101

Page 1

Anaphylaxis, Allergy, and Adverse Drug Reactions: Perioperative Considerations for Anesthesiologists

Jerrold H Levy, MD, FAHA, FCCM Durham, North Carolina

INTRODUCTION

Surgical patients receive multiple foreign substances in the perioperative period, including drugs, blood products, or
environmental antigens such as latex. Because any substance can produce an allergic or adverse reaction, clinicians must be
ready to manage patients in this perioperative environment. The most life-threatening form of an allergic reaction is
anaphylaxis, however, the clinical presentation of anaphylaxis may represent different immune and nonimmune responses.1
There is confusion in the literature about the term anaphylaxis, and multiple terms have been reported to describe this
reaction. In recent years, anaphylaxis has been redefined as a severe, life-threatening, generalized, or systemic
hypersensitivity reaction, mainly mediated by immunoglobulin E (IgE) antibodies. 2 Further, anaphylaxis represents a life-
threatening allergic reaction that is rapid in onset and is associated with a significant risk for mortality. 3-6 For the practicing
clinician, anaphylaxis is best defined as a clinical syndrome characterized by acute cardiopulmonary collapse following
antigen (also called allergen) exposure. Much of the confusion about anaphylaxis in the literature is because many older
anesthetic agents (e.g., d-tubocurarine) could directly degranulate mast cells. The incidence of immune-mediated anaphylaxis
during anesthesia ranges from 1 in 10,000 to 1 in 20,000 based on mostly European reports.7 This presentation will define
the spectrum of life threatening anaphylactic and allergic reactions an anesthesiologist may encounter.

ADVERSE DRUG REACTIONS

Adverse drug reactions (ADRs) are common in hospitalized patients. Reports suggest the overall incidence of serious
ADRs was 6.7% and of fatal ADRs was 0.32% from data evaluating 39 prospective studies from US hospitals.8,9 A recent
study noted fatal adverse drug reactions account for nearly 3% of all deaths in the general population, and noted hemorrhage
is responsible for ~2/3 of the fatal adverse drug reactions, and antithrombotic agents are involved in more than half of the
suspected fatal adverse drug reactions.10 Most serious predictable adverse drug reactions are not allergic mediated events and
related to other causes that include the amount of drug in the body (overdosage), unintended administration route, or known
side effects (i.e., opioid related nausea). However, some drugs have direct effects on inflammatory cells (i.e., heparin,
histamine-releasing agents). Unfortunately, patients often refer to any adverse drug effects as being allergic. Anesthetic
drugs can also produce hypotension via different mechanisms (e.g., propofol induced vasodilation), complicating the
diagnosis of perioperative adverse drug reactions. Allergic drug reactions are often differentiated from other adverse drug
reactions because they are unpredictable and dose-independent (i.e., reactions due to latex allergy from latex gloves).

ALLERGY AND ANAPHYLAXIS

Allergic reactions and anaphylaxis have the same pathophysiologic mechanisms, as both are immune mediated due to
previous exposure to the antigen or a substance of similar structure. Richet and Portier first used the word anaphylaxis (ana -
against, prophylaxis - protection) to describe the marked shock and resulting death that sometimes occurred in dogs
immediately following a second challenge with a foreign antigen. 11 The term “allergy” was introduced in 1906, but is now
often used to describe IgE-mediated allergic disease.6 The basis of acute allergic reactions, including anaphylaxis is the
release of inflammatory mediators released by mast cells and basophils when an allergen interacts with membrane-bound
IgE.5,6

PATHOPHYSIOLOGY
Anaphylaxis and allergy result from the release of multiple inflammatory mediators including membrane-derived lipids,
cytokines, and chemokines.12 When the offending antigen and IgE bind on the surface of mast cells and basophils, preformed
storage granules are released that contain histamine and tryptase.13 Other membrane derived lipid mediators are released,
including leukotrienes, prostaglandins, and other factors. 13 These inflammatory substances have a critical role in producing
acute cardiopulmonary dysfunction, characterized by a symptom complex of bronchospasm and upper airway edema in the
respiratory system, vasodilation and increased capillary permeability in the cardiovascular system, and urticaria in the
cutaneous system.14-16 Cardiovascular collapse during anaphylaxis results from the effects of multiple mediators on the heart
Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 2

and vasculature.17 The vasodilation seen clinically can result from a spectrum of different mediators that interact with
vascular endothelium and/or vascular smooth muscle. 1,18 Why some individuals develop severe cardiopulmonary
dysfunction instead of minor cutaneous reactions is unknown, but may relate to systemic compared to local release of
inflammatory mediators.19 Interestingly, the original description of anaphylaxis from sea anemone toxin represents an IgG-
mediated response. IgG mechanisms will be further discussed in protamine reactions that follow.

