Anaphylaxis: Where do we go wrong and how can we improve?

Authors: Bradley End, MD (EM Resident Physician, The Ohio State University Wexner Medical Center) and Mark J Conroy, MD (Assistant Professor Emergency Medicine, The Ohio State University Wexner Medical Center, @mjconroy_md) // Edited by: Jennifer Robertson, MD, MSed (Assistant Professor Emergency Medicine, Emory University) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Med Ctr / Parkland Memorial Hospital)

I: Case

A 17-year-old man with a history of asthma and multiple food allergies presents to an emergency department (ED) with a rash. It erupted suddenly 20 minutes before arrival while he was at a local bakery with his family.  He had just purchased and ate a delectable slice of biscotti.  As he was leaving, he noticed the sudden onset of a generalized pruritic rash. Since arriving to the ED, he developed nausea and a small amount of vomiting.

Initial vital signs: heart rate (HR) 95 and regular, respiratory rate (RR) 24 per minute, blood pressure (BP) 115/75 mmHg.  temperature (Temp) 99.1°Fahrenheit (F).  pulse oximetry (SpO2) 98% on room air (RA).

Examination:

Head/throat: normocephalic, no pharyngeal edema, uvula midline

Cardiovascular (CV): regular rate and rhythm

Pulmonary: Tachypneic with scant expiratory wheezes

Gastrointestinal (GI): hyperactive bowel sounds

Skin: diffuse urticarial rash across his chest, back, arms and legs, no obvious mucous membrane involvement or facial swelling

The patient has not taken any medications and does not carry an Epi-pen®. He reports similar episodes in the past and he is insistent that he be given only diphenhydramine and steroids and be discharged home immediately.

II: Anaphylaxis

Introduction, Epidemiology, and Historical Analysis

Anaphylaxis was defined in 1901 by Richet and Portier during their attempts to study sea urchin venom. They did so by injecting dogs repetitively with the venom venom.  Repeated exposures, however, resulted in increased sensitivity.  This phenomenon was derived from the Greek ana- (against or opposite) and -phylaxis (protection). [7]

On average, 100,000 anaphylactic reactions occur in the United States per year. Approximately 60,000 are first time events and up to 1500 deaths occur. Episodes are more common in summer and early fall months, in women older than 30 years of age and boys younger than 16 years. [8]

The lifetime prevalence of anaphylaxis is estimated to be 1.6%, but it is suspected to be underestimated due to underreporting. [4]

Pathophysiology

Anaphylaxis can be divided into two categories – (I) immunologic (involving immunoglobulin/complement activation) and (II) non-immunologic or anaphylactoid (involving substances or events directly triggering mast cell and basophil degranulation). [5]

Basic Recap:

(I) Allergen specific IgE produced by B-cells binds high-affinity IgE receptors on basophils and mast cells.  When allergens interact with the IgE, mast cells and basophils release a multitude of chemicals including histamine, tryptase, and tumor necrosis factor. [5]

(II) Non-immunologic anaphylaxis involves direct activation of complement/basophils/mast cells by a specific substance such as vancomycin (red-man syndrome) or opiate medications. [5]

Some substances can cause reactions through both pathways.

Common Triggers:

Food: eggs, peanuts, tree nuts, shellfish

Drugs: non-steroidal anti-inflammatory medications (NSAIDs) and antibiotics

Insects: hymenoptera, fire ants

Other: latex [8]

Diagnostic Criteria

Anaphylactic patients typically present with skin and mucosal involvement (90%) or respiratory symptoms (70%). However gastrointestinal and/or cardiovascular symptoms (hypotension) are still present in almost half of patients (45%). [1]

Diagnostic criteria have been changing within the last few years in order to simplify diagnosis. Emergency physicians and allergists have tried to minimize instances of missed or delayed recognition to hopefully improve care.

Anaphylaxis Criteria (Sensitivity 97%, Specificity 82%, positive predictive value (PPV) 69%,  negative predictive value (NPV) 98%)

  1. Illness with acute onset involving skin/mucosa AND one of the following: Respiratory compromise or Hypotension
  1. Two of the following after exposure to suspected antigen: Skin involvement, Respiratory compromise, Hypotension, GI complaints
  1. Hypotension after exposure to known allergen [4,7,12]

Blood tests such as tryptase and histamine levels do not rule out the diagnosis. Platelet activating factor levels have been shown to have diagnostic value but quickly return to baseline within 15-20 minutes of symptom onset. [4]

Treatment Algorithm

Critical Treatments:

Immediate intramuscular (IM) epinephrine administration in the anterior thigh.

