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A E R Editor‑in‑Chief :
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Open Access
HTML Format Anesthesia: Essays and
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Researches

Review Article
Anaphylaxis during the perioperative period
Shrikant Mali

MDS Oral and Maxillofacial Surgery, Sr Lecturer, Department of Oral and Maxillofacial Surgery CSMSS Dental College, Aurangabad, India
Corresponding author: Dr. Shrikant Mali, Flat no. 1, Varun Corner, Osmanpura, Aurangabad, Maharashtra, India. E‑mail: shrikantmali@gmail.com

Abstract
The incidence of anaphylaxis during anesthesia has been reported to range from 1 in 4000 to 1 in
25,000. Anaphylaxis during anesthesia can present as cardiovascular collapse, airway obstruction,
and/or skin manifestation. It can be difficult to differentiate between immune and nonimmune mast
cell‑mediated reactions and pharmacologic effects from the variety of medications administered
during general anesthesia. In addition, cutaneous manifestations of anaphylaxis are less likely to
be apparent when anaphylaxis occurs in this setting. The evaluation of IgE‑mediated reactions
to medications used during anesthesia can include skin testing to a variety of anesthetic agents.
Specifically, thiopental allergy has been documented by skin tests. Neuromuscular blocking agents
such as succinylcholine can cause nonimmunologic histamine release, but there have also been
reports of IgE‑mediated reactions in some patients. Reactions to opioid analgesics are usually
caused by direct mast cell mediator release rather than IgE‑dependent mechanisms.Antibiotics that
are administered perioperatively can cause immunologic or nonimmunologic reactions. Protamine
can cause severe systemic reactions through IgE‑mediated or nonimmunologic mechanisms. Blood
transfusions can elicit a variety of systemic reactions, some of which might be IgE‑mediated or
mediated through other immunologic mechanisms. The management of anaphylactic reactions that
occur during general anesthesia is similar to the management of anaphylaxis in other situations.

Key words: Anaphyllaxis during GA, antibiotic sensitivity, neuromuscular blocking drugs
anaphyllaxis

INTRODUCTION prophylaxis in Greek means “protection,” anaphylaxis means

The term “anaphylaxis” was coined by Nobel prize recipients
Portier and Richet[1] in 1902, when they described a dog that
had tolerated a previous injection of actinotoxin, a jellyfish
toxin, but reacted with bronchial spasm, cardiorespiratory
arrest, and death to a smaller dose 14 days later. Whereas
Access this article online
Website DOI
www.aeronline.org 10.4103/0259-1162.108286
Quick Response Code
“opposite protection” or “against protection”.[2] Anaphylaxis
generally occurs on re‑exposure to a specific antigen and
requires the release of proinflammatory mediators, but it can
also occur on first exposure, because there is cross‑reactivity
among many commercial products and drugs.
Immune‑mediated allergic reactions are classified,
according to their mechanism, on the basis of the Gell
and Coombs classification. Whereas anaphylaxis is a Type I
immunoglobulin (Ig)E‑mediated hypersensitivity reaction
involving mast cells and basophils, contact dermatitis
is a Type IV T‑lymphocyte cell‑mediated delayed‑type
hypersensitivity reaction. Other immune‑mediated
reactions include Type II reactions in which IgG, IgM, and
complement mediate cytotoxicity and Type III reactions in
which immune‑complex formation and deposition

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leads to tissue damage.[3] Anaphylactoid reactions
occur through a direct nonimmune‑mediated release
of mediators from mast cells and/or basophils or result
from direct complement activation, but they present with
clinical symptoms similar to those of anaphylaxis.[3,4]
Surgeons perform major operations under general
anesthesia. During anesthesia and pre and post anesthesia
period the patient is given wide variety of drugs, colloids
and exposed to natural latex rubber. Anesthesiologist
routinely administers multiple agents, namely anesthetic
drugs, antibiotics, polypeptides, and blood products etc,
perhaps too rapidly and in quick succession. Majority of
these have the potential to produce severe, at times fatal
hypersensitive reactions, which contribute for perianesthetic
morbidity and mortality. Many of these drugs can elicit
adverse drug reactions that fall apart into two major types.
First, reactions that are usually dose dependent and related
to the pharmacological properties of the drug and/or its
metabolites. Second, reactions that are unrelated to the
drug’s pharmacological characteristics and that are less dose
dependent. These reactions comprise drug intolerance,
idiosyncratic reactions and drug‑induced immune‑mediated
allergic and nonimmune‑mediated so‑called pseudo‑allergic
or anaphylactoid reactions.[5] Hence, it is quite essential
for the surgeon to identify anaphylaxis reaction and
anesthesiologist to be able to prevent them preoperatively,
diagnose and treat them intraoperatively and investigate
them further postoperatively.
