Allergy and Anaphylaxis

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Chapter 75 Allergy and Anaphylaxis

Susan A. Vassallo, MD

1 When was anaphylaxis first described?

In 2641 BC, a wasp from the Hymenoptera order (wasps, bees, ants, sawflies) stung Pharaoh Menes. The events were described in hieroglyphics, and this is believed to be the first recorded death of anaphylaxis. Another important event occurred during a cruise on the yacht of Prince Albert of Monaco when the prince asked Professor Charles Richet to apply his immunology skills in the study of the Portuguese man-of-war (Physalia or jelly). These invertebrates live in the Mediterranean Sea and are highly poisonous. In the early 1900s Richet worked at the Musée Océanographique de Monaco. Along with Paul Portier, he extracted the Physalia poison with glycerol, injected dogs with this mixture, and was able to reproduce the symptoms of Physalia poisoning (1902). He expected a second injection would be harmless, but instead his dogs “showed serious symptoms: vomiting, blood diarrhea, syncope, unconsciousness, asphyxia and death” (Nobel Lecture, 1913). Richet created the word anaphylaxis to describe this phenomenon. Phylaxis is protection in Greek, and the prefix ana implies away from protection. Anaphylaxis therefore means “that state of an organism in which it is rendered hypersensitive, instead of being protected.” Richet was awarded the Nobel Prize in Physiology and Medicine in 1913 for his discovery of anaphylaxis.

2 How often does anaphylaxis occur?

The incidence of anaphylaxis ranges from one to three people per 10,000. This includes allergic reactions to food, drugs, latex, and Hymenoptera. Lethal anaphylaxis probably occurs in 0.65% to 2.0% of recorded allergic events or in one to three per million people.

3 What are the immune mechanisms that lead to anaphylaxis?

The final common pathway for anaphylaxis is mast cell activation and subsequent release of vasoactive mediators—both preformed and newly generated substances. Preformed mediators include histamine and tryptase stored in cell granules. Newly generated mediators are synthesized at the time of antigen exposure and include leukotrienes (LTC₄, LTD₄, LTE₄), prostaglandins (PGD₂), platelet-aggregating factor (PAF), and cytokines. In the past, the leukotrienes were not well defined and were simply called “slow-reacting substances of anaphylaxis,” or SRS-A. It is now known that leukotrienes, prostaglandins, and PAF are much more potent bronchoconstrictors than histamine.

4 How are immunologic reactions in anaphylaxis classified?

The Gell and Coombs classification (1963) described four types of immunologic reactions (see Table 75-1). A fifth type of reaction, termed idiopathic, was added to the classification system several years later.

^{Table 75–1} Gell and Coombs Classification of Immunologic Reactions

Type	Description	Mediator
I	Immediate hypersensitivity	IgE usually
II	Cytotoxic or cytolytic	IgG, IgM
III	Immune complex disease	Antigen-antibody
IV	Delayed hypersensitivity	T cells
V	Idiopathic	Unknown

5 What substances activate mast cells?

Immunoglobulin (Ig) E (IgE) antibodies. IgE antibodies fixed to mast cell surfaces are cross-linked on exposure to an antigen. This initiates cell degranulation and release of mediators.

IgG and IgM antibodies. Immunologists have created knockout mice that lack the gene for synthesis of IgE antibody. These mice can still develop anaphylaxis via IgG antibodies and complement.

Complement-mediated reactions. Complement is the term given to plasma and cell membrane proteins that activate the release of inflammatory mediators. Complement activation occurs as a cascade of reactions. IgG or IgM antibody-antigen binding, heparin-protamine complexes, and radiocontrast dye activate the classic pathway. Endotoxins, certain drugs, and radiocontrast dyes can activate the alternate pathway.

Activated T cells can stimulate mast cell degranulation in a delayed hypersensitivity reaction.

Direct mast activation. Direct mast cell activation can occur in the absence of antibody or complement. Drugs such as morphine, vancomycin, and d-tubocurarine can cause histamine release, especially if administered quickly.

Bradykinin is thought to be involved in the systemic inflammatory response system and in angioedema associated with angiotensin-converting enzyme inhibitors. Kinins can mediate a nonhistamine anaphylactoid reaction. Certain polygeline plasma expanders (e.g., Haemaccel) have been implicated in anaphylactoid reaction during anesthesia.

6 How frequently do neuromuscular blocking drugs (NMBDs) cause anaphylaxis, and what is the mechanism?

NMBDs have long been considered the most common cause of intraoperative anaphylaxis in adults. This is true in all published studies from Australia, New Zealand, the United Kingdom, France, Norway, Belgium, and Spain. These drugs have accounted for 54% to 69% of reactions, depending on the study. Within this drug class, succinylcholine and rocuronium are the most common causes. Succinylcholine is a quaternary ammonium ion and is a flexible molecule that can cross-link two IgE molecules more easily than nondepolarizing muscle relaxants with a rigid backbone (e.g., pancuronium or vecuronium).

There are five important points to remember when considering allergy, anaphylaxis, and NMBDs:

Quaternary and tertiary ammonium ions are present in many drugs, cosmetics, and food products. Sensitization can occur outside of the operating room, and a serious reaction can occur with first exposure to a NMBD.

Cross-sensitivity between NMBDs can occur in up to 60% of people.

NMBDs can cause adverse reactions without IgE antibody mediation. This mechanism of action is via direct mast cell degranulation and release of histamine and other inflammatory mediators. Isoquinolinium compounds such as d-tubocurarine, metocurine, atracurium, and mivacurium are more likely to cause mast cell degranulation.

Anaphylaxis to NMBDs is rare in the United States but is reported more frequently in Europe, especially France. An important recent paper has challenged the results of previous French skin test studies. This investigation found that undiluted rocuronium and vecuronium extracts produced a positive wheal and flare response in 50% and 40% of nonatopic anesthesia-naïve volunteers, respectively. However, a dilution of 1:1000 did not yield any skin response at 15 minutes. Although their study was small (30 healthy adults), the authors questioned the reliability of skin prick testing with undiluted solutions of rocuronium and vecuronium when making the diagnosis of allergy. An accompanying editorial supported the recommendations for using dilute test extracts and suggested that the incidence of NMBD allergy may be overestimated.

No demonstrated evidence exists for improved outcomes with preoperative screening of sensitivity to NMBDs.

7 How common are latex allergies?

Although its incidence is decreasing, it is still the second most common cause of intraoperative anaphylaxis in adults. Latex is harvested from the Hevea brasiliensis tree and is used in hundreds of medical products. Latex remains the most common cause of intraoperative anaphylaxis in children. Certain subsets of patients have a higher risk of latex allergy:

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