VASODILATORY SHOCK AND ANAPHYLAXIS

Vasodilatory shock occurring in anaphylaxis is due to mechanisms that activate mediator induced vasodilation, including
nitric oxide that increases cGMP, and prostacyclin that increases cAMP in vascular smooth muscle that produces vasodilation
and shock.1,18 Nitric oxide and metabolic acidosis from shock also activate vascular potassium channels to cause persistent
vasodilatation despite catecholamine therapy.1,18 Other mediators that are released by non IgE mechanisms may also produce
shock by different mechanisms (e.g., protamine induced acute pulmonary vasoconstriction) and heparin will be discussed in
non IgE mediated reactions.1,18

RECOGNITION OF ANAPHYLAXIS
Because any parenterally administered agent can cause death from anaphylaxis, anesthesiologists must diagnose and treat
the acute cardiopulmonary changes that can occur. Studies from Europe suggest that perioperative drug-induced anaphylaxis
may be increasing. The onset and severity of the reaction relate to the mediator's specific end organ effects. Antigenic
challenge in a sensitized individual usually produces immediate clinical manifestations, but the onset may be delayed 2-20
minutes.14,20,21 The manifestations and course of anaphylaxis are variable, ranging from minor clinical changes, including
urticaria to cardiopulmonary collapse including severe bronchospasm, vasodilatory shock, and pulmonary vascular injury in
certain cases, leading to death. The enigma of anaphylaxis is the unpredictability of the event, the severity of the attack, and
the lack of a prior allergic history. 14,20,21

NON-IgE MEDIATED REACTIONS

Other immunologic and nonimmunologic mechanisms release inflammatory mediators independent of IgE, creating a
clinical syndrome identical to anaphylaxis. Polymorphonuclear leukocyte (neutrophil) activation can occur following
complement activation by immunologic (antibody-mediated: IgM, IgG-antigen activation) or non-immunologic (heparin,
protamine, endotoxin, cardiopulmonary bypass) pathways. 22,23,24 Complement fragments of C3 and C5 (C3a and C5a)
release histamine from mast cells and basophils, contract smooth muscle, and increase capillary permeability. In addition,
C5a binds receptors on neutrophils and platelets, causing chemotaxis, aggregation, and activation. 23,24 Aggregated leukocytes
embolize to various organs producing microvascular occlusion and liberation of inflammatory products, including oxygen-
free radicals, lysosomal enzymes, and arachidonic acid metabolites (i.e., prostaglandins and leukotrienes). IgG antibodies
directed against antigenic determinants or granulocyte surfaces can also activate leukocytes, and are thought to be responsible
for the clinical expressions of transfusion reactions, pulmonary vasoconstriction following protamine reactions, and
transfusion related acute lung injury (TRALI).25-27

HEPARIN, HIT, AND KININ GENERATION

Following heparin administration, IgG antibody formation that binds heparin-PF4 complexes on platelets can occur to
form immune complexes, activate platelets, and promote thrombin formation and heparin induced thrombocytopenia (HIT). 22
Up to 50% of heparin-treated patients form heparin-PF4 antibodies.22 However, recent reports about allergic reactions to
heparin from China were because of an oversulfated chondroitin sulfate contaminant that directly activated the kinin-
kallikrein pathway to produce bradykinin, a potent vasoactive mediator. In addition, this contaminant induced generation of
C3a and C5a.28 Angiotensin converting enzyme inhibitors also may potentially increase bradykinin levels, and this is the
mechanism of vasodilation, angioedema, and cough that can occur with their use.1

