Full text of DOI:10.2165/00002018-200124110-00005

Drug Safety 2001; 24 (11): 843-853
0114-5916/01/0011-0843/$22.00/0
PRACTICAL DRUG SAFETY
© Adis International Limited. All rights reserved.
Preventing and Managing
Drug-Induced Anaphylaxis
Kerry L. Drain and Gerald W. Volcheck
Department of Allergic Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
1. Definition and Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
2. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
3. Prevention of Anaphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
3.1 Patient History and Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
3.2 Other Preventative Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
3.2.1 Diagnostic Testing for Drug Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . 848
3.2.2 Skin Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
3.2.3 Other Diagnostic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
4. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Drug-induced anaphylaxis and anaphylactoid reactions have increased in fre-
Abstract
quency with more widespread use of pharmaceutical agents. Anaphylaxis is a sys-
temic, severe immediate hypersensitivity reaction caused by immunoglobulin
(Ig) E-mediated immunological release of mediators of mast cells and basophils.
An anaphylactoid reaction is an event similar to anaphylaxis but is not mediated
by IgE.
The incidence of anaphylactic or anaphylactoid reactions differs amongst
classes of medications. Antibacterials are the most usual offenders, and penicillins
are the most studied. Other compounds commonly causing reactions include non-
steroidal anti-inflammatory drugs, anaesthetics, muscle relaxants, latex and radio-
contrast media.
Prevention, if possible, is the purpose of detailed patient history taking and
physical examination. Simple strategies can be employed to decrease the risk of
anaphylaxis. These include consideration of the route of drug administration,
identification of patients with known causes of anaphylaxis, and the knowledge
that certain medications cross react and are contraindicated in those with known
history of anaphylaxis. Tests are available, and include IgE-specific skin tests and
radioallergosorbent tests. Penicillins are the only compounds whose antigenic
determinants are well documented, it is therefore difficult to determine the neg-
ative predictive value of other compounds tested. Oral challenge remains an
alternative, though entails risk. Desensitisation procedures, as well as gradual
dose escalation protocols, are available and can be implemented based on patient
history and diagnostic testing.

844
Drain & Volcheck
The management of anaphylaxis is based on control of the airway, breathing
and circulation. Treatment consists of epinephrine (adrenaline) and supportive
measures. Rapid diagnosis and intervention are important in these life-threatening
reactions. After stabilisation, all individuals with a documented history of ana-
phylaxis require a Medic-Alert bracelet or necklace, and an identification card
for their wallet or purse.
Since before the time of kings and pharaohs,
and platelet activating factor. These factors have
many systemic effects including smooth muscle
spasm, bronchospasm, increased capillary leak and
mucosal oedema and inflammation. The clinical man-
ifestations can involve any organ system, but are main-
ly seen in the cutaneous, respiratory, gastrointesti-
nal and cardiovascular systems. Classic signs and
symptoms include, but are not limited to, urticaria
and angioedema, dyspnoea, wheezing, upper air-
way oedema, dizziness, hypotension and shock, nau-
sea, vomiting, crampy abdominal pain, flushing,
headache and substernal chest pain.[2,6] Anaphylaxis
is a medical emergency requiring immediate atten-
tion or death may ensue. It is also important to re-
member that mast cells release mediators hours after
the initial reaction causing the biphasic or late phase
reaction of anaphylaxis.
The mast cell can be activated by means other
than IgE. These mechanisms include other immu-
nological and non-immunological provocations.
Complement-mediated anaphylatoxins are formed
when IgG aggregates from intravenous immuno-
globulin, causing an anaphylactic picture in those
with this type of response to the immunoglobulin.[7]
A similar reaction may occur when antibodies are
created to mismatched red blood cells during blood
transfusions. Non-immune mechanisms cause di-
rect release of vasoactive substances from the mast
cells. Medications such as opioids, aspirin (acetyl-
salicylic acid), radiocontrast media, dextrans and
neuromuscular blocking agents have been found to
directly stimulate mast cells.[7]
anaphylaxis has mystified generations. As early as
2641BC there was evidence of an unexplained death
due to airway obstruction and irreversible vascular
collapse.[1] The term anaphylaxis was coined by Por-
tier and Richet in 1902.[2] Drug-induced anaphy-
laxis has become a problem with the widespread
use of novel pharmaceutical agents within the past
60 years. These medications have provided new
therapies to cure and control many diseases that pre-
viously had caused considerable morbidity and
mortality, but there has been a cost. The advent of
these new agents has resulted in an increase in the
severity and incidence of adverse drug reactions.
Pencillin is an example of a lifesaving drug that has
been found to cause 1 case of anaphylaxis for every
10 000 courses of therapy.[3] These numbers are for-
midable considering that one managed care or-
ganisation’s prescription plan records found that, of
the 1 699 074 oral antibacterial prescriptions writ-
ten over a 1-year period, 870 610 were for a peni-
cillin antibacterial.[4] In this group, 87 cases of ana-
phylaxis due to penicillin would be expected.
