Steve LaFond, PharmD Jill Wall, BSN, CRNI · 2017. 4. 20. · Anaphylactic and Anaphylactoid Reactions Steve LaFond, PharmD Jill Wall, BSN, CRNI April 27, 2017

Anaphylactic andAnaphylactoid Reactions

Steve LaFond, PharmDJill Wall, BSN, CRNI

April 27, 2017

Objectives• Describe anaphylactic and anaphylactoid

reactions• Understand the mechanism of action in

anaphylaxis• Describe the risk factors for developing

anaphylaxis• Describe the clinical manifestations in

anaphylaxis• Identify management of a patient experiencing

anaphylaxis

Approximately 1,500 deaths caused by

anaphylaxis annually in the

U.S.

http://www.tipdisease.com/2013/12/anaphylaxis-causes-symptoms-diagnosis.html

Anaphylaxis Subtypes• Drugs• Latex• Food• Insect stings

Anaphylactic & Anaphylactoid Reactions

• Life-threatening events result from overactive and misdirected immune response to a substance (antigen) that is viewed as foreign to the body.

• Reaction is systemic, involves multiple organ systems, and a direct result of the release of chemical mediators from mast cells and basophils.

Limmer DD., Mistovich JJ., Krost WS. (2004, June 1). Anaphylactic and Anaphylactoid Reactions. EMS World. Retrieved from https://www.cgc.maricopa.edu/Academics/LearningCenter/Writing/Documents/APA_References.pdf.


• Anaphylaxis (allergic reaction)– Requires patient to be sensitized and the

reaction mediated through IgE antibodies– Occurs only after patient has been previously

exposed at least once to antigen and is sensitized



• Anaphylactoid reaction (nonallergic reaction)– Does not need presence of IgE antibodies.

Substances initiating the reaction cause a direct breakdown of the mast cell and basophil membranes (e.g., radiopaque contrast media, blood products [e.g., IVIG], NSAIDs, aspirin)

– Can occur following a single, first-time exposure to certain agents in nonsensitized patients

• Both produce same clinical manifestations and treated exactly the same.


World Allergy Organization

• Recommends replacing anaphylaxis and anaphylactoid with immunologic anaphylaxis (IgE-mediated and non-IgE mediated [IgG and immune complex complement-mediated]) and nonimmunologic anaphylaxis (events resulting in sudden mast cell & basophil degranulation in the absence of immunoglobulins), respectively.

Shahzad Mustafa, S., Kaliner Michael A., et al. (2017, Feb 22). Anaphylaxis. Retrieved from http://emedicine.medscape.com/article/135065-overview

Mechanisms of Action

Mechanisms of Action (Anaphylaxis)

• Sensitization– An immunologic process that occurs when the

body views a substance as foreign. – In response, IgE antibodies are produced to

fight off the substance. – IgE antibodies have a strong affinity for mast

cells and basophils and attach to receptors on the cell membrane.


• Mast cells– Located in connective tissue, near blood vessels,

in mucosal layer in lungs, and GI tract. Filled with granules that release chemical mediators (e.g., histamine, heparin, proteases, chemokines, cytokines).

• Basophils– Contain granules and are polymorphonuclear

leukocytes that circulate in blood; become mast cells


• Patient becomes sensitized when IgE antibodies attach to mast cells and basophils.

• IgE antibodies can stay attached for seconds, minutes, days, weeks, months, or years.

Anaphylactic Reaction

http://healthlifemedia.com/healthy/what-is-anaphylaxis


• With reintroduction of the antigen in a sensitized patient, it attaches to IgE antibodies located on the cell membranes of the mast cells and basophils.

• This linkage causes breakdown or degranulation of cell membranes, releasing chemical mediators from the cell granules into extracellular fluid.

• These chemical mediators are responsible for producing the clinical condition found in anaphylaxis.