ANGIOEDEMA
Angioedema is the rapid swelling of skin, mucosa, and submucosal tissues, most commonly produced by allergic reactions
and ACE inhibitors, as noted above.29 Oral, laryngeal, and pharyngeal swelling can occur with acute airway compromise
needing urgent airway control. There are also inherited qualitative and quantitative
Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 3

deficiencies of the complement C1 esterase inhibitor (C1-INH) called hereditary angioedema (HAE). Patients with HAE also
have recurrent episodes of gastrointestinal manifestations of the disease. Bradykinin plays a critical role in angioedema as
previously noted. Therapy of attacks includes symptomatic management and C1-INH from C1-INH concentrates. Patients
with this history and documented HAE need short-term prophylaxis before surgery or dental treatment because tissue injury
activates complement to increase C1-INH levels and also antifibrinolytics that inhibit plasmin mediated activation. New
therapies are also being studied for this life-threatening disease. (16) A C1-INH concentrate (Cinryze™) is currently FDA-
approved indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary
Angioedema (HAE).29

NONIMMUNOLOGIC RELEASE OF HISTAMINE

Many diverse molecular structures administered during the perioperative period degranulate mast cells to release
histamine in a dose-dependent, nonimmunologic fashion.30-33 Intravenous administration of morphine, atracurium, or
vancomycin can release histamine, producing vasodilation and urticaria along the vein of administration. Although the
cardiovascular effects of histamine release can be treated effectively with intravascular volume administration and/or
catecholamines, the responses in different individuals may vary.1 The newer neuromuscular blocking agents (e.g.,
rocuronium and cisatracurium) lack histamine releasing effects but can produce direct vasodilation and false-positive
cutaneous responses that confuse allergy testing and interpretation.31,34 The mechanisms involved in nonimmunologic
histamine release represent degranulation of mast cells but not basophils by cellular activation and stimulation of
phospholipase activity in mast cells.35

TREATMENT PLAN
Most anesthetic drugs and agents administered perioperatively have been reported to produce anaphylaxis. 1 Therefore, a
plan for treating anaphylactic reactions must be established before the event. 1 Airway maintenance, 100% oxygen
administration, intravascular volume expansion, and epinephrine are essential to treat the hypotension and hypoxia that
results from vasodilation, increased capillary permeability, and bronchospasm. 1 A protocol for the management of
anaphylaxis during general anesthesia should be considered by all clinicians. The standard considerations of
cardiopulmonary resuscitation with vasoactive therapy should be followed. Therapy must be titrated to needed effects with
careful monitoring. The route of administration of epinephrine and the dose depends on the patient's condition. Rapid and
timely intervention with common sense must be used to treat anaphylaxis effectively. Management considerations are as
follows:

Initial Therapy: Although it may not be possible to stop the administration of antigen, limiting antigen administration may
prevent further mast cell and basophil activation.

Maintain Airway and Administer 100% Oxygen: Profound ventilation–perfusion abnormalities producing hypoxemia can
occur with anaphylactic reactions. Administer 100% oxygen with ventilatory support as needed including treating
bronchospasms if it occurs.

Discontinue Anesthetic Drugs: Inhalational anesthetic drugs are not the bronchodilators of choice in treating bronchospasm
after anaphylaxis, especially during hypotension. These drugs interfere with the body’s compensatory response to
cardiovascular collapse, and direct acting bronchodilators should be administered if needed.

Volume Expansion: Hypovolemia rapidly follows during anaphylactic shock with up to 40% loss of intravascular fluid into
the interstitial space during reactions. Therefore, volume expansion is important along with epinephrine in correcting the
acute hypotension. Initially, 25 to 50 mL/kg of crystalloid or colloid solution should be administered, with an additional 25 to
50 mL/kg may be necessary if hypotension persists.

Administer Epinephrine: Epinephrine is the drug of choice when resuscitating patients during anaphylactic shock. The α-
adrenergic effects vasoconstrict to reverse hypotension; β2 receptor stimulation bronchodilates and inhibits mediator release.
Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 4

The route of epinephrine administration and the dose depend on the patient’s condition. Rapid and timely intervention is
important when treating anaphylaxis. Of note is that patients under general anesthesia may have altered sympathoadrenergic
responses to acute anaphylactic shock. In contrast, the patient under spinal or epidural anesthesia may be partially
sympathectomized and may need even larger doses of catecholamines. In hypotensive patients, 5- to 10-μg boluses of
epinephrine should be administered intravenously and incrementally titrated to restore blood pressure. (This dose of
epinephrine can be obtained with 0.05 to 0.1 mL of a 1:10,000 dilution

[100 μg/mL]. Additional volume and incrementally increased doses of epinephrine should be administered until hypotension
is corrected. Although an infusion is ideal for administering epinephrine, infusing the drug through peripheral intravenous
access lines during acute volume resuscitation is usually impossible. With cardiovascular collapse, Advanced
Cardiopulmonary Life Support (ACLS) protocols should be following with full cardiopulmonary resuscitative support.
Epinephrine should not be administered intravenously to patients with normal blood pressures.