1. Definition and Mechanisms
Anaphylaxis is a systemic, immediate hypersen-
sitivity reaction caused by immunoglobulin (Ig) E-
mediated immunological release of mediators of
mast cells and basophils.[5] The mast cell has a Fc
receptor on its surface that binds IgE. An individual
previously exposed to an offending antigen produces
specific IgE. Upon re-exposure, if the IgE antibody
has reached high enough levels, it will activate the
mast cell and cause release of its vasoactive con-
tents. The mediators released include histamine, the
leukotrienes C4, D4, and E4, eosinophil chemotac-
tic factor of anaphylaxis, neutrophil chemotactic
factor of anaphylaxis, the mast cell marker tryptase
The symptoms of anaphylaxis and anaphylac-
toid reactions are at times misinterpreted, which may
lead to improper treatment. The differential diag-
nosis of anaphylaxis and anaphylactoid reactions
is summarised in table I.
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

Preventing and Managing Drug-Induced Anaphylaxis
845
Table I. Differential diagnosis of anaphylaxis and anaphylactoid
lance Program tried to answer this question. In
1973, they found 6 drug reactions and 0.87 deaths
per 10 000 patients studied.[8] Four years later they
reported drug-induced anaphylaxis in 12 of 32 812
monitored patients on selected medical wards. This
reflected an incidence of 0.04%.[9] In 1990, a re-
view of patients admitted to a university hospital
noted 9 patients with anaphylaxis of out of a total
of 20 064 admissions. The causes of anaphylaxis
were predominantly drug related, but food and
stinging insect reactions were also included. Again
an incidence of 0.04% was recorded.[10] A report
using data from emergency rescue teams in Mu-
nich, Germany found the rate of anaphylaxis to be
9.79 per 100 000 individuals or 0.01%.[11] Klein
and Yocum[12] noted the incidence of anaphylaxis
to be 0.09% as determined by a chart review of 19 122
patients seen at the Emergency Department in Ro-
chester, Minnesota, US during a 4-month period.
In another study by Yocum et al.,[13] the annual
incidence of anaphylaxis was 21 per 100 000 in-
dividuals per year, with a fatality rate of 0.65%
during the 5-year period. Causes of the anaphyl-
actic reactions were medications, foods and insect
stings.
reactions (reproduced from Lieberman,[5] with permission)
Anaphylaxis and anaphylactoid reactions
to exogenously administered agents
to physical factors
exercise
cold, heat, sunlight
idiopathic
Vasodepressor reactions
Flush syndromes
carcinoid
postmenopausal
chlorpropamide alcohol
medullary carcinoma thyroid
autonomic epilepsy
‘Restaurant syndromes’
monosodium glutamate (MSG)
sulfites
scrombroidosis
Other forms of shock
haemorrhagic
cardiogenic
endotoxic
Excess endogenous production of histamine syndromes
systemic mastocytosis
urticaria pigmentosa
basophilic leukaemia
acute promyelocytic leukaemia (tretinoin treatment)
hydatid cyst
The incidence of anaphylactic or anaphylactoid
reactions varies amongst different classes of med-
ications. Antibacterials are the most common class
of medications to produce anaphylactic or anaphy-
lactoid reactions. Penicillin is the most studied.
The rate of anaphylactic or anaphylactoid reactions
is 1 to 5 per 10 000 patient courses of treatment.[14]
The rate of fatal anaphylaxis from penicillin has
been shown to be 0.002%, and this drug accounts
for 75% of all fatal anaphylactic episodes in the US
each year.[15] The incidence of anaphylactoid reac-
tions to aspirin or nonsteroidal anti-inflammatory
drugs (NSAIDs) varies greatly depending on who
is included in the study population. The incidence
was 2% in a questionnaire-based study of children
and 97% in a study of adults with concomitant
asthma, rhinosinusitis and nasal polyps.[16,17] To
clarify the prevalence of anaphylactoid reactions
to aspirin and other NSAIDs, a study of 51 797
patients taking these medications was initiated. In
Nonorganic disease
panic attacks
Munchausen’s stridor
vocal chord dysfunction syndrome
globus hystericus
undifferentiated somatoform anaphylaxis
Miscellaneous
hereditary angioedema
‘progesterone’ anaphylaxis
urticarial vasculitis
phaeochromocytoma
hyperimmunoglobulin E, urticaria syndrome
neurological (seizures, stroke)
pseudoanaphylaxis
red man syndrome (vancomycin)
capillary leak syndrome
2. Incidence
The exact incidence of drug-induced anaphylaxis
isunknown. The Boston Collaborative Drug Surveil-
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

846
Drain & Volcheck
this group there were 35 cases of shock, 11 cases
of angioedema and 106 cases of urticaria.[18] In other
studies, including one of 808 non-atopic individu-
als, 7 such individuals (0.9%) reported an anaphy-
lactoid episode after ingesting aspirin.[19] In another
series of patients with anaphylaxis, aspirin was a
frequent offender accounting for approximately 3%
of all events.[20]
Finally, hypersensitivity reactions to preservative-
free amide local anaesthetics have been reported,
but are rare. True immunological reactions to local
anaesthetics are rare, making up less than 1% of all
adverse reactions to local anaesthetics.[25]
Latex exposure can cause anaphylaxis in an in-
creasing number of patients. Reactions were un-
common until the 1980s with the introduction of
universal precautions and the use of latex gloves to
protect against the spread of infectious diseases.
Healthcare workers and patients exposed to multi-
ple surgical procedures are at greatest risk for latex
sensitivity. The rate of sensitivity is estimated to be
as high as 36% in atopic, frequently exposed work-
ers.[26] In patients with spina bifida, the incidence
of sensitisation ranges from 18 to 73%.[27] Studies
of blood donors have shown that 6% have measur-
able anti-latex IgE.[28]
Radiocontrast media reactions have decreased
with the introduction of lower osmolar agents.
