Johnson 2004
Johnson 2004
Johnson 2004
ABSTRACT
Objectives: After reading this article, the reader should be able to: (1) discuss the pathophysiology of anaphylactic shock; (2) recognize
anaphylactic reactions; and (3) summarize the essential steps in treatment of anaphylactic shock.
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A naphylaxis is a systemic, type I hypersensitivity Anaphylaxis occurs in persons of all ages and has
reaction that occurs in sensitized individuals resulting in many diverse causes, the most common of which are
mucocutaneous, cardiovascular, and respiratory manifes- foods, drugs, latex, hymenoptera stings, and reactions to
tations and can often be life threatening. Anaphylaxis immunotherapy. Of note, a cause cannot be determined
was first described in 1902 by Portier and Richet when in up to one third of cases.2–4 Anaphylactoid reactions
they were attempting to produce tolerance in dogs to sea are identical to anaphylaxis in every way except the
anemone venom. Richet coined the term aphylaxis (from former are not mediated by immunoglobulin E (IgE).
the Greek a, against, –phylaxis protection) to differenti- Common causes of anaphylactoid reactions include
ate it from the expected ‘‘prophylaxis’’ they hoped to radiocontrast media, narcotic analgesics, and nonsteroi-
achieve. The term aphylaxis was replaced with the term dal antiinflammatory drugs.
anaphylaxis shortly thereafter. Richet won the Signs and symptoms can be divided into
Nobel Prize in medicine or physiology in 1913 for his four categories: mucocutaneous, respiratory, cardiovas-
pioneering work.1 cular, and gastrointestinal. Reactions that surpass
Management of Shock; Editor in Chief, Joseph P. Lynch, III, M.D.; Guest Editors, Arthur P. Wheeler, M.D., Gordon R. Bernard, M.D. Seminars
in Respiratory and Critical Care Medicine, volume 25, number 6, 2004. Address for correspondence and reprint requests: Roger F. Johnson, M.D.,
Center for Lung Research, T-1217 MCN, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN 37232-2650. E-mail:
roger.johnson@vanderbilt.edu. 1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University
School of Medicine, Nashville, Tennessee. Copyright # 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662. 1069-3424,p;2004,25,06,695,703,ftx,en;srm00340x.
695
696 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004
mucocutaneous signs and symptoms are considered to be 53% of those experiencing anaphylaxis and an allergy
severe, and, unfortunately, mucocutaneous manifesta- consultation was obtained in 52%. The hospitalization
tions do not always occur prior to more serious mani- rate was 7% and the case fatality rate was 0.91% (one
festations. Mucocutaneous symptoms commonly consist patient out of 133 expired).3 When projected to the
of urticaria, angioedema, pruritis, and flushing. Com- entire U.S. population on an annual basis these numbers
mon respiratory manifestations are dyspnea, throat are significant.
tightness, stridor, wheezing, rhinorrhea, hoarseness, Neugut et al sought to improve understanding of
and cough. Cardiovascular signs and symptoms include the epidemiology of anaphylaxis by surveying the med-
hypotension, tachycardia, and syncope. Gastrointestinal ical literature.2 They estimated that between 3.3 and 43
manifestations include nausea, vomiting, abdominal million people in the United States (based in 1999
cramps, and diarrhea.2,3,5,6 population estimates of 272 million) are at risk for
First-line treatment of anaphylactic shock is epi- anaphylaxis. In addition, they estimated that between
nephrine. Other adjuvant treatments are often also used; 1453 and 1503 people die each year from anaphylactic or
however, there is no substitute for prompt administra- anaphylactoid reactions (due to food 100, penicillin 400,
tion of epinephrine. radiocontrast media 900, latex 3, stings 40–100). Lim-
A century has passed since the discovery of itations of this study include underreporting, misdiag-
anaphylaxis, and much knowledge has been added to nosis, and failure to recognize cases of anaphylaxis by
our understanding of this syndrome. This article reviews health care providers.2 Regardless, these numbers show
the pathophysiology, recognition, and treatment of ana- that anaphylaxis is a serious health problem in the
including prostaglandins, principally prostaglandin D2 system development, which leads to less stimulation of
(PGD2) and leukotrienes, principally leukotriene C4 the Th1 pathway.