Various studies have proven that many anesthetic drugs,
natural latex rubber and antibiotics and analgesics
can induce life‑threatening anaphylaxis reactions. It
is important for surgeon to have detailed knowledge
of anaphylaxis including diagnosis and treatment. The
correct management of anaphylaxis during anesthesia
requires a multidisciplinary approach with prompt
recognition and treatment of the acute event by the
attending anesthesiologist, and subsequent determination
of the responsible agent(s) with strict avoidance of
subsequent administration of all incriminated and/or
cross‑reacting compounds. However, correct identification
of the causative compound(s) and safe alternatives is
not always straightforward and, too often, not done.
Diagnosis of anaphylaxis during anesthesia is not always
straight forward. It can be hampered as a broad spectrum
of different drugs can elicit heterogeneous allergic and
nonallergic reactions with distinct and sometimes unclear
pathological mechanisms.[5]
The terms anaphylactic and anaphylactoid, however, have
been used inconsistently in the literature. Therefore, the
nomenclature task force set up by the European Academy
of Allergy and Immunology (EAACI) has proposed that
anaphylactic‑type reactions should be reclassified into
allergic anaphylaxis and nonallergic anaphylaxis.[6] Allergic
anaphylaxis being further subdivided in IgE‑mediated
and non‑IgE‑mediated reactions.[6,7] During general
anesthesia, anaphylactic and anaphylactoid reactions
cannot be distinguished clinically, according to Mertes
and coworkers.[8] However, in that study, in which a
classification of symptom severity was applied, it was
found that clinical manifestations seemed to be more
severe in patients with documented anaphylaxis than in
individuals presenting with an anaphylactoid reaction.
Cutaneous manifestations were more frequent in
anaphylactoid reactions, but they were not confined
to that setting; cardiovascular and broncho‑obstructive
events, on the other hand, were more frequent during
anaphylaxis. In the case of cardiovascular and respiratory
complications, clinical symptoms may also occur as
isolated events, which can easily be misdiagnosed,
according to those authors, if we consider all diseases
presenting identical clinical manifestations.[8]
The pathological processes involving the IgE‑mediated
release of vasoactive substances after exposure to an
antigen to which there has been previous exposure
and sensitization are known as anaphylactic reactions.
An anaphylactoid reaction is clinically indistinguishable
but occurs by a different, nonimmune mechanism.
These pseudoallergic reactions are caused by the
release of histamine and, probably, other mediators.
The histamine‑releasing effect depends on the dose of
the medication and the most potent medications are
morphine and almost all muscular relaxants. Regrettably,
the legion case reports of severe drug reactions use
these terms loosely and interchangeably. This only
causes confusion when trying to establish the cause and
mechanism of reactions to different drugs.[9,10] Laxenaire’s
group, who are the French experts on anaphylaxis during
anesthesia, has proposed that all reactions should be
described as anaphylactoid unless an immune mechanism
has been demonstrated.[8]
Incidence
The incidence of anaphylaxis and anaphylactoid reactions
during anesthesia is very difficult to estimate but has been
calculated to range from 1 in 3500 to 1 in 13,000 cases.[12,13]
Another report from Australia estimated the incidence
to be between 1 in 10,000 and 1 in 20,000.[14] Another
recent report, from Norway, estimated the incidence to
be 1 in 6000.[15] Muscle relaxants are associated with the
most frequent incidence of anaphylaxis, and over the last
two decades, natural rubber latex (NRL) has emerged as
the second most common cause of anaphylaxis.[16,17]
The incidence of anaphylaxis after administration
of muscle relaxants has been assessed at 1 in 6500
procedures in which such a relaxant was administered.[18]
Mortality can be high (3.4%) and anaphylactic deaths can
account for as many as 4.3% of all deaths occurring during
general anesthesia.[19,20] In vitro studies of the effects of
increasing concentrations of different anesthetics on the
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release of preformed and de novo mediators from human
basophils and mast cells isolated from lung parenchymal,
skin and heart tissue have demonstrated that most
general anesthetics are able to induce histamine and
tryptase release from human basophils and mast cells.[21,22]
The prevalence of bronchial hyper‑reactivity is
approximately 10% and this condition is an important
risk factor for perioperative bronchospasm, a
potentially life‑threatening event whose incidence in
anesthesia practice varies from relatively low rates
of 0.17% or 4.2%[23,24] to higher ones of about 7%[25] or
20%.[26] Obstructive bronchial reactions tend to increase in
proportion to the proximity of the latest asthma attack in
relation to the date of surgery.[23,26,27] Tracheal intubation
also constitutes a high risk factor for intraoperative
bronchospasm[23,26,27] and diagnostic approaches such as
bronchoscopy and endobronchial biopsy may aggravate
respiratory symptoms in children with asthma.[28] Increased
bronchial symptoms in the week following bronchoscopy
have also been reported in children.[28]
The degree of severity varies and does not allow
differentiation between an IgE‑mediated or non‑IgE
mediated reaction resulting from nonspecific mediator
release[17] The mortality from these reactions is in the
range from 3% to 6%, and an additional 2% of patients
experience significant residual brain damage.[14] An
IgE‑mediated mechanism has been confirmed in 40% to
70% of cases.[29] Severe adverse reactions are infrequent
during surgery, and IgE‑mediated allergic reactions are the
main contributors to morbidity and mortality in this kind
of reaction during surgery.[30] Serious problems are unusual
during surgery (0.4% of cases), but anesthesia contributes
to a third of these cases. Allergic reactions are among the
major factors that contribute to morbidity and mortality
during an anesthetic and to changes in postoperative
care. A recent review of serious intraoperative problems
highlighted a case of fatal anaphylactic shock and
suggested that preventive strategies are needed for
anaphylaxis.[30]
Pathophysiology
Anaphylactoid reactions are derived from the activation
of the complement and/or bradykinin cascade and
the direct activation of mast cells and/or basophils.
