#151 Anaphylaxis with Dr Olajumoke Fadugba

May 27, 2019 | By Emi Okamoto

Recognize, treat, dominate anaphylaxis

Recognize common presentations of anaphylaxis and stop under-treating this deadly allergic reaction with tips from Dr. Olajumoke Fadugba, Assistant Professor of Medicine, University of Pennsylvania! We review the basic pathophysiology and the standard criteria for diagnosing anaphylaxis, treatment basics, the primary importance of epinephrine, and the utility of adjunctive therapies. Also included are great tips on counseling patients about auto-injectable epinephrine, and a reminder not to panic…even when you inject your own thumb?! ACP members can claim CME-MOC credit at https://acponline.org/curbsiders (CME goes live at 0900 ET on the episode’s release date).

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Credits

• Producer, infographic, and cover art: Emi Okamoto MD
• Hosts: Matthew Watto MD, FACP; Stuart Brigham MD
• Editor: Matthew Watto MD, FACP
• Guest: Olajumoke Fadugba MD
• Special thanks to Sarah Phoebe Roberts MPH for booking!

Time Stamps

• 00:00 Intro and disclaimer
• 03:00 Guest one-liner, book recommendation, advice to fellows and trainees
• 07:15 Case of anaphylaxis with mucocutaneous and GI symptoms
• 09:05 Anaphylaxis (IgE mediated mast cell action) vs anaphylactoid (non-IgE mediated mast cell activation; e.g. contrast allergy, vancomycin)
• 12:34 Vancomycin and non-IgE mediated reactions
• 14:40 Common presentations of anaphylaxis and the three diagnostic criteria
• 22:09 Biphasic reactions and predicting severity
• 26:42 Counseling patients on the use of epinephrine
• 28:35 Stuart’s thumb question
• 30:00 Adjuvant medications: antihistamines and corticosteroids
• 33:20 Are there any contraindications to epinephrine use?
• 34:25 Use of tryptase levels when the diagnosis of anaphylaxis is uncertain
• 37:10 Outro

Anaphylaxis Pearls

Anaphylactic reactions, which are non-IgE mediated, like radiocontrast media and vancomycin, can occur on the first exposure to the allergen.

Diagnostic criteria are used to help identify anaphylaxis, and note that a cutaneous reaction is not required for anaphylaxis.

Shock is an end-stage manifestation of anaphylaxis, and ideally anaphylaxis can be diagnosed and treated prior to potential progression to shock.

Progression to anaphylaxis is quick! The average time from allergen exposure is 5 minutes for iatrogenic reactions, 15 minutes for venom, and 30 minutes for food.

There is no absolute contraindication to epinephrine.

An elevated tryptase level supports the diagnosis of anaphylaxis, and is ideally measured 1-3 hours after symptom onset.

Biphasic reactions occur in about 5% of patients, and a common strategy is to monitor patients for 8 hours.

Epinephrine pens should be injected in the outer thigh. Inject through clothes if needed, maintain the needle inserted for 10 seconds before removal, and always have a second pen available! It may be needed!

Anaphylaxis Show Notes

Pathophysiology

Allergic and anaphylactic reactions can be classified based on their pathophysiology (Johansson, 2004). Both types can range from mild reactions to anaphylaxis.

IgE Mediated Reaction

When a susceptible person is exposed to an allergen the first time (like peanuts, tropomyosin protein in shellfish, or even pollen), the allergen can bind to allergen-specific IgE molecules. Note the first exposure may be occult and unnoticed, even with food products. Then, the IgE binds to mast cells. This process is called “sensitization”, and there will not be an allergic reaction on the first exposure. Then, at a future time when the person is exposed to the allergen, which could be the next encounter or the 100th encounter, the allergen can bind to the allergen-specific IgE, which is now already on a sensitized mast cell, causing activation, degranulation, histamine release and other reactions which cause allergic symptoms.

Non-IgE Mediated Reaction

This was previously called “anaphylactoid”, a term which is no longer recommended.

Vancomycin, opioids, radiocontrast media trigger mast cells directly binding to the mast cells and triggering a cascade (without any IgE involvement). Since no sensitization is required, this can occur on the first exposure to an allergen. Premedication with diphenhydramine may be helpful prior to re-exposure (Lieberman, 2015). Red man syndrome is a non-IgE medication reaction that is typically mild, and the infusion can be slowed and/or pretreatment with diphenhydramine (Martel, 2019).

Diagnosing Anaphylaxis

The National Institute of Allergy and Infectious Diseases (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) have defined diagnostic criteria for anaphylaxis for three phenotypes (Sampson, 2006).

Diagnostic Criteria #1:

Acute onset of symptoms (minutes – hours) involving the mucocutaneous regions AND either symptoms of respiratory compromise or reduced blood pressure/end organ dysfunction.