(LTC4), are elaborated by mast cells and to a lesser
extent basophils during anaphylaxis and, in addition to
histamine, are also thought to be pathophysiologically DIAGNOSIS
important.8,9 PGD2 mediates bronchospasm and vascu- Diagnosis of anaphylaxis in the acute setting is a clinical
lar dilatation, principle manifestations of anaphylaxis. one and starts with a brief, directed history because
LTC4 is converted into LTD4 and LTE4, mediators of treatment must be rendered quickly. This history should
hypotension, bronchospasm, and mucous secretion dur- include questions regarding a previous history of atopy or
ing anaphylaxis in addition to acting as chemotactic anaphylaxis, and exposure to new foods, medications,
signals for eosinophils and neutrophils.8,9 Other path- and insect bites or stings. Due to the varied presentation
ways active during anaphylaxis are the complement of anaphylaxis, it is often not recognized or misdiag-
system, the kallikrein–kinin system, the clotting cascade, nosed. Other conditions that mimic anaphylaxis include
and the fibrinolytic system.8 vasovagal events, mastocytosis, pheochromocytoma, car-
Specific lymphocyte subtypes (CD4þ Th2 T- diac arrhythmias, scromboid poisoning, panic attacks,
cells) are central in the induction of the IgE response. and seizures.5,12,13 Evaluation should focus on manifes-
CD4þ T-cells are segregated into either T-helper 1 tations that are likely to be life threatening. This includes
(Th1) or Th2 types, defined by the cytokine profile evaluation of the respiratory and cardiovascular systems
produced by the individual T cell. Th1 cells are impor- with particular attention to signs and symptoms of
Table 1 Symptoms and Signs, the Number Out of 133 new information regarding a new method to prophylax
Patients with Anaphylaxis Who Experienced Them against peanut allergy and recognition that gelatin is a
Patients (N ¼ 133) significant cause of anaphylaxis are summarized in the
next sections. Also, latex allergy has been recognized as
Symptom or Sign N %
an important cause of anaphylaxis in the past 20 years,
Cutaneous and we will review some aspects of latex allergy as well.
Urticaria 73 55
Angioedema 74 56
Pruritus 73 55 PEANUT ALLERGY
Flushing 48 36 It is estimated that 1.5 million people in the United
Conjunctivitis or chemosis 30 23 States suffer from peanut and other nut allergies. Nut
Respiratory allergies account for a majority of life-threatening and
Dyspnea 57 43 fatal anaphylactic reactions involving food in the United
Throat tightness 37 28 States.2,11,16 Peanut allergic patients typically live a life
Wheezing 34 26 of careful avoidance. Avoidance, however, is not always
Rhinitis 22 17 enough because inadvertent exposure still occurs in
Laryngeal edema 9 7 sensitized patients every 3 to 5 years.17
Hoarseness 9 7 Currently, management options for patients who
Oral and gastrointestinal suffer from peanut allergy are limited. Prevention by
hypersensitivity to eggs. In the minds of Dr. Kelso and decades. The advent of the human immunodeficiency
his colleagues, this made little sense because many virus (HIV) epidemic in the early 1980s and the institu-
children with egg hypersensitivities were uneventfully tion of the universal precautions policy in the late 1980s
administered MMR vaccines whereas only two of 28 are commonly cited contributors to latex hypersensitiv-
reports of anaphylactic reactions to vaccines occurred in ity.26 Furthermore, changes in the manufacturing pro-
egg-allergic children.21 The astute observations of these cess of latex gloves driven by increased demand may have
investigators, coupled with serendipity (their patient led to production of latex products with increased
reported that the reaction to the vaccine was ‘‘kind of allergenicity. The first reported case of anaphylaxis
like what happens when I eat Jell-O’’)21 led these attributed to latex was published in 1984, and by the
investigators to a paradigm-shifting discovery. end of the decade, reports of anaphylaxis to latex were