Clinical manifestations of anaphylactoid reactions are
indistinguishable from anaphylactic reactions. These
reactions are rapid in onset and start within seconds to
minutes of exposure to the allergen. Symptoms progress
rapidly and can affect most organ systems, including the
skin (pruritus, flushing, urticaria, and angioedema) and
eyes (conjunctivitis), the upper (rhinitis and angioedema)
and lower (bronchoconstriction with wheezing and
dyspnea, and cyanosis) airway, the intestinal tract
(abdominal pain, nausea, vomiting, and diarrhea), and
the cardiovascular system (tachycardia, hypotension,
126
and shock), and can lead to cardiovascular collapse and
death.[4]
Regardless of the initiating trigger and mechanism,
cellular events involving activation of tyrosine kinases
and calcium influx in mast cells and basophils result in
rapid release of granule associated preformed mediators
such as histamine, tryptase, carboxypeptidase A3,
chymase, and proteoglycans. Downstream activation of
phospholipase A2, COXs, and lipoxygenases leads to
production of arachidonic acid metabolites, including
prostaglandins and leukotrienes and synthesis of the
platelet‑activating factor. In addition, an array of cytokines
and chemokines are synthesized and released, including
IL‑6, the newly recognized IL‑33 and TNF‑a, which is both
a late‑phase mediator and a preformed mediator. The
opening of the endothelial barrier through endothelial Gq/
G11‑mediated signaling has been identified as a critically
important process leading to anaphylaxis symptoms in
many body organ systems.[31]
Recognition of anaphylaxis during general
anesthesia
The lack of an adequate diagnosis could lead to
a potentially fatal re‑exposure to the same agent.
The common findings that clinical manifestations of
intraoperative reactions differ from those of anaphylactic
reactions outside of anesthesia might be explained
by the fact that patients are draped during anesthesia
and cannot complain of cutaneous symptoms such as
pruritus or a sense of flushing.[17] Moreover, concomitantly
administered drugs may alter the expression and degree
of clinical manifestations. The difficulty in recognizing
anaphylactic symptoms in anesthetized subjects may also
be explained by the need to exclude various other clinical
conditions.[32]
Alertness in recognition is essential, because reactions
may be well established before they are noticed. The most
commonly reported initial features are pulselessness,
difficulty in lung inflation and desaturation.[33] A decreased
etCO2 value is also of valuable diagnostic interest. If the
signs appear later, during the maintenance of anesthesia,
they suggest an allergy to latex or volume expander. Latex
allergy should also be considered when gynaecological
procedures are performed. Particles from obstetricians’
gloves, which accumulate in the uterus during obstetrical
manoeuvres, could suddenly be released into the systemic
blood flow following oxytocin injection. Anaphylactic
reactions to antibiotics have also been reported following
removal of tourniquet during orthopaedic surgery.[34]
Etiology
The two primary causes of true anaphylaxis in the
patient under anesthesia are muscle relaxants and latex
allergy. The muscle relaxants indicated in clinical studies
most responsible for reactions include succinylcholine,
atracurium, vecuronium, and pancuronium.[35]
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Neuromuscular blocking agents
The most common cause of anaphylaxis during general
anesthesia or postoperatively is neuromuscular blocking
agents (muscle relaxants), which are responsible for
60% to 70% of episodes of anaphylaxis occurring during
this period.[8,36‑44] All NMBA can elicit anaphylaxis and
there is an agreement that the short‑acting depolarizing
succinylcholine poses the greatest risk, despite its close
structural homology to acetylcholine.[45‑47] Neuromuscular
blocking agents can induce two types of reactions.