Older agents caused reactions in approximately 1%
of patients, with a fatality rate of 0.009%. Reactions
are reported to occur in 0.04% of patients receiving
lower osmolar preparations.[29] Patients with a his-
tory of contrast media reactions can receive con-
trast again with pretreatment and use of a low mole-
cular weight contrast. Various pretreatment regimes
have been described.[30]
Many anaesthetic medications can cause ana-
phylactic or anaphylactoid reactions. The largest stu-
dies have been conducted in France, where the in-
cidence of intraoperative anaphylactic reactions was
been found to be 1 in 6000. When taking into con-
sideration all immediate reactions (both anaphy-
lactic and anaphylactoid), the incidence was 1 in
3500.[21] A recent survey completed in 27 centres
found that the cause of shock could be determined
by radioimmunoassay of serum in 57.8% of the
patients investigated. 59% of the time the aetio-
logical agent causing the reaction was muscle re-
laxants. Implicated agents include suxamethonium
chloride, vecuronium bromide, pancuronium bro-
mide, alcuronium bromide or chloride, atracurium
besilate and gallamine triethiodide.[22] Similar re-
sults were seen in studies done in Australia, Great
Britain, the US and Canada.[23] Hypnosedatives and
opioids, including morphinomimetics, antipsy-
chotics and benzodiazepines, have also been found
to cause anaphylactoid reactions.
3. Prevention of Anaphylaxis
Local anaesthetics may cause allergic reactions.
A metabolite of the ester local anaesthetics, para-
aminobenzoic acid, has been found to be aller-
genic.[24] This highly antigenic substance is thought
to be the source for reactions attributed to the ester
class of local anaesthetic agents which includes ben-
zocaine, cocaine, procaine, propoxycaine and tetra-
caine. Methylparaben, a preservative and bacterio-
static agent found in many older local anaesthetic
preparations, other drugs, foods and cosmetics, is
related to aminobenzoic acid and has allergenic
properties. Currently it has been taken out of local
anaesthetic cartridges, but is still found in multi-
dose vials. Another preservative used, which is also
allergenic, is sodium bisulfite (metabisulfite). Ana-
phylaxis to sodium bisulfite has been reported.[24]
3.1 Patient History and Physical Examination
Unfortunately, anaphylactic reactions to medi-
cations often can not be predicted. A thorough pa-
tient history and physical examination can decrease
the number of reactions by allowing precautions to
be implemented. Aclinician with knowledge of the
immunological and biochemical cross reactivity
between medications can often foresee and prevent
imprudent drug choices. Cross reactivity exists
amongst β-lactam antibacterials. A study of β-
lactam antibacterials by Adkinson[31] found that
cross reactivity was predictable and nearly com-
plete across semi-synthetic penicillins, partial and
incomplete across β-lactams with 2 nuclear rings
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

Preventing and Managing Drug-Induced Anaphylaxis
847
and negligible across monobactams. Cross reactiv-
ity also exists between local anaesthetics. Any ester
or amide local anaesthetic containing the preserv-
ative methylparaben may cause reactions. Ester lo-
cal anaesthetics may cross react and if there is a
reaction, another class of anaesthetic should be
used. Amide anaesthetics, although only noted in a
handful of case reports,[24] can also cross react. The
clinician has an important role in determining
whether the history of a reaction can be classified
as a true IgE-mediated allergic reaction from the
medication.
History of ‘drug allergy’ may not be a good in-
dicator of true immunological reaction. Up to 10%
of the outpatient population will report a history of
penicillin allergy.[32] About 80 to 95% of patients
with a history of penicillin allergy have a negative
penicillin skin test.[33] Patient examination at the time
of reaction has been found to be a more accurate
predictor of true allergic reaction to β-lactam anti-
bacterials than patient history alone, but this method
still over-estimates the rate of IgE-mediated events
in 66% of patients.[34] Because of these statistics,
recent studies have looked at ways of testing for
allergic reactions before offending agents are pre-
scribed. Some of these studies will be discussed in
section 3.2.1.
There are a number of factors which appear to
affect the incidence and severity of anaphylaxis
and anaphylactoid reactions that must be consid-
ered when evaluating patients. Women seem to
have more frequent anaphylactic reactions to intra-
venous muscle relaxants containing quaternary
ammonium ions than men.[35] This may be a result
of prior sensitisation through exposure to these
ions via cosmetics. The route of administration of
the offending agent increases both the frequency
of occurrence and the severity. Events may occur
if given by any route, but are most frequent and
severe with the intravenous route.[5] If prior ther-
apy was interrupted, creating gaps in administra-
tion, there is an increased risk of subsequent reac-
tion.[36] Finally, studies have shown that the greater
the number of years since the last administration
of the offending agent, the less chance of recur-
rence of reactions.[5]
Depending on the history of the reaction offered
by the patient, a number of paths may be taken. The
first is to simply substitute the offending agent with
another that is not cross-reactive but offers a sim-
ilar effect. When that is not possible, and the clini-
cian has a high level of suspicion that the prior
reaction was allergic in nature, skin testing may be
performed. This is outlined in section 3.2.2. Re-
sults can then be used, weighted by the patient’s
history of reaction, to decide if the medication
could be administered using a desensitisation pro-
tocol. There are certain instances when a medica-
tion should never be re-administered. These include
life-threatening reactions such as exfoliative der-
matitis syndromes and dermatoses with mucous
membrane lesions (Stevens-Johnson syndrome-
like).[37]
Clinicians need to weigh up the health of the
individual with the benefits and risks of adminis-
tration of the agent in question. There are situations
which demand certain medications, such as neuro-
syphilis.[38] Patients with this disease require intra-
venous penicillin even if they have a positive his-
tory and skin test to penicillin, so desensitisation is
crucial. At other times, serious underlying medical
problems, such as severe coronary heart disease or
multisystem organ failure, may make desensitisa-
tion an unattractive option.
