CONTENTS

• Rapid Reference 🚀
• Diagnosis
  • Clinical findings & definition
  • Causes
  • Differential diagnosis
  • Investigation
  • Anaphylaxis vs. bradykinin-mediated angioedema
• Treatment
  • Source control
  • Components of therapy
    • Epinephrine
      • IV epinephrine infusion
    • Fluid resuscitation
    • Antihistamines
    • Steroid
    • Inhaled beta-2 agonists
  • Overall treatment strategy
    • General treatment strategy
    • Anaphylaxis in the beta-blocked patient
  • Airway management
  • Recovery phase & extubation
  • Disposition
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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management of anaphylaxis ✅

#1/5) epinephrine is the most important therapy (more)

• Indications for epinephrine = any of the following:
  • Airway involvement.
  • Breathing difficulty.
  • Circulation (hypotension).
  • 2 organs involved (e.g., vomiting + urticaria).
• Dosing:
  • if IM is faster: 0.5 mg IM, repeat q5min for up to three cumulative doses if needed (then, if needed, transition to epinephrine infusion.)
  • if IV faster: 👇

#2/5) fluid resuscitation (more)

• Aggressive fluid resuscitation may be needed initially.

#3/5) albuterol (more)

• May be used for refractory bronchospasm despite ongoing administration of epinephrine.
• (Albuterol is not intended to substitute for epinephrine.)

#4/5) steroid (more)

• Not needed for all patient with anaphylaxis, but should be given to patients with ICU-level anaphylaxis.
• 10 mg dexamethasone or 60 mg IV methylprednisolone may be reasonable.

#5/5) antihistamines (more)

• 🛑 Least important therapy, should never delay administration of other treatments (e.g., epinephrine or crystalloid). Antihistamines aren't routinely needed, but may improve urticaria.
• Typical regimen:
  • Diphenhydramine 50 mg IV q6hr.
  • Famotidine 20 mg IV q12 hr.

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clinical findings & definition

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clinical findings

• Cardiovascular:
  • Hypotension
  • Tachycardia
  • Syncope, presyncope
• Pulmonary/Airway:
  • Upper airway obstruction (stridor, tongue/uvula swelling, voice change)
  • Bronchospasm (wheeze originating in lower airways on auscultation)
  • Dyspnea, cough
• GI (involved in ~45% of patients):(34052784)
  • Crampy abdominal discomfort.
  • Nausea,vomiting.
  • Diarrhea.
• Skin/mucosa (involved in ~90% of patients):
  • Flushing.
  • Itch.
  • Urticaria.
  • Angioedema (~80% sensitive) – may involve lips, eyelids, airway, hands, feet, genitalia.
  • Conjunctivitis, conjunctival swelling, tearing.
  • Nasal discharge & congestion.

timing of anaphylaxis onset

• Anaphylaxis due to intravenous medication or bee sting usually begins within <30 minutes.
  • Initiation of reaction immediately following exposure is a poor prognostic sign.
• Anaphylaxis due to food or oral medication usually begins within a few hours.
• Among patients who die, the time between exposure & death is: (10931122)
  • ~5 minutes for iatrogenic anaphylaxis (e.g. IV medication induced).
  • ~15 minutes for insect venom anaphylaxis.
  • ~30 minutes for food anaphylaxis.

approach to the diagnosis: main pieces to consider

• [1] Exposure history and chronicity:
  • Exposure to known causative agent increases index of suspicion.
  • Some patients can have idiopathic anaphylaxis, so absence of a trigger doesn't exclude anaphylaxis.
• [2] Number of organ systems involved:
  • Having two organ systems involved strongly supports the diagnosis.
  • The diagnosis of anaphylaxis can be made on the basis of only one organ, within a highly suggestive clinical context.
• [3] Competing diagnoses (when in doubt, it's generally wise to treat empirically for anaphylaxis while continuing to investigate other diagnostic possibilities).

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causes

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• Foods, especially:
  • Peanuts.
  • Seafood.
• Insects (e.g. bees).
• Medications, especially:
  • Antibiotics (especially penicillin & first-generation cephalosporins).
  • NSAIDs, aspirin.*
  • Monoclonal antibodies (e.g. anti-TNF antibodies).
  • Radiocontrast dye.*
  • Paralytics.
  • Protamine.
  • Local anesthetics (e.g. lidocaine, benzocaine, mepivacaine).
• Blood products in an IgA deficient person.
• Exercise, cold or heat exposure.