One is driven by an immunological mechanism and
is IgE‑dependent with the quaternary ammonium
(NH4 +) structures as main antigenic epitope,[47,48]
while the second one, particularly described with
benzylisoquinolinium‑type NMBA such as mivacurium,
atracurium, and d‑tubocurarine, results from nonspecific
stimulation of mast cells.[49‑52] Cross‑reactivity between
NMBA is said to be common because of ubiquitous
ammonium groups in these drugs. The estimated
prevalence of cross‑reactivity between NMBA is about
65% by skin tests and 80% by radioimmuno assay (RIA)
inhibition tests.[5]
Most of the muscle relaxants cause direct release of
mast cell histamine without the requirement for specific
antibody. However, life‑threatening reactions usually are
IgE‑ mediated.[53] The tertiary or quaternary ammonium
group, common to all muscle relaxants, is likely the
immunodominant determinant recognized by IgE.[47] The
antigenicity of the shared ammonium structures may
be responsible for cross‑reactivity among the muscle
relaxants. Cross‑reactivity occurs most consistently
between pancuronium and vecuronium.[54] Cross‑reactions
also may occur between muscle relaxants and other
classes of pharmaceuticals, based upon in vitro inhibition
of specific‑IgE binding to the muscle relaxants. Agents
that potentially cross‑react with muscle relaxants include:
Acetylcholine, choline, morphine, neostigmine, and
pentolinium. Cross‑inhibition suggests that previous
exposure to these nonanesthetic drugs may sensitize
individuals to muscle‑relaxing agents, resulting in
reactions among patients without prior anesthesia.[55,56]
Natural rubber latex
Latex allergy is an important cause of anaphylaxis during
anesthesia.[8,17] Latex sensitization is due to IgE‑mediated
reactivity to any number of antigens from Hevea
brasiliensis, the source of latex. Sensitization occurs in up
to 12% of health care workers, up to 75% of patients with
spina bifida and in patients undergoing multiple surgical
procedures.[57‑59] IgE‑mediated NRL allergy has become
a well‑defined condition with recognized risk groups,
established diagnostic tools, and adequate prevention
strategies.[60] In 1984, Turjanmaa et al.[61] described the
first cases of NRL‑associated intraoperative anaphylaxis.
The at‑risk individuals for perioperative anaphylaxis from
NRL can be subdivided into those genetically predisposed
(i.e., atopics) and those with significant exposure such
as healthcare workers and children requiring multiple or
repetitive surgical and medical interventions (e.g., neural
tube defects, spinal cord trauma, and urogenital
malformations) that need chronic bladder care with
repeated insertion of NRL catheters or chronic indwelling
catheters.[5] In contrast, adult patients with spinal cord
injury and repeated latex exposure seem not at risk for
latex allergy.[5]
It is important to distinguish this from contact dermatitis
to chemicals used in the manufacture of rubber, which
is a different disorder with different implications and
requiring less stringent avoidance during surgery. Contact
dermatitis causes slow‑onset eczematous reactions, is not
life threatening and caused by a type IV reaction and thus
IgE antibodies are not involved.[62] Allergic reactions to
latex occur intraoperatively as time is needed to absorb
the allergen through the mucosa or peritoneum.
A systemic reaction is unlikely to occur within a few
minutes of latex exposure. If latex allergy is suspected,
skin prick test SPTs and serum‑specific IgE tests should
be undertaken. SPTs are superior to serum assays[20,63]
with a greater sensitivity and specificity than specific IgE.
If latex allergy is strongly suspected and skin test and
serum‑specific IgE is negative, glove challenge (exposing
the patient to latex by wearing a latex glove for increasing
periods while monitoring for objective signs of an allergic
reaction) should be undertaken. If glove challenge is
negative, a buccal challenge should be undertaken.[62]
With exposure, sensitized individuals may develop
urticaria, angioedema, allergic rhinitis, asthma, and
anaphylaxis. Latex‑induced anaphylaxis from powdered
latex gloves, as well as other sources, may present in
the operating room in patients, surgeons, nurses or
anesthesiologists. Latex has been reported to account for
up to 17% of intraoperative anaphylaxis.[63]
The features of intraoperative anaphylaxis may differ
considerably from anaphylaxis not associated with surgical
procedures. While cutaneous, hypotensive and respiratory
events occur in both, hypotensive cardiovascular collapse
is a feature of reactions to latex during surgery while
dizziness or syncope is found largely in anaphylaxis
induced by nonsurgical procedures.[64,65]
Latex‑induced anaphylaxis may occur in a variety of
situations, all involving direct contact with latex, usually
gloves, or instruments, or with aerosolization of latex
antigen adherent to the cornstarch powder of latex
gloves. Thus, latex reactions can occur during operative
procedures, when gloves are donned. Latex reactions may
occur immediately with latex contact or may be delayed
from 30 to 60 min. Intraoperative latex anaphylaxis may
be related to the administration of drug through a latex
port prior to surgery, or during the surgical procedure
itself. Latex reactions have also been reported to occur
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during dental procedures from latex gloves or dams,
during obstetrical or gynecologic examinations and during
latex condom use. Spina bifida patients are potentially
at risk during each surgical procedure because of the
numbers of procedures they undergo.[56,65]
For the sensitized health care worker, latex gloves
should not be worn and the worker’s colleagues should
wear nonpowdered latex gloves or nonlatex gloves. The
workplace should be “latex safe” with all nonglove latex
devices replaced by nonlatex devices. A “latex free”
emergency cart should be available to treat reactions.