An example of a specific physical finding which
affects the risk of anaphylactoid reactions is nasal
polyps in patients with asthma. As discussed pre-
viously, the incidence of anaphylactic reaction in
these patients when given aspirin or NSAIDs is as
high as 97% in some studies.[16]
3.2 Other Preventative Strategies
There are other simple measures that can be im-
plemented to reduce the incidence of anaphylaxis
and related mortality. As mentioned above, paren-
teral administration of drugs increases the fre-
quency and severity of reaction. When drugs are
given intravenously, the patient should remain un-
der medical supervision until 20 to 30 minutes after
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

848
Drain & Volcheck
administration. Patients with a documented history
of anaphylaxis should wear a Medic-Alert bracelet
or necklace and keep an identification card in their
purse or wallet to alert medical personnel in case of
emergency. Patients should also have on their per-
son an epinephrine (adrenaline) kit for self admin-
istration in case of problems.
Certain medications should be avoided in pa-
tients with a history of anaphylaxis. These include
β-adrenoceptor antagonists, ACE inhibitors, angio-
tensin II receptor antagonists, monoamine oxidase
inhibitors and tricyclic antidepressants. β-Adreno-
ceptor antagonists decrease epinephrine’s effec-
tiveness. ACE inhibitors and angiotensin II recep-
tor antagonists reduce the body’s ability to activate
compensatory mechanisms in the face of a hypo-
tensive crisis. The monoamine oxidase inhibitors
and certain tricyclic antidepressants enhance the
adverse effects of epinephrine administration such
as tachycardia and hypertension.[5]
cated in patients with a convincing history by which
the medication in question caused a severe reac-
tion.[39] Prick and skin testing can be performed to
test for β-lactam antibacterials, latex and local an-
aesthetics.
The mechanism of immune system activation
for penicillin is well documented. During degrada-
tion, a number of metabolites are formed. The ma-
jor antigenic determinant is the penicilloyl moiety.
Most penicillin-reactive patients create antibodies
to this component. Other antigen were discovered
that cause reactions, but in fewer patients, the mi-
nor antigenic determinants. In vivo skin testing uti-
lises penicilloyl polylysine to test for the major de-
terminant and benzylpenicillin (penicillin G) for
the minor determinant. Testing for both the major
and minor determinants is necessary in the assess-
ment of penicillin allergy.[41]
Taking the history along with the skin test re-
sults, a clinician can interpret future risk of reaction
upon retreatment with the agent. Unfortunately, the
rate of false negative tests is only known for some
antibacterial agents.[40] One large outpatient study
was conducted in 1993 at an inner city sexually
transmitted disease clinic and from this, data pre-
dictions for penicillin can be made. Allergic reac-
tions observed in patients with a positive history
and a negative skin test at the time of readministra-
tion of penicillin were virtually all mild and self
limited. There were no life-threatening reactions
reported.[42]
Some other drugs including other β-lactam an-
tibacterials, ciprofloxacin, trimethoprim, cisplatin,
neuromuscular blocking agents, thiobarbiturates,
some anticonvulsants and local anaesthetics elicit
a positive skin test in their native form. Stand-
ardised skin testing for medications, however, has
only been established for penicillin. It should be
noted that the intravenous preparation of ciproflox-
acin is highly irritative to skin so if used for skin
testing must be diluted. Insulin and other native or
recombinant proteins are complete antigens and
thus can be used to yield reliable skin tests when
used in appropriate concentrations.[40]
3.2.1 Diagnostic Testing for Drug Hypersensitivity
There are 3 methods of testing for drug sensitiv-
ity. In vivo skin testing for immediate reaction to
the suspected agent is one mode. The second in-
volves in vitro determination of drug-specific IgE
from the affected patient’s blood. A major problem
with diagnostic testing is that in most cases, except
for penicillin, the principal drug allergen is un-
known. The third type of testing is an oral challenge.
3.2.2 Skin Testing
Prick and intradermal testing are performed to
assess immediate IgE allergic reaction. Prick test-
ing uses a small amount of test solution containing
the suspect medication which is placed on the skin.