Diagnostic Criteria #2:

After a likely allergen exposure, with involvement of two or more of: (1) mucocutaneous involvement, (2) respiratory compromise, (3) reduced blood pressure or associated symptoms, and/or (4) persistent gastrointestinal symptoms

Diagnostic Criteria #3:

After a known allergen exposure, having evidence of reduced blood pressure.

Examples of organ system symptoms

Mucocutaneous symptoms: itching, flushing, hives, swollen lips. Present in up to 90% of anaphylaxis (Lieberman, 2015).

Respiratory symptoms: dyspnea, wheezing, bronchospasm, stridor, hypoxemia

Reduced blood pressure and end organ manifestation: dizziness, lightheadedness, hypotension, shock

Gastrointestinal symptoms: abdominal pain or cramping, nausea and vomiting

Clinical Judgement Remains Paramount

Epinephrine can be considered in patients even with mild symptoms or single-system involvement depending on the clinical situation (Lieberman, 2015). Dr Olajumoke notes the example of someone with a history of an anaphylactic episode to an allergen who is re-exposed and develops hives. Given there is a higher concern for anaphylaxis, empiric treatment of anaphylaxis (epinephrine injection) should be considered before waiting for further manifestations (expert opinion).

Diagnose anaphylaxis before shock occurs

Recognize that shock is an end-stage manifestation that is not necessary for the diagnosis of anaphylaxis. Our goal is to recognize and initiate treatment before any potential progression to shock.

Mortality

Though anaphylaxis is life threatening, the case mortality rate is very low (1 death in 154 anaphylaxis episodes in a series from Yocum, 1999). The U.S. prevalence of fatal anaphylaxis cases was 0.69 per million persons over a decade (Jerschow, 2014). However there is no way to predict which patients with anaphylaxis will progress.

Higher Risk Patients

Older persons with cardiac and pulmonary disease are at high risk for death from anaphylaxis given comorbid disease (Greenberger, 2007). Also histamine can cause vasospasm of the coronary artery and disrupt arteriosclerotic plaques (Lieberman, 2015) so treating anaphylaxis early in these patients is important.

Treatment of Anaphylaxis

The average time to anaphylaxis is 5 minutes for iatrogenic reactions (anesthetics, contrast, antibiotics), 15 minutes for venom, and 30 minutes for food (Pumphrey, 2000). Treatment should be initiated upon diagnosis.

Remember your ABC’s

Though not explicitly mentioned in the show material, Dr Fadugba reiterated the importance of airway, breathing, and circulation as applicable.

Epinephrine

Epinephrine is the first-line treatment for anaphylaxis and the main priority. It works immediately to stop histamine release from mast cells, increase blood pressure, promote bronchodilation, and reduce mucosal edema. Epinephrine is the only agent that can act quickly and broadly enough for treatment.

Contraindications to Epinephrine?

There is no absolute contraindication to epinephrine! Though it can increase blood pressure, cardiac contractility, and vasoconstriction, epinephrine is the only medication which could prevent a fatal anaphylaxis episode. Keep in mind that older patients with comorbid cardiovascular disease have higher risk of death from anaphylaxis (Lieberman, 2015).

Corticosteroids and Antihistamines

These could be considered as adjunctive therapy, and should not be replace epinephrine (though they are often mistakenly administered instead of epinephrine for anaphylaxis). Meta-analyses show no evidence from high-quality studies of corticosteroid benefit (Choo KJ 2010), though they are commonly used for their potential or theoretical benefit. Antihistamines, particularly H1 blockers, can work over longer periods to reduce itching and hives thus improving patient comfort.

Tryptase Levels

Tryptase is a enzyme released by mast cells during degranulation and anaphylaxis. Levels peak around 90 minutes after an event and normalize within 5-8 hours. This can be measured in bloodwork, ideally 1-3 hours from symptom onset, and levels over 11 mcg/L may support a diagnosis of anaphylaxis (Castells, 2017). This can be particularly helpful to check immediately during hypotension or bronchospasm with anesthesia, when the diagnosis often is not clear. A normal tryptase does not rule out anaphylaxis, and tryptases are more likely to be lower in food-induced anaphylaxis and normotensive patients.

Biphasic Anaphylactic Reactions

These are defined as symptom recurrence without re-exposure to the trigger within 72 hours of an anaphylactic event. According to a large systematic review of over 4000 patients, 5% of patients with anaphylaxis had a biphasic reaction (Lee, 2015). The median time to symptom onset for the biphasic reaction was 11 hours (with a range of 0.2 – 72 hours, the cutoff for definition). Patients who initially presented with low blood pressure with unknown trigger were more likely to have a biphasic reaction.

How long should we monitor?

