Anaphylaxis is the quintessential medical emergency. While the vast majority of anaphylaxis cases are relatively benign, about 1 percent of these patients die from anaphylactic shock quickly—within about five to 30 minutes of onset. Many of these deaths occur because the anaphylaxis was misdiagnosed and/or the treatment of anaphylaxis and anaphylactic shock was inappropriate.

Anaphylaxis is not simply an acute onset of an itchy rash with hypotension. To the contrary, up to 20 percent of patients do not manifest a rash. Moreover, anaphylaxis can present with isolated hypotension, making the diagnosis even more challenging.

Criteria

In order for time-sensitive lifesaving treatment to be initiated promptly, it’s imperative that emergency medicine providers understand the diagnostic criteria for anaphylaxis:

1. Acute illness with skin, mucosal tissues (or both) involvement, and at least one of the following:
   • Respiratory compromise
   • Reduced blood pressure or associated symptoms of end-organ dysfunction
2. Two or more of the following that occur rapidly after exposure to a likely antigen:
   • Skin-mucosal tissue involvement
   • Respiratory compromise
   • Reduced blood pressure or associated symptoms of end-organ dysfunction
   • Gastrointestinal symptoms
3. Reduced blood pressure after exposure to a known allergen

Anaphylaxis can present with isolated hypotension, hypotension plus vomiting, or hypotension plus wheezing, without rash. Not recognizing this in a timely manner can lead to misdiagnosis and death.

Anaphylaxis is not simply an acute onset of an itchy rash with hypotension. To the contrary, up to 20 percent of patients do not manifest a rash. Moreover, anaphylaxis can present with isolated hypotension, making the diagnosis even more challenging.

Epinephrine: Timing, Location, and Dose

All patients who fulfill the criteria for anaphylaxis require epinephrine. Epinephrine is the only drug to show a mortality benefit in the management of anaphylaxis.

Epinephrine should be administered as soon as possible intramuscularly (IM) in the anterolateral thigh. Administering epinephrine IM in the deltoid muscle or subcutaneously is not recommended.

The most common cause of death in anaphylaxis is not giving epinephrine at the right time at the correct dose. The correct dose of epinephrine for the treatment of anaphylaxis is 0.01 mg/kg (to a max of 0.5 mg) IM, repeated after five minutes if there’s no clinical improvement. It’s common practice to underdose epinephrine in this setting.

The combination of 50 mg of diphenhydramine plus 50 mg of ranitidine compared to diphenhydramine plus placebo as a second-line agent for anaphylaxis was shown in one study to be significantly more likely to result in absence of urticaria at two hours. However, there’s a paucity of evidence for the efficacy of steroids in patients with allergic reactions or anaphylaxis, and recent evidence suggests that steroids have little effect on preventing the dreaded biphasic reaction. Nonetheless, steroids are standard care in many jurisdictions. My practice is that if the patient fulfills the diagnostic criteria for anaphylaxis, I give epinephrine and steroids.

If you do give steroids, I recommend a single 10 mg dose of dexamethasone in the emergency department, which has the advantage of a long half-life of 53 hours, thus negating the need for prescribing steroids upon discharge.

Some patients who present to the emergency department with anaphylaxis in shock require IV epinephrine. After two IM doses of 0.01 mg/kg (max 0.5 mg) epinephrine five minutes apart, give IV epinephrine:

• Inject 1 mg of epinephrine 1:10,000 into a 1 L bag of normal saline
• Draw up 10 mL from the 1 L bag in a 10 mL syringe

Push dose: 10 mL every two to five minutes (10 mcg)

Dose of epinephrine given via infusion: 1 mL/min (1 mcg/min) and titrate to a maximum of 20 mL/min

Do not underestimate the profound vasodilatory shock that may accompany anaphylactic shock. Aggressive fluid resuscitation is indicated for patients with anaphylactic shock. Consideration may be given to a second vasopressor with alpha properties such as vasopressin.

One of the more common causes of death in anaphylaxis is patients failing to self-administer the epinephrine auto-injector (even if they’re carrying it on their person) or not administering it properly. It is, therefore, imperative to take the time to counsel patients before they leave the emergency department: Carry two epinephrine auto-injectors (many patients will require two doses), be sure that the blue end points away and the orange end points to the thigh (“blue to the sky, orange to the thigh”), and hold the auto-injector firmly in place against the thigh for 10 seconds.

Observation Time in Anaphylaxis

Traditionally, patients with anaphylaxis are observed in the emergency department for four to six hours before discharge. However, there’s no literature to support this practice. Some experts recommend observing patients until they become asymptomatic regardless of time. It may be prudent to observe patients who are at high risk for severe anaphylaxis for a longer time, including patients taking antihypertensive medications, with an early symptom onset/late treatment initiation, with asthma, and with a past history of severe reactions.

Biphasic reactions in anaphylaxis can occur any time between one hour and seven days after the initial anaphylactic episode in approximately 2 to 5 percent of patients. Recent literature has found that the rate of biphasic reactions may be lower than previously thought, biphasic reactions rarely result in death, and the number needed to treat (NNT) with steroids to prevent one ED relapse visit is 176. However, these studies have included not only patients with true anaphylaxis but also those with simple allergic reactions who did not receive epinephrine. Many of these patients would have gotten better by themselves regardless of medications.

Unfortunately, this means we cannot assume from these studies that steroids play no role in preventing relapses or biphasic reactions in anaphylaxis. Until large validated random controlled trials can show definitively that steroids aren’t effective in this respect, it still remains standard care to administer steroids along with epinephrine for patients with true anaphylaxis.

Kounis Syndrome: Anaphylaxis of the Coronary Arteries

A 43-year-old man is brought to the emergency department with an allergic reaction to cloxacillin. He complains of nausea, vomiting, and shortness of breath, along with an itchy rash. He’s given 0.5 mg epinephrine IM and soon after complains of chest pain. His ECG shows an obvious STEMI (ST elevation myocardial infarction).

Did the epinephrine cause the STEMI? Epinephrine in the correct dose for anaphylaxis generally does not cause coronary ischemia. There are no absolute contraindications to epinephrine in severe anaphylaxis.

The diagnosis in this case is Kounis syndrome: an allergic myocardial infarction, an acute coronary event in the setting of an anaphylactic reaction. When anaphylaxis occurs, chemical mediators induce coronary artery vasospasm as well as platelet activation, which can promote plaque rupture and stent thrombosis.

The management of patients with Kounis syndrome is challenging because you must treat both the allergic and cardiac manifestations of anaphylaxis. Unfortunately, no guidelines exist for the management of patients with acute coronary events in the setting of anaphylaxis. Theoretically, epinephrine may worsen coronary vasospasm and worsen myocardial ischemia. Cardiac catheterization has been used successfully to treat patients with Kounis syndrome.

Notwithstanding, epinephrine should still be given as the initial treatment of choice. In a recent case series, one quarter of patients with Kounis syndrome received epinephrine, and there were no deaths.

Resource from Emergency Medicine Cases Website

Podcast: Episode 78 Anaphylaxis and Anaphylactic Shock – Live from The EM Cases Course (emergencymedicinecases.com/anaphylaxis-anaphylactic-shock/).

A special thanks to Dr. David Carr for his participation in the Emergency Medicine Cases podcast on which this article is based.

DR. HELMAN is an emergency physician at North York General Hospital in Toronto. He is an assistant professor at the University of Toronto, Division of Emergency Medicine, and the education innovation lead at the Schwartz/Reisman Emergency Medicine Institute. He is the founder and host of Emergency Medicine Cases podcast and website (www.emergencymedicinecases.com).