• Histamine ➜ Vasodilation, hypotension (increased vascular permeability), flushing, bronchospasm, pruritus, and rhinorrhea

• Leukotrienes ➜ Antihistamine-resistant bronchoconstriction

• Prostaglandins/Thromboxanes ➜ Vasoactive compounds causing bronchoconstriction

Mechanism of Action (Anaphylactoid)

• Complement-mediated by an antigen-antibody complex

• Byproducts of complement cascade (C3a and C5a) and substances called anaphylatoxins

• Cause mast cell and/or basophil degranulation

• Similar systemic manifestations as IgE-mediated anaphylaxis (thus treated in the same manner)

Major Pathophysiologic Factors

• Most signs & symptoms of anaphylaxis are related to:– Increase in vascular permeability– Vasodilatation– Bronchiole smooth muscle contraction (mostly

histamine-mediated)

Risk Factors

Risk Factors• Atopy

– Genetic tendency to develop allergic diseases

• Pre-existing allergies– Foods, drugs, bee stings, environmental allergies

• Female• Older age• Previous exposure to drug• Newly diagnosed, untreated patient• Circulating lymphocyte counts of ≥25,000

Risk Factors• Hematologic malignancies• Route, dosing interval, duration of therapy• Presence of nonhuman sequences (foreign

compounds)• Complex chemical structures (e.g., proteins)• Albumin, enzyme replacement• High-molecular weights (>6000 daltons)• Dextran, Humira®, Remicade®

Risk Factors• Haptens/aggregates (e.g., antibiotics)• Variety of chemicals

– Drugs, food, perfume

• Lack of endogenous proteins• Bee stings, venoms

Clinical Manifestations

Signs & Symptoms of Anaphylaxis

https://en.wikipedia.org/wiki/Anaphylaxis

Clinical Manifestations• Cardiovascular

– Chest pain, palpitations, hypotension, syncope, hypertension, tachycardia, bradycardia, arrhythmia, edema, ischemia or infarction, cardiac arrest

• Central nervous system– Headache, (throbbing), dizziness, anxious,

confusion, altered mental status, level of consciousness (LOC)

Clinical Manifestations• Skin or mucous membranes (80%–90% cases)• Children may present more commonly with

respiratory symptoms followed by cutaneous• Some of most severe cases of anaphylaxis

present in absence of skin findings• Symptoms range from mild dermatologic

complaints to anaphylactic shock to death

Clinical Manifestations• Dermatologic

– Rash, pruritus, urticaria, flushing, local or diffuse erythema, conjunctival erythema and tearing, angioedema, warmth

• Endocrine– Rigors, diaphoresis, fever, generalized feeling of

warmth

Clinical Manifestations• Gastrointestinal

– Nausea, vomiting, metallic taste, diarrhea, abdominal cramping, bloating, dysphagia

• Genitourinary– Incontinence, uterine cramping or pelvic pain,

renal impairment

• Psychiatric– Anxiety, sense of impending doom

Clinical Manifestations• Respiratory

– Cough, dyspnea, nasal congestion, rhinitis, sneezing, hoarseness, tachypnea, wheezing, chest tightness, hypoxemia, bronchospasm, reduced pulmonary expiratory flow, oropharyngeal or laryngeal edema, stridor, pulmonary infiltrates, cyanosis, acute respiratory distress syndrome

AnaphylaxisClinical Syndrome

http://www.priory.com/med/adrenaline.htm

Management of Reaction

Management of Reaction• Emergency care• Support vital functions while eliminating

three primary factors:– Vasodilatation– Increased vascular permeability– Bronchoconstriction

Management of Reaction• Late-phase or biphasic anaphylaxis can occur

up to 72 hours following initial reaction (most occur within 8 to 10 hours)

• Potential risk factors include severity of initial phase, delayed or suboptimal epinephrine dose(s) during initial phase, laryngeal edema, or hypotension during initial phase

• Incidence varies from <1% up to 23% of cases

http://www.australianallergycentre.com.au/anaphylaxis-and-the-adrenaline-epipen

WAO Anaphylaxis Guidelines

• “Even a few minutes’ delay can lead to hypoxic-ischemic encephalopathy or death”

• “The importance of having a management protocol cannot be over emphasized because retention of memorized facts and algorithms can be poor in a crisis and there is little to no time to look up information”

http://www.karger.com/Article/PDF/354543

Prompt Initial Treatment• Initial assessment should take less than

1 minute• Any indication of airway, breathing, or

circulation failure should result in administration of epinephrine and calling 911

Assessment• Assess airway, breathing, circulation (ABC)

– LOC/mental status– Vital signs (sudden reduced BP, hypotonia,

collapse, incontinence)