A sterile needle or standard SPT lancet is then
placed through the test solution into the epidermis
and gently lifted upward. The area is evaluated af-
ter 15 minutes for a wheal or flare reaction that is
greater than seen with the positive control hista-
mine. Intradermal injection of potential allergen
can be used if the prick test is negative. Intradermal
skin tests increase the sensitivity of the testing. Three
case reports in the literature have related death to
skin testing by prick or intradermal methods for
penicillin allergy.[39] Skin testing may not be indi-
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

Preventing and Managing Drug-Induced Anaphylaxis
849
Eggleston and Lush[24] recommended skin testing
for local anaesthetics in patients with a history of
allergy or drug exposure that wasunclear. They noted
that if prick testing was not definitive then intra-
dermal skin testing should be performed. However,
a positive reaction to intradermal tests in patients
with a history of allergic reaction occurred only
25% of the time. In history-negative controls, a posi-
tive reaction occurred 9% of the time. Therefore
skin testing is not definitive in assessing anaesthe-
tic allergy. Patch testing using topical local anaes-
thetic agents was discussed as a way of assessing
delayed-type hypersensitivity, but was not found
to be very helpful.
assays are available for insulin, latex and neuro-
muscular blockers, but negative tests must be in-
terpreted with caution. For many other medications
the antigenic component is unknown. It is there-
fore difficult to evaluate a negative test.[40]
Oral challenges can be performed under super-
vision. In recent studies, these challenges have been
used in conjunction with skin testing to identify the
negative predictive value of skin tests as well as to
assess possible cross-reactivity reactions.[34] In
children and adults, oral challenges are done using
a standard dose in either tablet, capsule of liquid
form. The individual is then monitored for 30 min-
utes to detect any immediate reactions.
Li et al.,[43] in an attempt to decrease the amount
of vancomycin given prophylactically for ortho-
paedic procedures in patients with a history of pen-
icillin allergy, used skin tests to the major and mi-
nor determinants of penicillin to determine true
IgE-mediated reaction. 60 patients were enrolled
in the study. 48 of the 60 gave a history of allergy
to penicillin, 2 gave a history of cephalosporin al-
lergy, 5 gave history of both penicillin and cepha-
losporin allergy and 5 gave an unclear history of
an allergic reaction to an antibacterial. 59 patients
had skin tests performed. 55 (93%) had a negative
skin test and 4 had 1 or more positive skin tests.
There were no distinguishing features in the med-
ical history of the patients with positive skin tests.
55 of the patients had prophylactic antibacterials at
surgery. 49 (89%) were given cefazolin and 6 (11%)
were given vancomycin. None of the 55 patients
given prophylactic antibacterials had an immediate
reaction. One patient did develop a rash several
days later, but that patient had been taking many
medications at the time.
Macy[4] used elective skin testing prior to acute
administration of antibacterials, and amoxicillin
challenge in those with negative skin tests. 236 pa-
tients underwent penicillin skin test using penicil-
lin, benzylpenicilloyl polylysine, amoxicillin, peni-
lloate and penicilloate. 196 (83%) patients were
skin test negative, and, of those, 146 agreed to
amoxicillin challenge. Eight (5.5%) of the am-
oxicillin challenge patients reported an adverse re-
action, and 4 of those tolerated a penicillin antibac-
terial later in the study period. There were 15
patients with positive penicillin skin tests who re-
ceived at least 1 course of cephalosporin therapy.
There were no immediate reactions, and only 1 de-
layed reaction that was believed to be serum sick-
ness. The study also demonstrated that the resen-
sitisation rate in adults with a negative penicillin
skin test after therapeutic penicillin antibacterial
administration was 3.2%, substantially less than
previous estimates of 20%.[44]
In the paediatric population, Pichichero and
Pichichero[34] also used elective skin testing in pa-
tients with a history of β-lactam allergy. 247 chil-
dren and adolescents were enrolled. Skin testing to
benzylpenicillin, benzylpenicilloyl phosphate, pen-
icillin minor determinant mixture, ampicillin, cef-
azolin and ceftriaxone was completed. If the intra-
dermal skin test was negative the patient was given
a penicillin oral challenge and observed for 30
minutes for immediate reaction. If there was no
immediate reaction then a 5 to 10 day challenge of
3.2.3 Other Diagnostic Testing
The radioallergosorbent test (RAST) and other
immunoassays testing for drug-specific IgE anti-
bodies in serum are not very sensitive. Currently,
a commercial RAST assay is produced for the ma-
jor determinant of penicillin, but not for the minor
determinants. Those patients without IgE to the
penicilloyl determinant but with antibodies to one
of the minor determinants will be missed. RAST
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

850
Drain & Volcheck
the β-lactam antibacterial that caused the historical
adverse reaction was administered. 53 (21.5%) of
the 247 skin tested children had an initial positive
reaction. 194 were skin test negative and were given
a 10-day course of antibacterial. After the challenge,
the children had skin tests repeated. 26 (10.5%) of
the 247 were positive to skin test during the second
test period. 163 (66%) were both skin test negative
and challenge negative and were allowed to reini-
tiate therapy with β-lactam antibacterials. The rest
were advised to avoid the tested β-lactams. Multi-
ple courses of penicillins and cephalosporins were
administered to the skin test-negative group during
the 6-month to 8-year follow-up. Only 3 (1.8%)
children experienced an adverse IgE-mediated re-
action, and all were mild. 84 children with a posi-
tive skin test or oral challenge to penicillins were
advised that they could receive cephalosporins.
Two children (2%) developed a mild IgE-type re-
action, and both had a positive reaction to prick or
intradermal skin testing to more than one penicillin
reagent.[34]
as necessary at 10 to 15 minute intervals 2 to 3
times.[5] The intramuscular route was found to be
the route of choice in a study done by Simons et
al.[45] which evaluated the absorption of epineph-
rine given by either subcutaneous or intramuscular
injection.