Following the lead of Kelso et al, investigators in commonplace.26
Japan characterized anaphylactic reactions to vaccines as Risk groups for latex hypersensitivity include
also mediated by anti-gelatin IgE.22 In addition, they patients with spina bifida, patients who have had multi-
uncovered a link to hypersensitivity reactions to orally ple catheterizations of the genitourinary system such as
ingested gelatin, which, interestingly, developed after patients with congenital genitourinary abnormalities,
the vaccine-related reaction in five of seven children. patients who have undergone multiple surgical proce-
The same investigators also traced gelatin as the cause of dures, people working in the manufacture of latex
anaphylaxis in erythropoietin administered intravenously or latex products, atopic individuals, and health care
to hemodialysis patients.23 workers.27,28 Although controversial, a recent study has
Figure 1 Acute management of anaphylaxis. Reproduced with permission from Joint Task Force on Practice Parameters.5
AIRWAY OR
CUTANEOUS REACTIONS
Epinephrine Bronchospasm, laryngeal 0.3–0.5 mL of 1:1,000 Maintain airway patency,
edema, hypotension, solution IM, every reduce fluid extravasation
urticaria, angioedema 10 minutes as needed
Oxygen Hypoxemia Up to 100% Maintain SaO2 > 90%
Albuterol Bronchospasm 0.5 mL of 0.5% solution in 2.5 mL Maintain airway patency
of isotonic saline by nebulizer, or
two puffs by metered-dose inhaler
every 15 minutes, up to three doses
Diphenhydramine Urticaria 1 to 2 mg/kg or 25–50 mg Reduce pruritis and
parenterally antagonize histamine
effects
Methylprednisolone Bronchospasm 125 mg IV every 6 hours Reduce late-phase
reactions
CARDIOVASCULAR
as 24 hours has been advocated12; however, we advocate similar to biphasic anaphylaxis, is impossible to antici-
monitoring for no more than 10 hours after severe, life- pate based on initial patient presentation.12
threatening episodes of anaphylaxis. Biphasic reactions There are no absolute contraindications to using
can be treacherous because they often occur after symp- epinephrine in the context of anaphylactic shock, and
toms of anaphylaxis have completely resolved. Biphasic failure to do so promptly can lead to adverse outcomes.4
reactions are poorly understood; however, some data This is illustrated by a study in dogs in which treatment
suggest that they tend to occur in cases of more severe with epinephrine at maximal hypotension produced no
initial presentations and in instances when treatment benefit in hemodynamic recovery in a canine model of
with epinephrine has been delayed.11 Others, however, anaphylaxis.33 It is also important to point out that
suggest that it is not possible to predict the occurrence of proper dose and route of administration are essential
biphasic reactions based on initial presentation.4,12 because both over- and underdosage may be life threa-
Furthermore, biphasic reactions can be more difficult tening.13,34 The proper dose of epinephrine in adults is
to treat than the initial episode, often requiring intuba- 0.3 to 0.5 mL of a 1:1000 solution given intramuscularly.
tion.11 Persistent anaphylaxis, anaphylaxis that continues Some authors advocate 0.1 mL of 1:1000 epinephrine IV
for a protracted period of time, has also been described in for the treatment of hypotensive patients or those
the literature.4,8,12 Some authors have observed rates as refractory to IM dosing; however, intravenous dosing
high as 28%, whereas data from others suggest that may be associated with more side effects. Repeat dosing
persistent anaphylaxis is rare.4,12 Persistent anaphylaxis, may be necessary to reverse anaphylaxis. Many health
702 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004
care providers do not recognize the difference between selves are unsure of how to properly use the device.38,39
epinephrine given for treatment of anaphylaxis and Patients with a history of anaphylaxis should be advised
epinephrine given for resuscitation with respect to to carry the autoinjector kit on their person at all times.