Secondary Treatment

Antihistamines. Because H1 receptors mediate many adverse effects of histamine, administering 0.5 to 1 mg/kg of an H 1
antagonist such as diphenhydramine may be useful in treating acute anaphylaxis. Antihistamines do not inhibit anaphylactic
reactions or histamine release, but compete with histamine at receptor sites. H 1 antagonists are indicated in all forms of
anaphylaxis, but should be given slowly to prevent precipitous hypotension in potentially hypovolemic patients. 1 The
indications for administering an H2 antagonist after anaphylaxis remains unclear.

Catecholamines. Epinephrine infusions may be useful in patients with persistent hypotension or bronchospasm after initial
resuscitation.1 Epinephrine infusions should be started at 0.05 to 0.1 μg/kg/min (5 to 10 μg/min) and titrated to correct
hypotension. Norepinephrine infusions may be needed in patients with refractory hypotension due to decreased systemic
vascular resistance. It may be started at 0.05 to 0.1 μg/kg/min (5 to 10 μg/min) and adjusted to correct hypotension51.

Bronchodilators. Inhaled ß-adrenergic agents, including inhaled albuterol or terbutaline, if bronchospasm is a major
feature54. Inhaled ipratropium may be especially useful for the treatment of bronchospasm in patients receiving ß-adrenergic
blockers54. Special adaptors allow the administration of bronchodilators through the endotracheal tube.

Corticosteroids. Corticosteroids have multiple antiinflammatory effects mediated by different mechanisms, including
altering the activation and migration of other inflammatory cells (i.e., PMNs) after an acute reaction. They should be
administered as adjuncts to resuscitative therapy when refractory bronchospasm or refractory shock occurs. The exact
corticosteroid dose and choice of methylprednisone versus hydrocortisone are unclear, starting doses include 0.25 to 1 g of
hydrocortisone, or equivalent doses of methylprednisone. Corticosteroids may also be important in attenuating the late-phase
reactions reported to occur 12 to 24 hours after anaphylaxis.

Airway Evaluation. The airway should be evaluated before extubation of the trachea because of the potential for laryngeal
edema. Persistent facial edema suggests airway edema. Therefore, the trachea of these patients should remain intubated until
the edema subsides. Developing a significant air leak after endotracheal tube cuff deflation and before extubation of the
trachea is useful in assessing airway patency.

Refractory Hypotension. Reactions may be protracted with persistent hypotension, pulmonary hypertension and right
ventricular dysfunction, that persist 5 to 32 hours despite resuscitation. During general anesthesia, patients may have altered
sympathoadrenergic responses to acute anaphylactic shock. Additional hemodynamic monitoring may be needed when
hypotension persists despite therapeutic interventions as listed. Following anaphylaxis, patients should be carefully
monitored for 24 hours as they may develop recurrence of manifestations following successful treatment and covered with
corticosteroids for the acute event.1

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 5

After the initial resuscitation, norepinephrine is also an effective agent that should be considered for treating shock and
dopamine should be avoided.37 Based on the efficacy of vasopressin in reversing vasodilatory shock, it should also be
considered in therapy for anaphylactic shock not responding to therapy. 1,18,38 There are increasing laboratory and clinical
reports supporting the use of vasopressin in anaphylactic shock. 39,40 When available, the use of transesophageal
echocardiography in an intubated patient, or potentially transthoracic echocardiography, can be useful in diagnosing the cause
of acute or persistent cardiovascular dysfunction.1 For the patient with undetectable blood pressure or following a cardiac
arrest, full ACLS protocol and resuscitation must be utilized.