Rubber stoppered vials should be avoided.[56]
Antibiotics
Penicillin, cephalosporins, and other‑lactam antibiotics
These are the most commonly used antibiotics during
the perioperative period and perhaps some of the
most commonly used drugs overall. Penicillin is the
most common cause of anaphylaxis in the general
population. The antibiotics most commonly implicated
in reactions during this period are b‑ lactam antibiotics
and vancomycin.[66] Taken together, penicillins and
cephalosporins elicit approximately 70% of perioperative
anaphylactic reactions elicited by antibiotics.[8,13]
After muscle relaxants and latex allergy, antibiotics
are targeted as the third leading cause of anaphylactic
reactions in the surgical patient.[17] Sulfonamide allergy
is also fairly common in surgical patients. Keeping the
incidence of drug‑allergy‑induced anaphylaxis in the
surgical patient in perspective, up to 2% of the population
is allergic to penicillin, but approximately only 0.01%
of penicillin administration results in an anaphylactic
reaction.[11] In patients with a history of a prior reaction
to penicillin, one review of the literature found that only
10% to 20% of patients who report a penicillin allergy have
a documented allergy.[67] A review of this subject found
that patients with an allergy to penicillin were more likely
(threefold) to experience an anaphylactic reaction to any
other drug.[68] Although some experts state that it is safe
to administer cephalosporins to penicillin‑allergic patients
and that penicillin skin tests are not indicated[68] others
have recommended avoidance of cephalosporins in those
with positive penicillin skin tests or anaphylaxis.[67,69,70]
Goodman et al.[70] performed a retrospective chart review
of intraoperative anesthesia records over a 14‑month
period and demonstrated that cephalosporins can be
given to patients who claim to be allergic to penicillin.
However, a limitation of this study is that patients who
reported anaphylaxis to penicillin were excluded.
Vancomycin is a glycopeptide antibiotic selectively
used for treatment of resistant organisms and for use
in individuals with penicillin allergy. It is commonly
used for antibiotic prophylaxis in the surgical and it
is commonly associated with anaphylactoid reactions
128
consisting of pruritus, erythema of the head and
upper torso, and arterial hypotension. Administration,
especially when it is rapid, may result in life‑threatening,
non‑IgE‑mediated anaphylaxis.[71‑73] Direct histamine
release and direct myocardial depression partially
explain this phenomenon.[74] These nonimmunologic
reactions to vancomycin can be reduced or eliminated by
administering this drug as a dilute solution, dissolved in
at least 200 mL, and infused over at least a 2‑h period.
Other antibiotics that are often used in the operating
room and that may rarely trigger an anaphylactic reaction
include clindamycin, gentamicin, and metronidazole.
Clindamycin is used against Gram‑positive and anaerobic
bacteria and usually causes a contact dermatitis. No
specific IgE antibody has been found, and skin prick
and intradermal skin tests are negative. Gentamicin
is a broadspectrum aminoglycoside often used in
patients at risk for endocarditis, whereas metronidazole
is a nitroimidazole derivative used against anaerobic
infections. IgE‑mediated hypersensitivity, although
previously reported, is extremely rare in both cases.[75]
Plasma volume expanders (colloids)
Today, colloids have been recognized to cause up to 4%
of all perioperative anaphylactic reactions.[8,13,76] These
reactions were severe in 20% of the cases and generally
occurred 20 min after start of infusion. Fatalities to
colloids have been reported.[77] For a comprehensive
review of anaphylactoid reactions to colloids, the reader
is referred elsewhere.[78]
Dextran and hydroxyethyl starch (HES),
large‑molecularweight polysaccharides, may be used
as a nonblood, highoncotic fluid replacement during
surgery. These agents are infrequently associated with
adverse reactions and anaphylaxis. Estimates of reaction
rates are 0.008% to 0.08% for dextran and 0.08% for
HES.[79] The incidence of allergic reactions to colloids
seems to be increasing. Whereas earlier reports from the
1980s described an incidence of 0.03% for dextran and
hetastarch[80,81] a French study from 1994 demonstrated an
overall frequency of 0.22%. Gelatins (0.34%) and dextrans
(0.27%) were more likely to cause an allergic reaction than
albumin (0.1%) or hetastarch (0.06%). Individuals with prior
drug allergies were three times more likely to develop
anaphylaxis, and males were more likely than females
to develop an allergic reaction.[82] Egg allergy does not
appear to be a contraindication to the use of albumin,
because the principal egg protein, ovalbumin (45 kd), is
different from human serum albumin (67 kd).[83] A report
from France demonstrated that 2.9% of intraoperative
anaphylaxis cases were due to colloids.[16]
Intravenous drugs used for anesthetic induction
It can cause perioperative anaphylaxis. More than
290 cases of anaphylaxis are reported in the literature
from the use of barbiturates, especially thiopental. The
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incidence of anaphylaxis to thiopental is estimated to
be 1 in 30,000 administrations, and previous exposure
and female sex are associated with an increased
incidence.[84] However, the reaction rate with barbiturates
is only 1:25,000, with the reported occurrence of
reactions reflecting the common use of these compounds.