dose, route, and rapidity of infusion.13 It has also been Patients should be instructed to seek medical attention,
reported that some proportion of patients die regardless especially if they have had a reaction serious enough to
of treatment with epinephrine.11,13 require use of an epinephrine autoinjector. Ideally,
Recent data have come to light regarding the EpiPen1 or EpiPen Jr1 should be used before its
preferred method of administering epinephrine. Simons expiration date, and this is recommended because epi-
et al performed a study in children in which they nephrine from outdated autoinjectors has considerably
reported that IM injection of epinephrine is superior reduced bioavailability.40 If, however, a patient is sud-
to subcutaneous administration.35 This conclusion was denly in need of epinephrine, it has been shown that
based in delayed epinephrine absorption with subcuta- outdated epinephrine autoinjectors have a percent of
neous compared with IM administration. The difference labeled epinephrine content inversely proportional to
was hypothesized to be due to the cutaneous vasocon- months past expiration date. The authors of this study
strictive properties of epinephrine. They extended their concluded that outdated EpiPen1 and EpiPen Jr1 can
findings to adults and further defined that IM injection be used if no discoloration or precipitate is present. The
into the thigh (vastus lateralis) is preferred to IM basis of their conclusion is that if a life-threatening
injection into the deltoid.36 This conclusion is based anaphylactic episode occurs, the potential benefits of
on the superior serum levels of epinephrine achieved by using outdated autoinjectors outweigh potential risks.40
3. Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology an 23. Sakaguchi M, Kaneda H, Inouye S. A case of anaphylaxis to
anaphylaxis in Olmsted County: a population-based study. gelatin included in erythropoietin products. J Allergy Clin
J Allergy Clin Immunol 1999;104:452–456 Immunol 1999;103:349–350
4. Kemp SF, Lockey RF. Anaphylaxis: a review of causes 24. James JM, Zeiger RS, Lester MR, et al. Safe administration of
and mechanisms. J Allergy Clin Immunol 2002;110:341– influenza vaccine to patients with egg allergy. J Pediatr 1998;
348 133:624–628
5. Joint Task Force on Practice Parameters. The diagnosis and 25. American Academy of Pediatrics. Summaries of infectious
management of anaphylaxis. J Allergy Clin Immunol 1998; diseases. In Pickering LK, ed. 2000 Red Book: Report of the
101:S465–S527 Committee on Infectious Diseases. 25th ed. Elk Grove Village,
6. AAAAI Board of Directors. Anaphylaxis in schools and other IL: American Academy of Pediatrics; 2000;175:357–358
child-care settings. J Allergy Clin Immunol 1998;102:173– 26. Ownby DR. A history of latex allergy. J Allergy Clin
176 Immunol 2002;110:S27–S32
7. Long A. The nuts and bolts of peanut allergy. N Engl J Med 27. Condemi JJ. Allergic reactions to natural rubber latex at home,
2002;346:1320–1322 to rubber products, and to cross-reacting foods. J Allergy Clin
8. Dykewicz MS. Anaphylaxis and inflammation. Clin Allergy Immunol 2002;110:S107–S110
Immunol 2002;16:401–409 28. Turjanmaa K, Alenius H, Reunala T, Palosuo T. Recent
9. Daffern PJ, Schwartz LB. Allergic response. In Dale DC, ed. developments in latex allergy. Curr Opin Allergy Clin
WebMD Scientific American Medicine. New York: WebMD Immunol 2002;2:407–412
Reference Group; 2003 29. Garabrant DH, Schweitzer S. Epidemiology of latex
10. Kay AB. Allergy and allergic diseases: first of two parts. N sensitization and allergies in health care workers. J Allergy
Engl J Med 2001;344:30–37 Clin Immunol 2002;110:S82–S95