If the patient is found to be severely hypotensive
then intravenous access must be obtained. Epine-
phrine as well as intravenous fluids need to be ini-
tiated. A suggested protocol is as follows: 0.1ml
:
(0.1mg) of 1 1000 aqueous epinephrine solution
can be diluted in 10ml of normal saline. The 10ml
dose can then be infused over 5 to 10 minutes re-
sulting in a total dose of 100μg at a rate of 20μg
per minute. Repeating the dose would be depend-
ent on response, with dose escalation reflecting
more critical situations. If a constant infusion is
required, the patient needs to be monitored for car-
diovascular complications. There is a commer-
:
cially available 1 10 000 epinephrine formulation
that is available in a 10ml syringe. If intravenous
access is not obtainable, sublingual injection may
be tried since it is richly vascular. The intramuscu-
lar dose can be injected into the posterior one-third
of the sublingual area. If the patient is intubated,
epinephrine can be given via the endotracheal tube.
The dose in children is 0.1 mg/kg or 0.1 ml/kg for
4. Management
In the midst of the acute anaphylactic or anaphy-
lactoid event, immediate action is lifesaving. The
initial steps in the management of anaphylaxis are
the same as for all life-threatening events which are
the control of airway, breathing and circulation. One
must assess the patient’s airway, and if compromis-
ed this must be rectified immediately. Blood pres-
sure and pulse should be checked. The patient
should be placed in a supine position with feet el-
evated. Modifications must be made in positioning
if the patient is wheezing. Oxygen should be started
and the patient’s bodyweight should be estimated
for medication dosage determinations.
:
a 1 1000 solution. The dose in adults is unknown.
Recommendations[5] are to start at 1mg, but up to
2 to 2.5 times the intravenous dose may be neces-
sary. The dose will be rapidly absorbed after 5 to
10 breaths.
Intravenous fluids help restore intravascular
volume lost with fluid shifting from the intravas-
cular to the extravascular space during anaphy-
laxis. Large volumes may be required and fluid
must be infused rapidly. 1000 to 2000ml of crystal-
loid solution, either normal saline or lactated Ring-
er’s, should be given rapidly depending upon the
patient’s blood pressure. Arate of 5 to 10 ml/kg can
be infused over the first 5 to 10 minutes. Children
should receive a 30 ml/kg bolus of crystalloid so-
lution in the first hour. If colloid solution is pre-
ferred, adults should receive 500ml followed by a
slow infusion thereafter. If large amounts of fluids
Epinephrine should be administered during the
above mentioned procedures. The route depends on
what is most immediately available. In either chil-
dren or adults in an office setting, intramuscular or
subcutaneous administration can be utilised. The
:
intramuscular dose for adults, using 1 1000 epi-
nephrine, is 0.3 to 0.5ml (0.3 to 0.5mg). In children
the dose is 0.01 mg/kg. The dose can be repeated
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

Preventing and Managing Drug-Induced Anaphylaxis
851
are required, these patients will require intensive
monitoring to help guide volume status. This may
include monitoring of central venous pressure, pul-
monary artery wedge pressure, cardiac output, ox-
ygen consumption, urinary output and electrocar-
diographic monitoring.
In certain situations of recalcitrant hypotension,
vasopressors may be used. Their effectiveness is
limited if the patient’s peripheral vascular resistance
is already elevated from endogenous compensatory
mechanisms. Vasopressors have been used for years
and can be helpful. Dopamine is the drug of choice
in most instances. A rate of 2 to 20 μg/kg/minute
should be adjusted according to effect on the pa-
tient’s blood pressure.
An important caveat is the patient treated with
a β-adrenoceptor antagonist for baseline hyperten-
sion. This patient can experience recalcitrant hypo-
tension, at times requiring up to 5 to 7 litres of fluid.
In such patients glucagon, a glycopeptide produced
by the α-cells of the pancreas, produces both ino-
tropic and chronotropic effects. The dose is 1 to 5mg
intravenously as determined by clinical response.
This dose may need to be followed by a continuous
infusion of 5 to 15μg per minute titrated again to
clinical response. Cardiotonic effects of glucagon are
seen in 1 to 5 minutes and are maximal at 15 min-
utes. Administration may be limited by nausea and
vomiting. In the case of isolated bradycardia, atro-
pine given at a dose of 0.3 to 0.5mg either intra-
muscularly or subcutaneously every 10 minutes, to
a maximum dose of 2mg, may be beneficial. If the
patient receiving a β-adrenoceptor antagonist has
bronchospasm but not shock, aminophylline be-
comes the drug of choice. It should be used very
cautiously if hypotension is present.
Histamine receptor antagonist therapy can be
used with epinephrine, although it is not consid-
ered to be lifesaving. It may offer dramatic relief of
symptoms in selected patients. Clinical trials have
shown that combinations of histamine H1 and H2
receptor antagonists are superior to H1 receptor an-
tagonist monotherapy.[46] In adults, diphenhydra-
mine may be given by the intramuscular or intra-
venous route, depending on the severity of the
situation, at a dose of 25 to 50mg. Children can be
administered the medication by the oral, intramus-
cular or intravenous route at a dose of 1 to 2 mg/kg.
Ranitidine can be given at a dose of 1 mg/kg.