Adult: 0.3-0.5 mg 1:1000 epinephrine IM q5 min

Children: 0.01 mg/kg q5 min 1:1000 epinephrine IM q5 min

In refractory cases when patients do not respond to two IM doses, proceed to intravenous epinephrine.

Epinephrine infusion:

Adult: 1 mg in 250 mL D5W, 0.25-1 mL/min (1-4 ug/min) up to 2.5 mL/min (10ug/min)

Children: 0.1 ug/kg/min with max of 1.5 ug/kg/min (0.6 x body weight (kg) of epinephrine diluted in 100 mL normal saline (NS) yields 0.1 ug/kg/min if run at 1 mL/hr)

Additional medications:

-Diphenhydramine 50mg IV x1

-Histamine 2 (H2) antagonist of choice IV x1

-Dopamine/Dobutamine for refractory shock: 5-20 ug/kg/min

-Glucagon (for those on beta-blockers): 1-5 mg IV over 5 minutes, then 5-15 ug/min (20-30 ug/kg up to 1 mg in children)

Hemodynamic instability is secondary to intravascular volume shifts. Volume resuscitation of 2-7 liters should be used in those with persistent hypotension, with NS preferred over Ringer’s Lactate. [8]

III: Controversies

Recent Cochrane Reviews

“Clinicians should nonetheless be aware of the lack of a strong evidence base for the use of a glucocorticoid for the treatment of anaphylaxis” [3]

“…H1 antihistamines… relieve itching, hives, other cutaneous symptoms, and rhinorrhea in anaphylaxis, they are not expected to relieve airway obstruction, gastrointestinal symptoms, or shock… the evidence base in support… remains very weak.” [10]

“This review failed to uncover any evidence from randomized trials on the effectiveness of adrenaline for the emergency management of anaphylaxis…the benefits of using appropriate doses of intramuscular adrenaline is likely to far exceed the risk.” [4]

Delayed Recognition

Most case series involving fatal episodes of anaphylaxis center on a quick onset of cardiopulmonary arrest following the start of symptoms.  Five minutes for iatrogenic cause, 15 minutes for insect venom, and 30 minutes for food associated anaphylaxis. [1, 7] The onset of Benadryl is typically 45 minutes and this reinforces the importance of quick recognition and intervention with epinephrine.

Not all cases of anaphylaxis (up to 20%) exhibit the classic pruritic rash. Shock and fatal anaphylaxis can occur without cutaneous symptoms. [8]

There are no absolute contraindications to epinephrine, and the anaphylactic reaction alone may cause ischemia, dysrhythmias, and decreased cardiac output. [4,8]

Disposition

For mild to moderate anaphylaxis (with complete resolution of symptoms), observation is recommended for 4-8 hours.  If patients remain asymptomatic, consider a short course of H1/H2 blockers and glucocorticoid therapy, despite the lack of evidence.  All patients should be discharged home with epinephrine auto-injectors.  All patients without complete resolution of symptoms or requiring an infusion of medication should be admitted for further observation. [7, 8]

Rebound Reactions

Anaphylactic reactions typically are uniphasic and resolve within one hour. A few episodes may last hours to days. Up to 23% may experience resolution of symptoms with recurrent symptoms in hours to days (average of 10 hours).  This biphasic reaction is typically less severe than the initial reaction.  At least one study has demonstrated that less than 0.25% of these cases are ‘clinically significant’ and reported no fatalities.  No studies have documented THAT glucocorticoids reduce the rates of biphasic reactions. [6]

Special considerations

Some studies have implied that nitric oxide is a potential mediator of anaphylaxis. Case reports have documented success of methylene blue in treating anaphylaxis refractory to epinephrine.  [5]

Several anaphylaxis related fatalities have been associated with disseminated intravascular coagulation secondary to activation of complement/coagulation pathways, with case reports of tranexamic acid (TXA) administration. [5]