PRETREATMENT FOR ALLERGIC REACTIONS

Hypersensitivity reactions are more likely to occur in patients with a history of allergy, atopy, or asthma. However, this
does not make it mandatory to pretreat these patients with antihistamines and/or corticosteroids
because there is no data in the literature to suggest that pretreatment is effective for true anaphylactic reactions. Most of the
literature on pretreatment is from studies evaluating patients with previous radiocontrast media reactions that are non-
immunologic mechanisms. Although attempts to pretreat patients for anaphylaxis to latex have been used, there is no data to
support this as an effective preventative measure, and removal of latex from the perioperative environment is important. In
fact, pretreatment may lull physicians into a false sense of security. Further, even when large doses of corticosteroids have
been administered, life threatening anaphylactic reactions have occurred. 41 Allergists have used immunospecific
pretreatment therapies, but these are not practical for perioperative use.

MANAGEMENT OF THE ALLERGIC PATIENT

Patients presenting with an allergic history need to be carefully evaluated. Patients may report allergy when the reaction
was a predictable adverse drug reaction. However, for practical and medico-legal purposes, that class of drug should be
avoided if possible when the history is consistent with an allergic reaction, and preservative free alternatives should be
chosen. The problem occurs whenever multiple drugs are simultaneously administered or when patients present with muscle
relaxant reactions because of the risk of cross reactivity to the biquarternary ammonium ions in the molecule. In this
situation, skin testing may be required to see what the patient can safely be administered.

EPIDEMIOLOGY OF ANAPHYLAXIS: AGENTS IMPLICATED

Although any molecule can produce anaphylaxis, the drugs typically associated with producing perioperative anaphylaxis
include antibiotics, blood products, neuromuscular blocking drugs (NMBDs), polypeptides (aprotinin, latex, and protamine),
and intravascular volume expanders.1 During surgery, the risk of anaphylaxis is reported to be between 1:3500 and
1:20,000, with a mortality rate of 4% and an additional 2% surviving severe brain damage. 1,7 More recent data suggest the
incidence of perioperative anaphylaxis is 1 in 10,000–20,000. 7 Patients undergoing major surgery are an increased risk
group, because of the multiple blood products, polypeptides, and potential for impaired cardiovascular function. Mertes
reported an epidemiological study from 99-01 of 789 reactions diagnosed by clinical history, skin tests, and/or specific IgE in
518 cases (66%) and nonimmune reactions in 271 cases (34%). 42 The most common causes were NMBAs (58.2%), latex
(16.7%), and antibiotics (15.1%), of which rocuronium (43%) and succinylcholine (22.6%) were the most common NMBAs
reported. The positive predictive value of tryptase for the diagnosis of anaphylaxis in their study was 92.6%; the negative
predictive value was 54.3%.42 The agents most often implicated will be discussed.

LATEX ALLERGY
Latex represents an environmental agent often associated as a cause of perioperative anaphylaxis. Health care workers,
children with spina bifida and urogenital abnormalities, and certain food allergies have also been recognized as individuals at
increased risk for anaphylaxis to latex.43-45 Brown reported a 24% incidence of irritant or contact dermatitis and a 12.5%
incidence of latex-specific IgE positivity in Anesthesiologists.46 Of this group, 10% were clinically asymptomatic although
IgE positive. A history of atopy was also a significant risk factor for latex sensitization. Brown suggests these individuals
are in their early stages of sensitization, and perhaps, by avoiding latex exposure, their progression to symptomatic disease
can be prevented.46

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 6

Patients allergic to tropical fruits (e.g., bananas, avocados, and kiwis) and stone fruits have also been reported to have
antibodies that cross-react with latex.45,47 Multiple attempts have been made to reduce latex exposure to healthcare workers
and patients over the years. If latex allergy occurs, strict avoidance of latex from gloves and other sources must be
considered, following recommendations as reported.45 Latex, in the past, was a widespread environmental antigen, although
over time has been replaced with alternative synthetic replacements due to concerns regarding this potential exposure.