The role of corticosteroids in the management
of acute events is unclear. The use of these agents
makes good sense, based on findings in other aller-
gic diseases. Their use is especially salient because
of their theoretical effects on the late phase reac-
tion. Anaphylaxis can be biphasic, and prevention
of the second phase may be crucial. Studies are still
somewhat lacking in this area of treatment, and
there is no established drug of choice. Patients with
milder anaphylactic reactions may benefit from 30
to 60mg of oral prednisone. Methylprednisolone
can be used if an intravenous agent is required. The
usual dose can range from 125 to 250mg depending
on the clinical situation.
If wheezing occurs that is unresponsive to epi-
nephrine, aerosolised β-adrenoceptor antagonists,
and if necessary aminophylline, may be used. The
doses are the same as for asthma. β-Agonists 0.25
to 0.5ml are administered in 1.5 to 2.0ml of saline
every 4 hours unless required more frequently.
Aminophylline is administered intravenously in
adults and children over the age of 1 year, starting
with a loading dose of 6 mg/kg given over 20 to 30
minutes.
Patients need to be observed after stabilisation for
at least 2 hours for mild episodes and probably for
24 hours after severe anaphylaxis. There is the pos-
sibility of a biphasic episode and if this is not re-
cognised and treated results can be deadly.[5]
5. Conclusion
Anaphylaxis and anaphylactoid reactions are
potentially life-threatening events. Many different
agents can cause them. Prevention, if possible, is
the purpose of detailed patient history taking and
physical examination. Testing is available, but the
exact antigenic determinant of many medications
is unknown, making a negative test difficult to in-
terpret. Desensitisation procedures, as well as gra-
dual dose escalation protocols, are available and are
implemented based on history and diagnostic test-
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

852
Drain & Volcheck
19. Settipane GA, Chafee FH, Klein DE. Aspirin intolerance: II. A
prospective study in an atopic and normal population. J Al-
lergy Clin Immunol 1974; 53: 200
ing. The treatment of anaphylaxis is based on con-
trol of the airway, breathing and circulation. Treat-
ment revolves around epinephrine and supportive
measures. All individuals with a documented his-
tory of anaphylaxis require a Medic-Alert bracelet
or necklace, and an identification card for their
wallet of purse.
20. Kemp SF, Lockey RF, Lieberman P, et al. Anaphylaxis, a review
of 266 cases. Arch Intern Med 1995; 155: 1749-54
21. Laxenaire MC, Moneret-Vautrin DA, Widmer S, et al. Substances
anesthesiques responsables de chocs anaphylactiques. Enquete
multicentrique francaise. Ann Fr Anesth Reanim 1990; 9: 501-6
22. Laxenaire MC, Le Groupe d’etude des reactions anaphylac-
toides peranesthesiques. Substances responsables des chocs
anaphylactiques peranesthesiques: troisieme enquete multi-
centrique francaise (1992-1994). Ann Fr Anesth Reanim 1996;
15: 1211-8
23. Gueant JL, Aimone-Gastin I, Namour F, et al. Diagnosis and
pathogenesis of the anaphylactic and anaphylactoid reactions
to anaesthetics. Clin Exp Allergy 1998; 28: 65-70
24. Eggleston ST, Lush LW. Understanding allergic reactions to
local anesthetics. Ann Pharmacother 1996; 30: 851-7
25. Giovannitti JA, Bennett CK. Assessment of allergy to local an-
esthesia. J Am Dent Assoc 1979; 98 (5): 701-6
26. Lagier F, Vervloet D, Lhermet, I et al. Prevalance of latex allergy
in operating room nurses. J Allergy Clin Immunol 1993; 90:
319-22
27. Kelly KJ, Walsh-Kelly CM. Latex allergy: A patient and health
care system emergency. J Emerg Nurs 1998 Dec; 24 (6): 539-45
28. Latex Hypersensitivity Committee of the American College of
Allergy, Asthma, and Immunology: Latex allergy an emerg-
ing health care problem. Ann Allergy Asthma Immunol 1995;
75: 19-21
References
1. Kagy L, Blaiss MS. Anaphylaxis in children. Pediatr Ann 1998
Nov; 27 (11): 727-34
2. Freeman TM. Anaphylaxis: Diagnosis and Treatment. Primary
Care; Clinics in Office Practice 1998 Dec; 25 (4): 809-17
3. Hess DA, Rieder MJ. The Role of Reactive Drug Metabolites
in Immune-Mediated Adverse Drug Reactions. Ann Pharma-
cother 1997 Nov; 31 (11): 1378-87
4. Macy E. Elective penicillin skin testing and amoxicillin chal-
lenge: Effect on outpatient antibiotic use, cost and clinical
outcomes. J Allergy Clin Immunol 1998 Aug; 102 (8): 281-5
5. Lieberman, P. Anaphylaxis and Anaphylactiod Reactions. In:
Middleton E, Reed CE, Ellis EF, et al., editors. Allergy prin-
ciples and practice. St. Louis: Mosby, 1998: 1079-91
6. Douglas DM, Sukenick E, Andrade WP et al. Biphasic systemic
anaphylaxis: An inpatient and outpatient study. J Allergy Clin