IV: How we can improve

  • Severe allergic reactions and anaphylaxis share very similar presentations, are both life threatening, and require immediate lifesaving treatment with epinephrine.
  • Avoid a slow progression to epinephrine by thinking alternative medications (Benadryl, H2 antagonists, steroids) will work. The time of onset of these medications is too long to prevent severe reactions.
  • Consider glucagon for anaphylactic reactions in patients on beta-blockers.
  • The anaphylactic reaction itself is often responsible for coronary vasospasm and arrhythmia Do not avoid giving epinephrine because of these potential rea ctions.
  • Always prescribe Epi-pen® to all allergic reaction patients. Make sure to counsel these patients on its use in potential future episodes.

References / Further Reading

  1. Campbell, R and Kelso, J. Anaphylaxis: Acute Diagnosis (2016). UpToDate. Available from http://www.uptodate.com/
  2. Campbell, R and Kelso, J. Anaphylaxis: Emergency Treatment (2016). UpToDate. Available from http://www.uptodate.com/
  3. Choo, K et al. Glucocorticoids for the Treatment of Anaphylaxis. Cochrane Database of Systematic Reviews, 2016. DOI: 0.1002/14651858.CD007596.pub3
  4. Hernandez, L et al. Anaphylaxis. Primary Care: Clinics in Office Practice. Sept 2016. Volume 43 (3): 477-85. Available from https://www.clinicalkey.com/
  5. Kemp, S. Pathophysiology of Anaphylaxis (2016). UpToDate. Available from http://www.uptodate.com/
  6. Liberman, P. Biphasic and Protracted Anaphylaxis (2016). UpToDate. Available from http://www.uptodate.com/
  7. Liberman P, Nicklas RA, Randolph C, et al. Anaphylaxis–a Practice Parameter Update 2015. Ann Allergy Asthma Immunol. 2015; 115(5): 341-84.
  8. Tran TP, Muelleman RL. Allergy, Hypersensitivity, Angioedema and Anaphylaxis. Rosen’s Emergency Medicine. 8th Edition. 1543-1557.
  9. Sheikh A, et al. Adrenaline (Epinephrine) for the Treatment of Anaphylaxis with and without shock. Cochrane Database of Systematic Reviews, 2016. DOI: 10.1002/14651858.CD006312.pub2
  10. Sheikh A, et al. H1-Antihistamines for the Treatment of Anaphylaxis with and without Shock. Cochrane Database of Systematic Reviews, 2016. DOI: 10.1002/14651858.CD006160.pub2
  11. Kemp SF, Lockey RF, Simons FE. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy. 2008; 63(8): 1061-70.
  12. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States. J Allergy Clin Immunol. 2010; 126(60): S1-58.
  13. Russell WS, Farrar JR, Nowak R, et al. Evaluating the management of anaphylaxis in US emergency departments: Guidelines vs. practice. World J Emerg Med. 2013; 4: 98-106.
  14. Fineman SM, Bowman SH, Campbell RL, et al. Addressing barriers to emergency anaphylaxis care: from emergency medical services to emergency department to outpatient follow-up. Ann Allergy Asthma Immunol. 2015; 114(4): 301-5.

13 thoughts on “Anaphylaxis: Where do we go wrong and how can we improve?”

  1. Hey guys. Important topic but a couple of things I think should be clarified.
    1. If the patient simply has a rash and GI symptoms this would qualify as anaphylaxis under the allergy + immunology guidelines but it’s unclear if they need epi or if it would help. Stress should be put simply on this: if there’s any compromise to airway, breathing or circulation – give epi.
    2. Epi dosing: Ditch the 1:1000, 1:10,000 garbage. Give 300-500 mcg IM (0.3 – 0.5 mg) every 3-5 minutes. The strength simply confuses the issue more
    3. Epi infusion: there’s no max here. Give whatever you need to support the patient
    4. Airway is not stressed here. These airways can close quickly so consider intubation very early on
    5. Finally, let’s stop calling it Epi-Pen. We as physicians shouldn’t be advertising for any pharmaceutical company much less one that has no problem taking advantage of vulnerable customers. Let’s all agree to call them epi autoinjectors and write for this as they are cheaper.

