8±2 minutes after IM
administration (using the EpiPen®—a self-injecting adrenaline device;
DEY L.P., Napa, California; distributed in New Zealand by CSL (New Zealand) Ltd,
Auckland), significantly shorter than the 34±14 minutes (range 5–120)
after subcutaneous injection.16 In young adults, injection in the vastus
lateralis muscle in the lateral thigh gave higher plasma levels than IM
injection in the deltoid region, or subcutaneous injection in the deltoid
region, and thus it is the recommended site for injection.17
Adrenaline auto-injector devices provide the ability to
deliver IM adrenaline at fixed doses (currently 0.3 mg, 0.15 mg). At present, it
is not possible to use this device for young babies under 10 kg, as there is no
fixed-dose product with less than 0.15 mg content.
The use of an adrenaline ampoule, syringe, and needle may
lead to delayed dose, overdose, underdose, or no dose at all. In one study,
parents (after training) took substantially longer than nurses or physicians to
draw up a dose into a syringe, and the content of the parents’ doses
ranged 40-fold.18 For adolescents and adults to self-administer IM adrenaline
using an appropriate needle and syringe is also technically difficult and has
significant psychological barriers.
Reasons for delays in the use of, or lack of availability of
adrenaline may be the responsibility of the physician or paramedic, the
patient/caregiver or both. Failure to use adrenaline when appropriate is well
documented, as is failure to prescribe for the at risk patient. If an
auto-injector is prescribed and the device obtained, education in when and how
to use the device is frequently lacking. A recent UK study, for example, showed
that fewer than a third of patients and parents of affected children had
adequate knowledge of the indications and how to use the device.19 None of the
general practitioners who had prescribed for these patients personally showed
the patient how or when to use the device although the majority asked their
practice nurse to do so.
The psychological and social aspects of anaphylaxis are
complex, with a heavy psychological burden in patients and families of those
with food allergy, with effects on quality of life shown to be greater than for
children with insulin-dependent diabetes mellitus.20 Both denial and risk taking
play a role in risk of recurrence of anaphylaxis, with teenagers and young
adults being particularly at risk.
Anaphylaxis should be considered a chronic disease, and
patients ideally would be discharged from the emergency department with a
prescription for an adrenaline auto-injector device, an anaphylaxis management
plan, such as that available on-line from the Australasian Society for Clinical
Immunology and Allergy (ASCIA website: www.allergy.org.au), education in its
appropriate use and a referral to a specialist in allergy for evaluation and
treatment. This applies as much to patients who are found to be at risk of
anaphylaxis, as to those who have experienced anaphylaxis.
Critical role of self-injecting devicesIt is unrealistic to expect any patient who is experiencing
anaphylaxis to draw up and self-administer IM adrenaline in a timely and
accurate way, or for family and/or caregivers to do this for a child, although
this is the only option available at present for those who do not purchase an
EpiPen, at the minimum cost of NZ$120 (when ordered by the GP), or
$150–190 when obtained at a pharmacy. Many patients in New Zealand are
unable to afford to buy an auto-injector, and some patients who have purchased
one admit that they have been reluctant to use it because of the cost and have
preferred to travel to a GP or hospital.
Compounding this situation is the inability of many patients
in New Zealand to access specialist care for allergic disease because there are
so few specialists in clinical immunology and allergy in New Zealand, with only
one hospital-based paediatric immunologist for the entire country. Deaths from
anaphylaxis are, however, relatively rare, and the provision of adrenaline
auto-injectors for all at-risk individuals will be relatively costly. Risks and
values are variable and uncertain, and the ethics of provision (or
non-provision) of adrenaline auto-injectors complex.21,22
New Zealand (like many countries in Asia, South America, and
Africa) has fallen behind the UK, North America, and Australia in the provision
of this treatment for individuals at risk of anaphylaxis.23 Adrenaline
auto-injectors are available under National Health Service prescription in the
UK, and were made available on the Pharmaceutical Benefits Schedule in Australia
from November 2003, albeit with a limit of one injector for adults and two for
children, and requiring specialist recommendation. This funding followed the
anaphylaxic deaths of several Australian children in recent years—it will
be a great sadness if such a tragedy is needed to initiate funding for EpiPens
or similar devices in New Zealand.
The small community of allergy and clinical immunology
specialists in New Zealand as well as Allergy New Zealand (the not-for-profit
organisation which supports individuals and families affected by severe allergy
disease) have campaigned on this need for New Zealanders for many years.
Disclosures:
None.
Author information:
Penny Fitzharris, Marianne Empson, Rohan Ameratunga, Clinical Immunologists,
Immunology, Auckland City Hospital, Auckland; Jan Sinclair, Paediatric
Clinical Immunologist, Paediatric Immunology, Starship Children’s
Health, Auckland; Vincent Crump, Allergist and Physician, Auckland Allergy
Clinic, Auckland; Richard Steele, Clinical Immunologist, Immunology, Wellington
Hospital, Wellington; Brian Broom, Consultant Allergist, Arahura Health Centre,
Christchurch (and Adjunct Professor, Auckland University of Technology,
Auckland)
Correspondence: Dr
Penny Fitzharris, Immunology, Auckland City Hospital, Private Bag 92-024,
Auckland. Email: pennyf@adhb.govt.nz
References:
Interim
response from PHARMAC: PHARMAC advises
that it has not had enough time to draft a response this instance, but will do
so in coming issues of the
Journal.
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