Episode 7: Anaphylaxis Part I, Refine your Approach

Episode 7: Anaphylaxis Part I, Refine your Approach

Today, we’ve got not one, but two guest experts to help Dr. Rajiv Thavanathan tackle all things Anaphylaxis! Dr. Graham Wilson is an FRCPC EM resident at The Ottawa Hospital (TOH), who tackled this topic in-detail in his Grand Rounds presentation last year. Joining him is Dr. Derek Lanoue, an incoming McGill Allergy and Immunology Fellow. Let’s dive right in to Part 1 of 2 on this nutty topic!

What is the Diagnostic Criteria of Anaphylaxis?

It’s very difficult to summarize “anaphylaxis” in one definition. To tackle this problem, in 2005, The National Institute of Allergy and Infectious Diseases, and Food Allergy and Anaphylaxis Network came out with the criteria most ED docs probably teach on shift today.

2005 NIAID and FAAN Anaphylaxis Criteria

  • Anaphylaxis is highly likely if:
    • Unknown exposure with acute onset of illness
      • AND Skin OR mucosal changes
      • AND Respiratory compromise OR reduced blood pressure
    • Likely antigen:
      • Two or more organ system involvement: Skin, mucosa, respiratory system, cardiovascular changes, or persistent GI symptoms
    • Known allergen:
      • Reduction in blood pressure

This definition was prospectively validated with a sensitivity 95%, though we aren’t applying it as effectively as it should. A study in the USA by Russell et al. in 2013, and more recently out of the Childrens Hospital of Eastern Ontario in 2020 show that:

  • We are underdiagnosing anaphylaxis upwards of 50% of the time
  • Why? Definitions are too restrictive.
  • “What do persistent GI symptoms even mean?” “Is one episode of emesis enough?”

 

Things changed for the better in 2020, when the World Allergy Organization tried to simplify things for practitioners. 

2020 World Allergy Organization Anaphylaxis Criteria

  • Anaphylaxis is highly likely if:
    • Unknown exposure with an acute onset of illness
      • Skin findings, and one other organ system
    • Likely or known antigen
      • Respiratory AND/OR cardiovascular compromise

 

How can we improve allergy/immunology referrals?

The purpose of our anaphylaxis criteria is to maximize sensitivity to not miss this life-threatening diagnosis, and to administer the antidote, epinephrine, as soon as possible. This poses the question though – what might this approach be sacrificing, from the perspective of the consultant who will see this patient in follow up?

Dr. Lanoue brings up a great point – it’s all in the objective evidence. Did you hear wheezing when you examined them? Do they have hives you can photograph (with consent)? Have they vomited? How many times? Did they have an episode of diarrhea in the ED?

“Okay, but what about tryptase?”

Triptase is an intermediate in anaphylaxis, which causes activation of the compliment system, and mast cell degranulation. This test takes ages to come back, so often it won’t get drawn as part of the work-up for anaphylaxis – some centres won’t have it?

Dr. Lanoue recommends the following from the allergists’ perspective:

  • For the vast majority, get the level.
  • It doesn’t help in the acute setting; it won’t help you decide whether to give epinephrine or not.
  • It can be very useful, however, for the consultant allergist.
  • The level peaks within an hour, and is back to normal within 4-6h. Any patient who presents within this time period from onset may have benefit.

Tryptase levels are useful in the patient where there is an unclear trigger. We know there will be many patients who are tryptase negative, despite being in anaphylaxis. The reverse is also true. In the setting of an unknown trigger, especially when there is diagnostic uncertainty, this may provide another objective piece of evidence for your consultants. Anaphylaxis is not the only diagnosis that is indicated by an elevated tryptase (e.g. mast cell degranulation syndrome).

What is the dosing of epinephrine for anaphylaxis?

  • Epinephrine: 0.01mg/kg, up to a max of 0.5mg.
  • Anyone below 25kg: 0.15mg Epinephrine auto-injector (e.g. Epipen Jr).
  • Anyone above 25kg: 0.3mg Epinephrine auto-injector (e.g. Epipen).
  • We can provide weight-based dosing in the hospital setting, and encourage listeners to do the same to get the most benefit from epinephrine as possible.
  • No established RCT on dosing. Even the 0.01 mg/kg is opinion-based, and based on data on normal adults, not those having anaphylaxis, using measured levels of epinephrine in the blood level.

 

What is the ideal site of administration for anaphylaxis?

Dr. Estelle Simons is a (Canadian!) prolific researcher in the field of Allergy and anaphylaxis and has served as president of the American Academy of Allergy, Asthma and Immunology (AAAAI). She performed a study measuring peak epinephrine concentrations in healthy, adult volunteers in the deltoid muscle vs the lateral thigh, showing a higher level in the lateral thigh. This is likely due to a higher concentration of vasculature. More of her work showed a difference in the rates of absorption in intramuscular vs subcutaneous administration of epinephrine. Other researchers have demonstrated that the thinner subcutaneous tissue over the lateral thigh allows for more consistent penetration to the muscle.