Immunol 1994 Jun 93 (6): 977-85
29. KatayamaH, Yamaguchi K, Kozuka T, et al. Adverse reactions
to ionic and nonionic contrast media: a report from the Jap-
anese Committee on the Safety of Contrast Media. Radiology
1990; 175: 621
30. Adkinson FN. Drug allergy. In: Middleton E, Reed C, Ellis EF,
et al., editors. Allergy principlesand practice. St Louis: Mosby,
1998: 1217
7. Atkinson TP, Kaliner MA. Anaphylaxis. Med Clin Nor Am 1992;
76: 841-55
8. Boston Collaborative Drug Surveillance Program: Brief reports:
drug induced anaphylaxis, JAMA 1973; 224: 613
9. Porter J, Jick H. Boston Collaborative Drug Surveillance Pro-
grams: drug induced anaphylaxis, convulsions, deafness and
extrapyramidal symptoms. Lancet 1977; I: 587
10. Amornmarn L, Bernard L, Kumar N, et al. Anaphylaxis admis-
sions to a university hospital. J allergy Clin Immunol 1992;
89 Suppl.: 349
11. Bresser H, Sander C, Rakoski J. Anaphylactic emergencies in
Munich. J Allergy Clin Immunol 1995; 95: 386
12. Klein JS, Yocum MN. Underreporting of anaphylaxis in a com-
munity emergency room. J Allergy Clin Immunol 1995; 95:
637-8
13. Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology of
anaphylaxis in Olmstead County: a population-based study. J
Allergy Clin Immunol 1999: 104: 452-6
14. Weiss ME, Atkinson NF. Immediate hypersensitivity reactions
to penicillin and related antibiotics. Clin Allergy 1988: 18:
515-40
15. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United
States. Arch Intern Med 2001; 161: 15-21
16. Falliers, CJ. Aspirin and subtypes of asthma: risk factor analy-
sis. J Allergy Clin Immunol 1973; 52: 141
31. Adkinson NF. Beta-lactam crossreactivity. Clin Exp Allergy 1998;
28 (4) 37-40
32. Craig TJ, Mende C. Common allergic and allergic-like reactions
to medications. Postgrad Med 1999 Mar; 105 (3): 173-81
33. Sogn DD, Evans III R, Shepard GM, et al. Results of the Na-
tional Institutes of Allergy and Infectious Diseases Collabo-
rative Clinical Trial to test the predictive value of skin testing
with major and minor penicillin derviatives in hospitalized
adults. Arch Intern Med 1992; 152: 1025-32
34. Pichichero ME, Pichichero DM. Diagnosis of penicillin, am-
oxicillin and cephalosporin allergy: reliability of examination
assessed by skin testing and oral challenge. J Pediatr 1998 Jan;
132: 137-43
35. Vervloet D, Arnaud A, Vellieux P, et al. Anaphylactic reactions
to muscle relaxants under general anesthesia. J Allergy Clin
Immunol 1979; 63: 348
36. Lieberman P. Difficult allergic drug reactions. Immunol Allergy
Clin North Am 1991; 11 (1): 331
37. Wolkenstein P, Revuz J. Drug-induced severe skin reactions.
Drug Safety 1995; 13 (1): 56-68
17. Manning ME, Stevenson DD, Mathison DA. Reactions to aspi-
rin and other nonsteroidal anti-inflammatory drugs. Immunol
Allergy Clin North Am 1992 Mar; 12 (3): 611-31
18. Strom BL, Carson JUL, Morse ML, et al. The effect of indica-
tion on hypersensitivity reactions associated with zomepirac
sodium and other non-steroidal anti-inflammaotry drugs. Ar-
thritis Rheum 1987; 30: 1142
38. Gleckman RA, Borrego F. Adverse reactions to antibiotics. Post-
grad Med 1997 Apr; 101 (4) 97-108
39. Valyasevi MA, Van Dellen RG. Frequency of systematic reac-
tions to penicillin skin tests. Ann Allergy Asthma Immunol
2000 Nov; 85 (5): 363-5
40. Gruchalla R. Understanding drug allergies. J Allergy Clin Im-
munol 2000; 105: 637-44
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)

Preventing and Managing Drug-Induced Anaphylaxis
853
41. Solley GO, Gleich GJ, Van Dellen RG. Penicillin allergy: clin-
ical experience with a battery of skin-test reagents. J Allergy
Clin Immunol 1982; 69: 238-44
45. Simons PR, Roberts JR, Gu X, et al. Epinephrine absorption in
children with history of anaphylaxis. J Allergy Clin Immunol
1998; 101: 33-7
46. Mayumi H, Kimura S, Asano M, et al. Intravenous cimetidine
as an effective treatment for systemic anaphylaxis and acute
allergic skin reaction. Ann Allergy 1987; 58: 447-50
42. Gadde J, Spence M, Wheeler B, Adkinson NF. Clinical experi-
ence with penicillin skin testing in a large inner city STD
clinic. JAMA 1993; 270: 2456-63
43. Li JTC, Markus PJ, Osmon DR, et al. Reduction of vancomycin
use in orthopedic patients with a history of antibiotic allergy.
Mayo Clin Proc 2000; 75: 902-6
44. Parker DJ, Parrinello JT, Condemi JJ, et al. Penicillin resen-
sitization among hospitalized patients. J Allergy Clin Immunol
1991; 88: 213-7
Correspondence and offprints: Dr Gerald W. Volcheck, Aller-
gic Diseases and Internal Medicine, Mayo Clinic, 200 First
Street SW, Rochester, Minnesota 55905, USA.
E-mail: volcheck.gerald@mayo.edu
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (11)