Women are three times more likely to have reactions from
thiopental than men.[85,86]
Propofol is a nonbarbiturate induction agent that is
potentially useful if sensitivity to barbiturates is a
concern[87] IgE‑mediated reactions from propofol may
occur,[88,89] however, most adverse reactions to propofol
are nonimmunologic. Propofol may directly stimulate
histamine release, and this effect may be greater
when administered with muscle relaxants.[90] Propofol
(2,6‑diisopropylphenol) is currently formulated in a lipid
vehicle containing soybean oil, egg lecithin, and glycerol.
The incidence of anaphylactic reactions with the new
formulation is 1 in 60,000, although it has been reported
to cause 1.2% of cases of perioperative anaphylaxis in
France.[91] A more recent report from the same group in
France demonstrated that 2.1% of cases of intraoperative
anaphylaxis are due to propofol.[16]
Benzodiazepines
Diazepam is more likely than midazolam to cause
an anaphylactic reaction because of the propylene
glycol solvent that replaced Cremophor EL. The active
metabolite desmethyldiazepam may be responsible
for the cross‑reactivity with other benzodiazepines.[92]
Midazolam is a safe drug, because it does not have any
active metabolites. Although anaphylactoid reactions to
midazolam have been reported, no serologic or cutaneous
testing was performed[75] In addition, midazolam has been
used safely for the induction of anesthesia in patients
with drug allergy.[93,94]
Narcotics used in perioperative period are a common
cause of flushing and urticaria following intravenous
administration. Anaphylaxis, in contrast, is very rare.[95-97]
Morphine is a tertiary amine that causes
nonimmunological histamine release, and meperidine
causes nonimmunological histamine release more often
than any other opioid.[75] There are reported cases of
IgE‑mediated reactions to these opioids.[12,97,98]
Dermal mast cells express opioid receptors that bind
to the narcotic and stimulate histamine release. Other
populations of mast cells do not express this receptor.
Cutaneous flushing and hives often occur after intravenous
morphine administration, but with rare exceptions,
the amount of histamine release does not result in
hypotension or bronchospasm. Reducing the rate of
opioid administration usually limits the severity of these
reactions. Fentanyl does not directly stimulate histamine
release by way of the mast‑cell opioid receptor.[99] There
are reports of anaphylaxis to morphine and fentanyl.[98]
Local anesthetic agents readily induce cell‑mediated
immunologic reactions when applied topically to the
skin, but humoral immune responses are rare. Adverse
effects from local anesthetics are not uncommon, but
immunologically mediated reactions following parenteral
administration are very unusual. Anaphylactic reactions
to amide local anesthetics are extremely rare, and true
allergic reactions to esters account for 1% of all drug
reactions to local anesthetics.[100‑102] The most common
immune‑mediated reaction to local anesthetics is a
delayed hypersensitivity reaction (Type IV reaction), or
contact dermatitis.[102] Challenge tests remain the gold
standard, or rather reference test to diagnose anaphylaxis
from local anesthetics and different protocols exist.[103‑106]
Povidone‑iodine
Povidone‑iodine (betadine) is the most common topical
antiseptic solution use. Allergic contact dermatitis, a
Type IV cell‑mediated hypersensitivity reaction, is more
common with povidone‑iodine. Patch testing to diagnose
this type of reaction is best done with dried 10% povidone
iodine solution, because long exposure to povidoneiodine
in the aqueous state may yield a false‑positive result due
to direct skin irritation.[107]
Chlorhexidine
Chlorhexidine is widely used all over the world as a skin
disinfectant before surgery or invasive procedures and in
the general population in mouthwash or for disinfecting
minor scratches. Therefore, patients may become sensitized
before a surgical procedure. A report in the literature
describes four patients with a history of minor rashes or
faints in connection with previous chlorhexidine exposure
who developed severe hypotension requiring epinephrine
after subsequent exposure. Skin testing (prick test with
0.5% or intradermal test with 0.0002% chlorhexidine) was
positive for chlorhexidine, Evidence for an IgE‑mediated
hypersensitivity to chlorhexidine was first provided in
1984[110] and hapten inhibition studies have shown the
entire chlorhexidine molecule to be complementary to
the IgE antibody binding sites and the 4‑chlorophenol,
biguanide, and hexamethylene structures together
constitute the allergenic determinant.[111,112]
Symptoms of chlorhexidine anaphylaxis have been
attributed to cutaneous, percutaneous, mucosal, and
parenteral application. Life‑threatening reactions with
profound hypotension, ventricular fibrillation and cardiac
ischaemia are generally associated with mucosal or
parenteral exposure as might occur during application
of urethral gels, implanted antimicrobial surgical mesh,
and insertion of chlorhexidine‑coated central venous
catheters respectively. Severe, potentially life‑threatening
anaphylaxis from simple cutaneous application such as
perioperative skin disinfection and wound cleansing
remains anecdotal and probably underestimated. In a
recent survey, chlorhexidine accounted for 27% of the
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Anesthesia: Essays and Researches; 6(2); Jul-Dec 2012 Mali: Anaphyllaxis
overlooked perioperative hypersensitivity reactions.[113]
Nonsteroidal anti‑inflammatory drugs
Aspirin and NSAIDs are the second most common cause of
drug‑induced anaphylaxis (after antibiotics).[113] Anaphylactic
reactions to NSAIDs are unrelated to other reactions
caused by these drugs, such as respiratory reactions and
exacerbations of chronic idiopathic urticaria.[114] True
anaphylactic reactions to NSAIDs appear to be medication
specific in that some patients who have had an anaphylactic
reaction to one NSAID are able to tolerate structurally
unrelated NSAIDs, but this is largely based on clinical
experience rather than large scale challenge studies.