    1. Swami, thx for your thoughtful comments as always.
      #1: If somebody has a diffuse rash and is itching away or profuse n/v refractory to treatment, I wouldn’t hesitate to give IM epi if contraindications don’t exist; it’s a safe med. Many of these pts are quite thankful. the remainder of allergy cocktail we give doesn’t provide timely / adequate relief and steroids aren’t w/out bothersome side effects
      #2: must-know point; often a topic of confusion
      #3: would add that epi dose may be limited 2/2 side effects; also if higher than usual dose to help pt, must consider alternative diagnoses
      #4: must-know point; see our scary airway series
      #5: recent events have brought this to the forefront

  2. Hey guys. Important topic but a couple of things I think should be clarified.
    1. If the patient simply has a rash and GI symptoms this would qualify as anaphylaxis under the allergy immunology guidelines but it’s unclear if they need epi or if it would help. Stress should be put simply on this: if there’s any compromise to airway, breathing or circulation – give epi.
    2. Epi dosing: Ditch the 1:1000, 1:10,000 garbage. Give 300-500 mcg IM (0.3 – 0.5 mg) every 3-5 minutes. The strength simply confuses the issue more
    3. Epi infusion: there’s no max here. Give whatever you need to support the patient
    4. Airway is not stressed here. These airways can close quickly so consider intubation very early on
    5. Finally, let’s stop calling it Epi-Pen. We as physicians shouldn’t be advertising for any pharmaceutical company much less one that has no problem taking advantage of vulnerable customers. Let’s all agree to call them epi autoinjectors and write for this as they are cheaper.

    1. Swami, thx for your thoughtful comments as always.
      #1: If somebody has a diffuse rash and is itching away or profuse n/v refractory to treatment, I wouldn’t hesitate to give IM epi if contraindications don’t exist; it’s a safe med. Many of these pts are quite thankful. the remainder of allergy cocktail we give doesn’t provide timely / adequate relief and steroids aren’t w/out bothersome side effects
      #2: must-know point; often a topic of confusion
      #3: would add that epi dose may be limited 2/2 side effects; also if higher than usual dose to help pt, must consider alternative diagnoses
      #4: must-know point; see our scary airway series
      #5: recent events have brought this to the forefront

  3. I agree with Alex. For allergic GI symptoms I always use epi + IVF/antiemetic.

    Where does your recommendation for 4-8 hours observation come from? You mention that significant biphasic reactions are rare. Why not discharge once symptoms are resolved?

      1. Paranoia not an indication for prolonging a disposition in my opinion.
        Once anaphylaxis is resolved, okay for D/C!

  4. I agree with Alex. For allergic GI symptoms I always use epi IVF/antiemetic.

    Where does your recommendation for 4-8 hours observation come from? You mention that significant biphasic reactions are rare. Why not discharge once symptoms are resolved?

  5. The most important aspect of treatment is adrenaline. There is good evidence delayed administration of adrenaline increases mortality whereas there is no evidence (and I have specifically searched the medical literature looking back decades) that correct dosing of IM adrenaline is harmful. Several case reports do exist of side effects (including cerebral haemorrhage and cardiac arrest) if patients are given supratherapeutic amounts of IV adrenaline.

    A very simple and effective way of dosing IV adrenaline is to put 1 mg into a 1 litre bag of 0.9% NaCl and run at 2 gtt/s initially then titrated according to patient condition. This is easy for medical or nursing staff to make up using products they are already familiar with and simple to administer (i.e. dosed in gtt/s and not mL/min). You however may have a different preference and I do not think it is significant but may reduce dosing errors.

  6. The most important aspect of treatment is adrenaline. There is good evidence delayed administration of adrenaline increases mortality whereas there is no evidence (and I have specifically searched the medical literature looking back decades) that correct dosing of IM adrenaline is harmful. Several case reports do exist of side effects (including cerebral haemorrhage and cardiac arrest) if patients are given supratherapeutic amounts of IV adrenaline.

    A very simple and effective way of dosing IV adrenaline is to put 1 mg into a 1 litre bag of 0.9% NaCl and run at 2 gtt/s initially then titrated according to patient condition. This is easy for medical or nursing staff to make up using products they are already familiar with and simple to administer (i.e. dosed in gtt/s and not mL/min). You however may have a different preference and I do not think it is significant but may reduce dosing errors.

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