NEUROMUSCULAR BLOCKING AGENTS

Neuromuscular blocking agents (NMBAs) have several unique molecular features, making them potential allergens. All
neuromuscular blocking drugs are functionally divalent and are thus capable of cross-linking cell-surface IgE, causing
mediator release from mast cells and basophils without binding or haptenizing to larger carrier molecules. 1 NMBAs have
also been implicated in epidemiological studies of anesthetic drug-induced anaphylaxis. Epidemiological data from France
suggest that NMBAs are responsible for 62–81% of reactions, depending on the time period evaluated. 42,48 Rocuronium is
the NMBA most reported from France. We and others have reported previously that aminosteroidal compounds and
benzylisoquinoline-derived agents produce positive weal and flare responses when injected intradermally. 31,49,50 Estimates of
anaphylactic reactions in anesthesia vary, but data suggests that false-positive skin tests may overestimate the incidence of
rocuronium-induced anaphylactic reactions. 31,49,50 The differences noted in the incidence of reactions may reflect the
potential for false-positive weal and flare responses. 31,49,50 NMBAs can also produce direct vasodilation by multiple
mechanisms, which include calcium channel blockade. The false-positive skin tests that were reported to be biopsy-negative
for mast cell degranulation confound interpreting skin tests in patients who have had a life-threatening cardiopulmonary
collapse. Therefore, dilute solutions of NMBAs need to be used when skin testing for potential allergic reactions to these
agents. However, the exact concentration that should be used is unclear. Since skin-testing procedures are important in
evaluating potential drug allergies, the threshold for direct vasodilating and false-positive effects must be determined
whenever subjects are skin-tested for a particular drug.

POLYPEPTIDES AND BLOOD PRODUCTS

Polypeptides are larger molecular weight molecules with greater potential to be antigenic, including aprotinin, latex, and
protamine.41 Diabetic patients receiving protamine containing insulin as neutral protamine Hagedorn (NPH) or protamine
insulin have a 10-30 fold increased risk for anaphylactic reactions to protamine when used for heparin reversal, with a risk of
0.6-2% in this patient population.41,51 Because protamine is often given with blood products, protamine is often implicated as
the causative agent in adverse reactions, especially in cardiac surgical patients. Platelet and other allogeneic blood
transfusions can produce a series of adverse reactions by multiple mechanisms, and blood products have a greater potential
for allergic reactions, including TRALI.25 Although antigen avoidance is one of the most important considerations in
preventing anaphylaxis, this is not always possible, especially with certain agents with unavailable alternatives. Protamine is
an important example of where alternatives are under investigation, but not currently available.

EVALUATING THE PATIENT FOLLOWING ANAPHYLAXIS

A detailed history is one of the most important considerations for evaluating a patient following anaphylaxis, determining
what agents were administered and the temporal sequence.52 Also, after resuscitation, collect a red top tube (serum) for mast
cell tryptase, preferably within 1-2 hours of the reaction, and then repeat 24 hours later. Serum can also be collected
postmortem, which may be important for you medico-legally. Most hospital laboratories will need to send this test to a
reference laboratory. If tryptase is positive, sending the patient for an allergy consultation may be useful if the temporal
sequence is confusing, and the agent responsible needs further investigation. Often, a positive mast cell tryptase usually
represents an IgE-mediated reaction (i.e., anaphylaxis) but vancomycin and other histamine releasers can also increase
tryptase.35 Negative mast cell tryptase tests are rarely associated with positive skin and antibody tests. IgG reactions due to
protamine, or blood products are unlikely to increase tryptase. Few laboratory based tests are available for determining
immunologic testing, so skin testing is required if better differentiation of the agent responsible is required.

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
101
Page 7

CONCLUSIONS
Anaphylaxis represents an important potential problem and cause of life-threatening events. Clinicians must be able to
recognize and treat these life-threatening events if they occur. Anaphylactic reactions represent a continuing challenge, but
rapid diagnosis and treatment are important in preventing adverse clinical outcomes.