There is no consensus answer. Eight hours is a common recommendation, though the expert opinion varies widely (Lieberman, 2005). Patients should be educated to watch for symptoms, self-administering epinephrine, and returning, and we could also gauge their functional ability to do so. Dr. Fadugba notes that in her clinic setting, when stimulating patients with allergen testing, they can induce anaphylaxis. These patients will get epinephrine and often be monitored for an hour before discharge, sometimes with one or two prednisone doses (expert opinion in a specific scenario). Of note, there is not definitive evidence that corticosteroids decreases the risk for biphasic reactions, however there is a theoretical possibility. (Lieberman, 2005)

Prescribing Epinephrine for Patients

Concentration

The intramuscular bolus injection of epinephrine is 1:1,000 or 1 mg/mL, and the preferred adult dose is 0.3mg (Lieberman, 2015). This is more concentrated than the intravenous formulation of 1:10,000 or 0.1 mg/mL, which is given as a monitored slow infusion.

Counseling Patients

Dr Fadugba says, “If you feel like you are going to die, or an impending sense of doom, use your epinephrine!”. She also counsels them on watching for involvement of two organ systems (and reviews symptoms from diagnostic criteria #2). Also, she tells patients to use epinephrine if they have throat swelling, trouble breathing, or feel like they might pass out.

How do you use an auto-injectable epinephrine device?

Inject the pen, through any clothing, into the outer (mid-anterolateral) thigh and maintain the pen for 10 seconds (some brands require only 3 seconds, though others up to 10 seconds). Patients who require epinephrine should be taken to an emergency room for further monitoring. Dr Fadugba spends about three minutes doing this using models of the available pens.

I stuck my thumb!?

**Show notes bonus info** A literature review of all documented cases of accidental digital epinephrine injections shows no finger necrosis. The most commonly used treatments include phentolamine, warm compresses/water, and nitroglycerin ointment. (Fitzcharles-Bowe, 2007)

Two pens are better than one

Epinephrine pens should always be prescribed and carried in two! If a patient has symptoms that do not respond within 5-15 minutes, they should use a second dose (as they head to the emergency room). Also these can be helpful for biphasic reactions, or if a patient injects their thumb!

Goals

Listeners will explain the basic pathophysiology, diagnosis, and management of anaphylaxis to improve both inpatient emergent care and outpatient counseling.

Learning objectives

After listening to this episode listeners will…

1. Recall the basic pathophysiology of IgE and non-IgE mediated anaphylactic reactions.
2. Be familiar with the diagnostic criteria of anaphylaxis and their application.
3. Recognize the importance of epinephrine as the primary medicine for managing anaphylaxis.
4. Describe the utility of adjunctive medications and tryptase levels.
5. Learn about approaching biphasic reactions.
6. Feel comfortable counseling patients appropriately on auto-injectable epinephrine.

Disclosures

Dr Fadugba reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Links from the show

1. Eleanor Oliphant is Completely Fine, novel by Gail Honeyman

References

1. Johansson SG et al. Revised nomenclature for allergy global use: Report of World Allergy Organization. J Allergy Clin Immunol. 2004. [https://www.ncbi.nlm.nih.gov/pubmed/?term=15131563]
2. Lieberman P et al. Anaphylaxis– a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015.  [https://www.ncbi.nlm.nih.gov/pubmed/26505932] **this is a comprehensive, high-yield resource for anaphylaxis
3. Martel TJ and King KC. Red man syndrome. StatPearls. 2019. [https://www.ncbi.nlm.nih.gov/pubmed/29494112]
4. Sampson MA et al. Second symposium on the definition and management of anaphylaxis. J Allergy Clin Immunol. 2006. [https://www.ncbi.nlm.nih.gov/pubmed/16461139]
5. Yocum MC et al. Epidemiology of anaphylaxis in Olmsted County. J Allergy Clin Immunol. 1999. [https://www.ncbi.nlm.nih.gov/pubmed/10452770]
6. Jerschow E et al. Fatal anaphylaxis in the United States 1999-2010. J Allergy Clin Immunol. 2014. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260987/]
7. Greenberger PA et al. Fatal anaphylaxis: postmortem findings and associated comorbid disease. Ann Allergy Asthma Immunol. 2007. [https://www.ncbi.nlm.nih.gov/pubmed/17378256]
8. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000. [https://www.ncbi.nlm.nih.gov/pubmed/10931122]
9. Choo KJ et al. Glucocorticoids for treatment of anaphylaxis. Allergy. 2010. [https://www.ncbi.nlm.nih.gov/pubmed/20584003]
10. Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol. 2017. [https://www.ncbi.nlm.nih.gov/pubmed/?term=28780940]
11. Lee S et al. Time of onset and predictors of biphasic anaphylactic reactions. J Allergy Clin Immunol Pract. 2015. [https://www.ncbi.nlm.nih.gov/pubmed/25680923]
12. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005. [https://www.ncbi.nlm.nih.gov/pubmed/?term=16200811].
13. Fitzcharles-Bowe et al. Finger injection wtih high dose (1:1000) epinephrine: Does it cause finger necrosis and should it be treated? Hand. 2007. [https://www.ncbi.nlm.nih.gov/pubmed/18780041]

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