[113]
NSAIDs, including aspirin, can cause reactions, by
inhibition of cyclo‑oxygenase, resulting in generation of
leukotrienes.[115,116] NSAIDs are increasingly recognized
as a cause of non‑IgE‑mediated anaphylactic reactions.
They may be given rectally towards the end of surgery,
i.v., or sometimes with premedication, depending on the
procedure. The onset of reaction is usually up to 10 min
after i.v. administration, 15-30 min from rectal administration
and 30-60 min after oral administration. If the onset of
reaction is at the end of surgery, this immediately excludes
the induction agents, and the main differential diagnosis
is an NSAID given rectally late during the procedure,
latex allergy or a reaction to colloid. There are no reliable
diagnostic tests for NSAID intolerance and this is essentially
a clinical diagnosis, having excluded other potential causes
(such as NMBAs and latex rubber). However, the diagnosis
can be confirmed by provocation, but this should only be
considered if there is doubt from the history.[117]
Causes of severe adverse events during anesthesia[62]
• Exaggerated pharmacological effect, e.g., hypotension
during extradural anesthesia or with propofol;
bradycardia and hypotension after opiates
• Anaphylaxis to one of the i.v. NMBAs or anesthetic drugs
• Adverse reaction to another administered drug
e.g., drug with premedication; antibiotic with induction;
analgesic, e.g., NSAID rectally or opiate intraoperatively
• Latex rubber allergy
• Reaction to intravenous infusion, for example colloid,
blood, plasma
• Allergy to other substance given, e.g., chlorhexidine or
a diagnostic dye
• Problem with anesthetic technique, for example intubation
• Autonomic parasympathetic effects, e.g., during
laparoscopy, peritoneal traction, arthroscopy, squint
surgery, dental surgery
• Blood loss
• Medical (non‑allergic) cause, for example septicaemia;
cardiac; severe asthma, pneumothorax; air embolus
• Malignant hyperthermia
Clinical features
The clinical manifestations are more severe and longer
lasting in reactions of immunologic origin than in
130
pharmacologic reactions. The clinical signs do not
always fully exist and they may be misleading. The
most common clinical features of anaphylaxis during
anesthesia are cardiovascular and cutaneous signs and
symptoms.[1] However, cutaneous signs can be difficult
to identify, because the patient is draped.[17] Additionally,
while the patient is under anesthesia, there is an absence of
symptoms that the patient is experiencing an anaphylactic
reaction. The absence of cutaneous signs does not exclude
the diagnosis of anaphylaxis. The diagnosis of anaphylaxis
depends in large part on the patient’s ability to describe the
event, and the patient cannot describe symptoms because
they are unconscious or not fully conscious. Cardiovascular
collapse may be the sole manifestation of anaphylaxis
and may be confused with other causes of cardiovascular
collapse in this setting. The majority of surgical anaphylaxis
occurs during the induction period when muscle relaxants,
sedatives, and opiates are administered.
In anaphylaxis, the clinical features are to some extent
dependent on the cause and route of administration
of allergens. Allergy to a drug given i.v. as a bolus is of
rapid onset, usually within minutes of administration
and predominantly causes cardiovascular collapse 120. In
contrast, with a rectally administered drug, there is usually
a delay of 15-30 min to onset, and urticaria, angio‑oedema
or asthma is common. Similarly, an i.v. infusion of gelatin
usually takes 15-30 min to cause a reaction. In latex
rubber allergy, where the allergen is absorbed through
the peritoneum, mucosa or skin, a mixed clinical picture
is seen, and the onset may be >30 min from first contact.
Common initial clinical features seen by the anesthetist
are loss of pulse, fall in arterial pressure, difficulty in
inflating the lungs and flushing.[14] The timing in relation
to drug administration is important, and gives a clue
to the aetiology. If anaphylaxis occurs within minutes
of induction then Intravenous anesthetics, Intravenous
opiate, and Intravenous antibiotic are the culprits. And if
anaphylaxis occurs intraoperatively then the likely cilprits
are IV NSAIDs, opiods, antibiotics. And if anaphylaxis
occurs towards end of surgery or during recovery then
latex allergy, rectal NSAID and IV opiods are the cause.[62]
Management of patient with suspected anaphylaxis
during anesthesia
1. Stop administration of all agents likely to have caused
Clinical features[14,119] Frequency (%)
Cardiovascular collapse 88
Bronchospasm 36
Angio‑oedema (facial, periorbital, perioral) 24
Angio‑oedema (generalized) 7
Other cutaneous features
Erythema 45
Rash 13
Urticaria
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Anesthesia: Essays and Researches; 6(2); Jul-Dec 2012 Mali: Anaphyllaxis
the anaphylaxis.