In summary, use the lateral thigh and use the intramuscular route.

Another huge take away point by both guest speakers is that IV bolus delivery of epinephrine for the treatment of anaphylaxis is associated with increased adverse outcomes compared to both IM and SC.

Use of steroids and antihistamines

These are a very controversial topics, with lots of dogma surrounding the medications we use. In theory, steroids work in two ways. First, it decreases the symptom burden in the acute phase of anaphylaxis. Second, it helps to prevent the concerning, though ever-elusive unicorn that is the biphasic reaction.

In the acute phase, the evidence from steroids came from children with asthma and croup, looking at preventing hospital admissions, and relapse rates. Maximum steroid serum concentrations occur within 1-2 hours, which means that it’s highly unlikely to prevent death from anaphylaxis. We know that death from anaphylaxis occurs within 30 minutes of trigger exposure, which is well outside of the effective window for the steroid.

What we do know is that epinephrine is the first-line intervention for anaphylaxis, with the greatest mortality benefit. Despite, in a cohort study of close to 2000 children diagnosed with anaphylaxis, less than 25% received epinephrine, with almost 50% received steroids.

So what about the biphasic reaction? The biphasic reaction is recurrent anaphylaxis, after complete resolution of symptoms, without re-exposure, within 72 hours of the initial anaphylactic event.

A few facts about the biphasic reaction:

  • Rates range from 4-5% of anaphylaxis cases using the above definition.
  • Most present in a clinically similar manner to the first episode.
  • Only 20% of these patients required additional therapy on top of what they originally received.
  • Steroids in the ED first gained favor in 2007 when a single-centre prospective study showed decreased biphasic reactions with use of steroids.
  • Since that time, several systematic reviews argue against preventative association of biphasic reactions, and one study went so-far as to recommend against the routine use of steroids for anaphylaxis.
  • Further, there have been no reported cases of mortality due to biphasic anaphylaxis as per the 2020 AAAAI Practice Parameters
  • Clinical Features of biphasic anaphylaxis (low-quality evidence):
    • Those who required multiple epinephrine doses
    • Respiratory failure, end-organ damage, cardiovascular shock or arrest.

 

In summary, don’t extrapolate too much, but the routine use of steroids is probably not ideal. There are, however, select patients that will still benefit:

  • Refractory anaphylaxis
  • Cardiovascular shock
  • Concurrent asthma with anaphylaxis (clear benefit shown with steroids)

 

“If I’m going to use a steroid, which one should I use?”

If you choose to use a steroid, a careful agent selection that is ideal for your patient can have a much greater benefit than simply throwing IV methylprednisolone at them.

  • Methylprednisolone is associated with the highest rates of steroid-induced anaphylaxis, urticaria, and angioedema of all steroids
  • For this reason, consider using dexamethasone vs hydrocortisone, letting the patients presentation guide our choice
    • When to consider dexamethasone: Dominant upper/lower respiratory involvement are responsive to this medications anti-inflammatory effects, as well as its longer duration of action.
    • When to consider hydrocortisone: If the patient continues to be hypotensive, mineralocorticoid effects from hydrocortisone may play a higher benefit in this shock or shock-like state.

If there’s one take home point from biphasic reactions and steroid use, it’s that the number one medication to prevent relapse and bounce-back from anaphylaxis is epinephrine.

For part 2 episode and show notes, click here !

Episode 7: Anaphylaxis Part I, Refine your Approach

Episode 7: Anaphylaxis Part 2, Ready for Discharge

In part 2 of our 2-part series on Anaphylaxis, our host Dr. Rajiv Thavanathan interviews Dr. Graham Wilson, PGY4 Emergency Medicine at the University of Ottawa and Dr. Derek Lanoue, PGY3 Internal Medicine, University of Ottawa who will soon be an Allergy and Immunology Fellow starting July 1, 2022.

If you haven’t already, you should check-out Part 1 of the series, where the new definition for anaphylaxis and treatment guidelines, including the use of steroids were discussed.

In this part 2, let’s delve deeper into the subject, by discussing monitoring times, discharge instructions and follow-up.

Anaphylaxis Monitoring Times

Although easy to treat with the use of epinephrine, anaphylaxis management is labour intensive in the emergency department with regards to cost effectiveness and human resources, due to the often long “observation” time in the ED. These observation times have a single purpose – monitor for a refractory/biphasic reaction.