REFERENCES

1. Tacquard C, Iba T, Levy JH. Perioperative Anaphylaxis. Anesthesiology. 2023 Jan 1;138(1):100-110.
2. Johansson SG, Hourihane JO, Bousquet J, et al. A revised nomenclature for allergy. An EAACI position statementfrom the
EAACI nomenclature task force. Allergy 2001; 56: 813-24
3. Sampson HA, Munoz-Furlong A, Bock SA, et al.: Symposium on the definition and management of anaphylaxis:summary
report. J Allergy Clin Immunol 2005; 115: 584-91
4. Sampson HA, Munoz-Furlong A, Campbell RL, et al.: Second symposium on the definition and management of
anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. Ann Emerg Med 2006; 47: 373-80
5. Kay AB: Allergy and allergic diseases. Second of two parts. N Engl J Med 2001; 344: 109-13
6. Kay AB: Allergy and allergic diseases. First of two parts. N Engl J Med 2001; 344: 30-7
7. Mertes PM, Lambert M, Gueant-Rodriguez RM, et al.: Perioperative anaphylaxis. Immunol Allergy Clin North Am 2009; 29:
429-51
8. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of
prospective studies. JAMA 1998; 279: 1200-5
9. Zimmerman CR, Chaffee BW, Lazarou et al: Maintaining the enterprisewide continuity and interoperability of patient
allergy data. Am J Health Syst Pharm 2009; 66: 671-9
10. Wester K, Jonsson AK, Spigset O, et al: Incidence of fatal adverse drug reactions: a population based study. Br JClin
Pharmacol 2008; 65: 573-9
11. Portier MM RC: De l'action anaphylactique de certains venins. C R Soc Biol 1902; 54: 170-172
12. Stone SF, Cotterell C, Isbister GK, Holdgate A, Brown SG: Elevated serum cytokines during human anaphylaxis:
Identification of potential mediators of acute allergic reactions. J Allergy Clin Immunol 2009; 124: 786-92 e4
13. Metcalfe DD, Peavy RD, Gilfillan AM: Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol2009;
124: 639-46; quiz 647-8
14. Pumphrey RS: Fatal anaphylaxis in the UK, 1992-2001. Novartis Found Symp 2004; 257: 116-28; discussion 128-32, 157-
60, 276-85
15. Pumphrey RS, Roberts IS: Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000; 53: 273-6
16. Simons FE: Anaphylaxis: Recent advances in assessment and treatment. J Allergy Clin Immunol 2009; 124: 625-36
17. Levy JH, Adkinson NF, Jr.: Anaphylaxis during cardiac surgery: implications for clinicians. Anesth Analg 2008;106: 392-
403
18. Landry DW, Oliver JA: The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345: 588-95
19. Prussin C, Metcalfe DD: IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2006; 117: S450-6
20. Pumphrey R: Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy Clin Immunol 2004; 4: 285-90
21. Pumphrey RS: Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30:1144-50
22. Levy JH, Hursting MJ: Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am 2007; 21:
65-88
23. Walport MJ: Complement. Second of two parts. N Engl J Med 2001; 344: 1140-4
24. Walport MJ: Complement. First of two parts. N Engl J Med 2001; 344: 1058-66
25. Silliman CC, Ambruso DR, Boshkov LK: Transfusion-related acute lung injury. Blood 2005; 105: 2266-73
26. Silliman CC, Kelher M: The role of endothelial activation in the pathogenesis of transfusion-related acute lunginjury.
Transfusion 2005; 45: 109S-116S