2. Call for help.
3. Maintain airway, give 100% oxygen and lie patient flat
with legs elevated.
4. Give epinephrine (adrenaline). This may be given
intramuscularly in a dose of 0.5 mg to 1 mg (0.5 to 1 mL
of 1:1,000) and may be repeated every 10 min according
to the arterial pressure and pulse until improvement
occurs. Alternatively, 50 to 100 µg intravenously (0.5 to
1 mL of 1:10,000) over 1 min has been recommended for
hypotension with titration of further doses as required.
Never give undiluted epinephrine 1:1000 intravenously.
In a patient with cardiovascular collapse, 0.5 to 1 mg
(5 to 10 mL of 1:10,000) may be required intravenously
in divided doses by titration. This should be given at a
rate of 0.1 mg/min stopping when a response has been
obtained. Paediatric doses of epinephrine depend on the
age of the child.
Intramuscular epinephrine 1:1000 should be administered
as follows
>12 years 500 µg IM (0.5 mL)
6-12 years 250 µg IM (0.25 mL)
>6 months‑6 years 120 µg IM (0.12 mL)
<6 months 50 µg IM (0.05 mL)
Start rapid intravenous infusion with colloids or
crystalloids.
Adult patients may require 2 to 4 L of crystalloid.
Secondary therapy
1. Give antihistamines (chlorpheniramine 10-20 mg by
slow intravenous infusion).
2. Give corticosteroids (100 to 500 mg hydrocortisone
slowly iv).
3. Bronchodilators may be required for persistent
bronchospasm.
Strategies for prevention
The prevention of anaphylaxis after administration of
general anesthetics would require the identification
of patients at risk, but this approach is not easy to
implement considering the large number of drugs,
diagnostic reagents, devices containing latex, antiseptics,
and blood products that are all routinely used in
anesthesia. The low accuracy of diagnostic tests also plays
a part. Sufficient knowledge of pathogenic mechanisms
involved in systemic reactions to general anesthetics is
essential to optimize prevention strategies. It is widely
recognized that anaphylactic (immunoglobulin‑E‑mediated)
events usually occur after repeated administration of
sensitizing agents (especially general anesthetics and, in
some cases, contrast media). These events are somewhat
predictable in high‑risk patients or in subjects who have
had anaphylactic reactions previously.
If patient interviews, medical history taking, or previous
diagnostic tests are able to identify a culprit agent or
agents, an alternative product must be used. If the
reaction is attributed to a neuromuscular blocking drug,
there is risk from other such agents and consequently
it is proper to use a regional blocking agent or volatile
anesthetics if such techniques are suitable. Each reaction
occurring during general anesthesia should be entered
into a patient’s medical record by the anesthesiologist in
order to prevent future reactions. Investigations such as
skin prick test, intradermal test and tryptase tests can be
carried out to rule out allergies in suspected patients.
CONCLUSION
Anaphylaxis is life threatening condition, more so in
operating theater due to lack of cutaneous symptoms
because patient is unconscious or semiconscious and he
is draped so cutaneous signs are not discovered early.
Adverse drug reactions or side effects are usually expected,
are dose dependent, and occur at therapeutic doses.
Anaphylactic and anaphylactoid reactions are unexpected
and dose independent and can occur at the first exposure
to drugs used during anesthesia. Any drug can induce
a life‑threatening and sometimes fatal anaphylactic or
anaphylactoid event even in the absence of any evident
risk factor in the patient’s medical history. Although
anaphylaxis is a rare intraoperative event, most drugs used
in the perioperative period can lead to anaphylaxis. The
documentation of anaphylaxis is often lacking because the
cause and effect relationship is often hard to prove and
because the diagnosis is not easy to make with the patient
under anesthesia. And fatal or near‑fatal events may be
induced by diagnostic or surgical procedures usually
considered as routine and carried out in patients suffering
from less severe disorders. Muscle relaxants and NRL are
the most common anesthetic drugs or substances that
may lead to anaphylaxis. Prevention is the most important
component to decrease the incidence of anaphylaxis.
Documentation of anaphylaxis during anesthesia, referral
to an allergist for identification of the causative drug, and
appropriate labeling of the patient are essential to prevent
future episodes of anaphylaxis. Patient must be fully
informed about anaphylaxis, its cause, signs and symptoms
and causative agent. And he must be instructed to give
thorough history whenever he reports to any hospital for
treatment be it minor or major. He can be instructed to
wear bracelet or carry card with him detailing which drugs
he is allergic to. What is needed is improved accuracy in
assessment of the rate of occurrence of anaphylaxis, and
rapid, specific, sensitive in vitro test or panel of tests to
confirm the clinical diagnosis of acute anaphylaxis.
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How to cite this article: Mali S. Anaphylaxis during the
perioperative period. Anesth Essays Res 2012;6:124-33.
Source of Support: Nil, Conflict of Interest: None declared.
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