Throughout the literature on the topic, there is a wide variation on what is perceived to be an acceptable “mandatory” observation time [range extends between 2-24hrs]. Given the lack of consensus on a set timeframe, some literature has focused on trying to identify this value. A recent study by Ellis has successfully identified that the NPV for the observation of biphasic reaction only increases by 1% for every hour since time of epinephrine injection. This is one of the landmark trials questioning the need for extended observation, primarily for low-risk asymptomatic individuals 1-2hrs post epinephrine injection.

With these promising results, it wouldn’t be inconceivable to think that in the not-so-distant future, risk stratification could be used, and shorter observation periods considered for low-risk individuals. This would certainly help with the human/costly resources needed for extended observation periods.

This conclusion somewhat aligns itself with the 2020 Anaphylaxis guidelines which suggest firmly that high-risk patients require observation for a minimum of 6 hours. These high-risk patients are defined by:

  • Risk Factors: Lack of EMS services, Poor self-management skills, cardiovascular risk factors, and lack of access to epinephrine
  • Requirement for several doses of epinephrine
  • Severe anaphylaxis

 

Anaphylaxis Mimics: What the ED MD needs to know

Even anaphylaxis has its mimics. These diagnoses are hard to elicit in the moment when a patient presents to the ED with stridor, wheezing and respiratory distress. As such, it’s completely understandable that most ED physicians will provide these patients with at least 1 dose of epinephrine up front. However, if the patient is not responding to epinephrine, there are a few diagnoses that we should perhaps consider.

  • Chronic urticaria [including dermatographism]: This condition, whose pathophysiology is best explained as a hypersensitivity reaction, results in exaggerated weal and flare response to a stimulus – for example physical pressure (being stroked or scrathched) in the case of dermatographism. The condition may respond to the use of antihistamines. It often is an anaphylaxis mimicker when the urticaria is perioral and/or associated with a panic attack, resulting in the physical presentation of tachypnea and dyspnea.
  • Vocal cord dysfunction: This entity is often seen in individuals with allergies to perfumes or other aerosolizing products. In anaphylaxis cross-linking of IgE results in mast cell degranulation. Aromatic rings found in perfumes are incapable of cross-linking IgE or entering the blood stream, and as a result only stimulate a localized hypersensitivity reaction.

In addition to the above mimics, there are several instances when seeing a patient, where the dx of anaphylaxis seems clear from a symptom’s perspective, but the identification of triggers is difficult. It’s important to remember that idiopathic anaphylaxis is a medical entity of its own and is defined by sx of anaphylaxis with no clear trigger.

Furthermore, with the arrival of Lonestar ticks in Canada, Alpha-Gal [sugar molecule found in mammals] allergies from tick bites may gain prevalence. These anaphylactic presentations often are associated with anaphylaxis that wakes a patient up at night, as they encounter a delayed anaphylactic reaction to red meat.

Patient Discharge and Follow-up

Our general threshold for prescribing an epinephrine autoinjector upon discharge should be very low. If you suspect anaphylaxis in any shape or form, it is always safer to simply Rx an autoinjector. Remember that idiopathic anaphylaxis [i.e. anaphylaxis without a clear trigger] is a medical entity, and therefore if you aren’t able to identify a trigger, but their symptoms were consistent with anaphylaxis, you SHOULD prescribe an autoinjector.

Apart from good discharge instructions on when to seek emergency medical attention, how to use their autoinjector safely, a good follow-up is needed for patients presenting with a first-time episode of anaphylaxis. Although human resource constraints for allergist are pronounced in some regions, a referral to a specialist is often beneficial in these individuals. Even if the “trigger” is clear, and the diagnosis of anaphylaxis is clear cut, these patients often have several lingering questions and a need for supports, as this dx will be a “lifelong” struggle. Our allergy specialists can help provide support and reassurance to individuals even if diagnostic clarification is not required.

 

Take-Home Points 

[TAKE HOME #1] There is ever growing evidence that observation times in the ED can be adjusted based on risk stratification. Although not quite ready for primetime, remember that those with high-risk features [listed below] should be observed for an extended period [i.e. >6hrs].

  • Cardiovascular disease
  • Lack of EMS services
  • Lack of access to epinephrine
  • Poor coping skills

[TAKE HOME #2] Even anaphylaxis has mimics. Consider alternative diagnoses including chronic urticaria and vocal cord dysfunction when epinephrine does not help.

[TAKE HOME #3] Every patient with suspected anaphylaxis should be discharged home with a Rx for an autoinjector, and counselled on it’s use/reasons to return to the ED.

[TAKE HOME #4] Referral to an allergist is not just for dx clarification. It provides an additional line of support for a patient who received an anaphylactic dx that will affect them the rest of their lives.

 

For more information make sure to check out the EMOttawaBlog post on ANAPHYLAXIS in the ED.