• Observe for sudden cutaneous manifestations– Urticaria, angioedema, erythema, pruritus, hives,

swollen lips-tongue-uvula

Assessment• Auscultate lungs, listening for

stridor/wheezing, SOB– Dysphonia, cough, hoarseness, hypoxemia

• Assess for sudden gastrointestinal symptoms– Cramping, abdominal pain, vomiting

Interventions• Remove exposure to trigger • Assess airway, breathing, circulation• Administer epinephrine, if needed • Call 911• Place patient supine with legs elevated• Maintain patent airway (O2, high flow, prn)• Maintain IV with 0.9% NS

Interventions• CPR, if indicated• At frequent/regular interval, monitor BP,

HR and function, respiratory status, and oxygenation – Monitor continuously, if possible

Interventions• Obtain VS every 2 minutes until stable• Administer medications, as needed• Provide emotional support to patient/family• Keep patient warm• Stay with patient• Transport via ambulance to hospital

Epinephrine

EpinephrineWAO Guidelines

• “The evidence base for prompt epinephrine injection in the initial treatment of anaphylaxis is stronger than the evidence base for the use of antihistamines and glucocorticoids in anaphylaxis.”

http://www.waojournal.org/content/4/2/13

Epinephrine• Mixed adrenergic agonist (alpha & beta)• Alpha-1 adrenergic vasoconstrictor effect in

most body organ systems• Prevent and relieve airway obstruction

caused by mucosal edema (mediated by beta-2 receptor activity)

• Prevent and relieve hypotension and shock• Mitigates anaphylactic response indirectly

via cAMP second messenger system

Epinephrine• Inject IM as soon as anaphylaxis is

diagnosed or strongly suspected• Dose 0.01 mg/kg of a 1:1,000 (1 mg/ml)

solution to a maximum of 0.5 mg in adults (0.3 mg in children)

• Depending on severity and response to initial injection, dose can be repeated every 5–15 minutes, as needed

Epinephrine• Transient pharmacologic effects

– Pallor, tremor, anxiety, palpitations, dizziness, headache

• Serious adverse effects– Ventricular arrhythmias, hypertensive crisis,

pulmonary edema

Epinephrine Administration Devices

www.auvi-q.com www.epipen.com

www.my-generic-epinephrine-auto-injector.com/en

www.epinephrineautoinject.com

https://www.foodallergy.org/treating-an-allergic-reaction/epinephrine

Epinephrine• American Academy of Pediatrics

recommends epinephrine as a first-line therapy for anaphylaxis

• Update on Meridian’s voluntary worldwide recall of EpiPen® auto-injector– See http://www.mylan.com/epipenrecall

- Frellick M. (2017, Feb. 13). AAP Updates Guidance on Epinephrine Use for Anaphylasix. Medscape. Retrieved from http://www.medscape.com/viewarticle/875689- http://www.mylan.com/epipenrecall

http://www.medscape.com/viewarticle/875689

Other Medications

Glucocorticoids• Some effect on early phase reactions of

anaphylaxis, but mostly on mitigating late-phase reactions (caused by neutrophils and cytokines)

• Block transcription of genes that encode cytokines related to the inflammatory pathway

• Given orally (typically prednisone) for less severe reactions or IV (hydrocortisone or methylprednisolone)

Antihistamines (H1 & H2)• Not drug of choice for “initial anaphylaxis

treatment” • Relieves life-threatening respiratory symptoms

or shock• Decreases urticaria, pruritus, vascular

permeability• IV route can cause hypotension if

administered too rapidly• Diphenhydramine (H1 antagonist) drug-of-

choice dosed at 1 mg/kg up to 50 mg

Antihistamines (H1 & H2)• Diphenhydramine

– Can be given IM or IV for treatment, or PO if given as a premedication

• Hydroxyzine or cetirizine– Given PO as a premedication

• H2 antagonists (e.g., cimetidine or ranitidine)– Can be given for more thorough antihistamine

effect

0.9% Normal Saline• Crystalloid solution used to restore

intravascular volume (up to 35% loss due to increased vascular permeability)

• Infuse 1 liter in hypotensive adults or 20 mL/kg in pediatric patients over 15 minutes

Case Studies

Case Study 1• Elaprase® enzyme replacement

– 5-yo with Hunter syndrome (mucopolysaccharidosis II, MPS II)

– Developed initial infusion reaction after several previous infusions w/o reaction