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
 27. Sheppard CA, Logdberg LE, Zimring JC, Hillyer CD: Transfusion-related Acute Lung
Injury. Hematol Oncol ClinNorth Am 2007; 21: 163-76
28. Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, Pelzer K, Lansing JC,
Sriranganathan N, ZhaoG, Galcheva-Gargova Z, Al-Hakim A, Bailey GS, Fraser B, Roy S,
Rogers-Cotrone T, Buhse L, Whary M, Fox J, Nasr M, Dal Pan GJ, Shriver Z, Langer RS,
Venkataraman G, Austen KF, Woodcock J, Sasisekharan R: Contaminated heparin
associated with adverse clinical events and activation of the contact system. N Engl J Med
2008; 358: 2457-67
29. Levy JH: Hereditary angioedema: current and emerging treatment options. Anesth Analg: In Press.
30. Levy JH, Kettlekamp N, Goertz P, Hermens J, Hirshman CA: Histamine release by
vancomycin: a mechanism forhypotension in man. Anesthesiology 1987; 67: 122-5
31. Levy JH, Gottge M, Szlam F, Zaffer R, McCall C: Weal and flare responses to
intradermal rocuronium andcisatracurium in humans. Br J Anaesth 2000; 85: 844-
9
32. Levy JH, Brister NW, Shearin A: Wheal and flare responses to opioids in humans. Anesthesiology
1989; 70: 756-60
33. Levy JH, Adelson D, Walker B: Wheal and flare responses to muscle relaxants in humans.
Agents Actions 1991; 34:302-8
34. Levy JH, Davis GK, Duggan J, Szlam F: Determination of the hemodynamics and
histamine release of rocuronium (Org 9426) when administered in increased doses under
N2O/O2-sufentanil anesthesia. Anesth Analg 1994; 78: 318-21
35. Veien M, Szlam F, Holden JT, Yamaguchi K, Denson DD, Levy JH: Mechanisms of
nonimmunological histamineand tryptase release from human cutaneous mast cells.
Anesthesiology 2000; 92: 1074-81
36. Caplan RA, Ward RJ, Posner K, Cheney FW: Unexpected cardiac arrest during spinal
anesthesia: a closed claimsanalysis of predisposing factors. Anesthesiology 1988; 68: 5-
11
37. Levy JH: Treating shock: old drugs, new ideas. N Engl J Med: In Press.
38. Tsuda A, Tanaka KA, Huraux C, Szlam F, Sato N, Yamaguchi K, Levy JH: The in
vitro reversal of histamine-induced vasodilation in the human internal mammary
artery. Anesth Analg 2001; 93: 1453-9
39. Dewachter P, Jouan-Hureaux V, Franck P: Anaphylactic shock: a form of distributive
shock without inhibition ofoxygen consumption. Anesthesiology 2005; 103: 40-9
40. Dewachter P, Mouton-Faivre C, Emala CW: Anaphylaxis and anesthesia:
controversies and new insights. Anesthesiology 2009; 111: 1141-50
41. Levy JH, Ghadimi K, Kizhakkedathu JN, Iba T. What's fishy about protamine? Clinical
use, adverse reactions, andpotential alternatives. J Thromb Haemost. 2023 Apr 14, ePUB.
42. Mertes PM, Laxenaire MC, Alla F: Anaphylactic and anaphylactoid reactions occurring
during anesthesia in Francein 1999-2000. Anesthesiology 2003; 99: 536-45
43. Holzman RS: Latex allergy: an emerging operating room problem. Anesth Analg 1993; 76: 635-41
44. Peixinho C, Tavares-Ratado P, Tomas MR, Taborda-Barata L, Tomaz CT: Latex
allergy: new insights to explaindifferent sensitization profiles in different risk groups.
Br J Dermatol 2008; 159: 132-6
45. Cullinan P, Brown R, Field A, et al: Latex allergy. A position paper of the British
Society of Allergy and ClinicalImmunology. Clin Exp Allergy 2003; 33: 1484-99
46. Brown RH, Schauble JF, Hamilton RG: Prevalence of latex allergy among
anesthesiologists: identification ofsensitized but asymptomatic individuals.
Anesthesiology 1998; 89: 292-9
47. Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M: Latex allergy: clinical features
and cross-reactivity withfruits. Ann Allergy 1994; 73: 309-14
48. Moneret-Vautrin DA, Morisset M, Flabbee J, Beaudouin E, Kanny G: Epidemiology of
life-threatening and lethalanaphylaxis: a review. Allergy 2005; 60: 443-51
49. Levy JH: Anaphylactic reactions to neuromuscular blocking drugs: are we making the

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.
 correct diagnosis? AnesthAnalg 2004; 98: 881-2
50. Dhonneur G, Combes X, Chassard D, Merle JC: Skin sensitivity to rocuronium and
vecuronium: a randomizedcontrolled prick-testing study in healthy volunteers. Anesth
Analg 2004; 98: 986-9, table of contents
51. Levy JH, Schwieger IM, Zaidan JR, Faraj BA, Weintraub WS: Evaluation of patients at risk
for protamine reactions.J Thorac Cardiovasc Surg 1989; 98: 200-4
52. Mertes PM, Laxenaire MC: Allergic reactions occurring during anaesthesia. Eur J Anaesthesiol 2002;
19: 240-62

Refresher Course Lectures Anesthesiology 2023 © American Society of Anesthesiologists. All rights reserved. Note: This
publication contains material copyrighted by others. Individual refresher course lectures are reprinted by ASA with
permission.Reprinting or using individual refresher course lectures contained herein is strictly prohibited without permission
from the authors/copyright holders.