– Symptoms included stridor, wheezing, rigors, fever

– RN stopped infusion/maintained patency of IV– RN administered epinephrine 0.5 mg IM– 911 called and transported to hospital

Case Study 1 (cont.)– Patient recovered and received next 3 infusions

in outpatient short stay– Patient resumed home therapy 4 weeks later and

continued symptom-free for about 4 months– Patient experienced more severe reaction—

cardiorespiratory symptoms including shallow breathing with apneic spells, increased wheezing, hypotension, and bradycardia (from 92 bpm to 55 bpm within 10 minutes)

Case Study 1 (cont.)– Developed mild fever– RN stopped infusion/maintained patency of IV– RN administered epinephrine IM – 911 called– Supported patient in home– MD notified– Patient transported to hospital by ambulance– Patient received infusions in short stay for next

6 months

Case Study 2• IVIG administration (nonclassical S & S)

– Teenage patient with protein-losing enteropathy and immunodeficiency receiving IVIG

– Patient premedicated with ibuprofen and oral Benadryl®

– Patient developed headache, chills, nausea – RN stopped infusion – MD notified– IV diphenhydramine administered, infusion restarted;

tolerated the rest of the infusion– Symptoms resolved post-diphenhydramine

Case Study 2 (cont.)– Next infusion (emesis x1)– Infusion stopped, MD contacted,

IV diphenhydramine administered– Infusion restarted (emesis x1), MD notified,

infusion continued, no further emesis, BP slightly elevated

– IV diphenhydramine—premedicated for future infusions

– No further issues

Case Study 3• IV Zosyn® antibiotic

– 19-yo trached/vented, MRSA/MDRO, tracheobronchitis

– 5 minutes into infusion via Eclipse™ (30-minute infusion), patient developed adverse reaction

– Signs and symptoms• Facial and neck flushing, pruritus, swollen

lips/tongue, SOB, wheezing, hypoxemia, hypotension

Case Study 3 (cont.)– Interventions– Epinephrine administered via EpiPen®

– 911 called– IV diphenhydramine administered– O2 administered– Rapid administration of IV fluids - 0.9% NS– Positioned supine, legs elevated– VS monitored– Patient transported via ambulance– Admitted x 36 hours

Reminder

https://allergies.knoji.com/the-causes-symptoms-and-treatment-of-anaphylactic-shock

Conclusion • Anaphylaxis is a potentially life-threatening

condition.• Anaphylaxis and anaphylactoid reactions

produce the same clinical manifestations and are treated exactly the same.

• Risk factors should be identified in history.

Conclusion • 3 primary factors that result in need for

emergency care:– Vasodilation– Bronchoconstriction– Increased vascular permeability

• Be prepared for rapid implementation of emergency interventions– Any issues with ABC include administration of

epinephrine and calling 911

http://www.covermesongs.com/2013/04/cover-me-qa-whats-your-favorite-cover-song.html

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http://emedicine.medscape.com/article/136217-overview. 3. Cheng, A. Emergency treatment of anaphylaxis in infants and children. Pediatr Child Health. 2011 Jan; 16(1):

35-40.4. Frellick M. (2017, Feb. 13). AAP Updates Guidance on Epinephrine Use for Anaphylasix. Medscape. Retrieved

from http://www.medscape.com/viewarticle/8756895. Janeway, CA., Travers, P., Walport, M., et al. (2001). Immunobiology: The Immune System in Health and Disease, 5th

edition. New York: Garland Science. 6. Johnson, R., Peebles, R. (2004). Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Semin Respir

Crit Care Med. 25(6), 695-703.7. Limmer DD., Mistovich JJ., Krost WS. (2004, June 1). Anaphylactic and Anaphylactoid Reactions. EMS World.

Retrieved from https://www.cgc.maricopa.edu/Academics/LearningCenter/Writing/Documents/APA_References.pdf.

8. Rothenberg, M. (2000). Mechanisms of Disease: Pathophysiology A Plain English Approach. Eau Claire, Wisconsin: PESI Healthcare.

9. Shahzad Mustafa, S., Kaliner M., et al. (2017, Feb 22). Anaphylaxis. Medscape. Retrieved from http://emedicine.medscape.com/article/135065-overview.

10. Tang, A. (2003). A Practical Guide to Anaphylaxis. Am Fam Physician. 68(7), 1325-1333.