* The reaction to NSAIDs, aspirin, or radiocontrast dye is technically an anaphylactoid reaction, not anaphylaxis. The two disorders are treated the same fashion, however.

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differential diagnosis

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• Asthma:
  • Severe asthma is a risk factor for anaphylaxis.
  • Wheeze and dyspnea in an “asthmatic” is likely to be presumed due to asthma.
• Angioedema due to bradykinin accumulation (see chapter on angioedema).
• Systemic mastocytosis.
• Red person syndrome due to vancomycin.
• Scombroidosis (“histamine fish”).
• Upper airway obstruction of any etiology (e.g. vocal cord dysfunction, epiglottitis, abscess compressing airway).
• Acute pulmonary deterioration (e.g. pulmonary embolism, pneumothorax).
• Sepsis, toxic shock syndrome.

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investigation

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tests for anaphylaxis

• There are no tests to immediately diagnose anaphylaxis.
• Tryptase levels won't come back for a long time, but may eventually help clarify whether the patient had anaphylaxis.

evaluation of competing diagnoses

• Depending on the presentation, it may be necessary to evaluate for other diagnostic possibilities.
• Clinical example: A patient presents with vasodilatory shock and urticaria. Anaphylaxis is suspected, but there is also a concern for septic shock. The patient is treated empirically for both conditions (with IV epinephrine infusion, steroid, antihistamine, and antibiotic). Infectious workup is pursued with chest X-ray, procalcitonin, and blood cultures. The infectious evaluation is negative, so antibiotics are stopped – leaving the patient with a clinical diagnosis of anaphylaxis.

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anaphylaxis vs bradykinin-mediated angioedema

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clinical characteristics of histamine-mediated versus bradykinin-mediated angioedema

approach to sorting out the etiology of angioedema

• Clearly differentiating the cause of angioedema is important (because the treatments are entirely different).
• Anaphylaxis is histamine-mediated, so it will almost always respond rapidly to aggressive treatment (with epinephrine, antihistamine, and steroid, as discussed below). In contrast, bradykinin-mediated angioedema won't respond to these treatments (and tends to progress slowly, over a period of hours). Therefore, an immediate therapeutic trial of therapies for anaphylaxis can be used as a diagnostic/therapeutic approach to differentiating anaphylaxis versus bradykinin-mediated angioedema.(29721614)

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source control

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• Any potentially causative infusion (e.g., medication or blood transfusion) must be stopped.
• Consider placing a tourniquet proximal to site of sting or antigen infiltration (e.g., local anesthetic) until the patient can be stabilized.

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epinephrine

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indications for epinephrine = any of the following:

• A = Airway involvement
• B = Breathing difficulty
• C = Circulation (hypotension)
• Involvement of any two organ systems (e.g. nausea/vomiting plus urticaria).

intramuscular epinephrine

• Traditional approach, useful in most situations.
• Start with 0.5 mg IM into the mid anterolateral thigh.(33895231) If symptoms are refractory to treatment, then one or two additional 0.5-mg doses may be given every five minutes.(33895231) If three doses fail to work, then consider initiation of an epinephrine infusion (as below).(33895231)
• If symptoms recur, then consider a repeat dose or initiation of an IV epinephrine infusion (as below).

physiology of epinephrine in anaphylaxis

• Effects of epinephrine:
  • Hemodynamic stabilization (vasoconstriction, inotropy, chronotropy).
  • Stabilization of mast cells (prevents ongoing mediator release).
  • Reduction of airway edema.
  • Bronchodilation (via beta-2 receptors).
• Key points:
  • (1) Epinephrine has many beneficial effects in anaphylaxis (above and beyond hemodynamics). Even if the patient's hemodynamics are stable, epinephrine can still be life-saving.
  • (2) Epinephrine is the only real disease-modifying medication for acute anaphylaxis. For example, antihistamines may make the patient less itchy, but they don't do much else.

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intravenous epinephrine infusion

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intravenous epinephrine infusion

• Intravenous epinephrine may be useful for anaphylaxis which occurs in a context where providers are well versed in the use of IV epinephrine (especially the ICU or OR, where epinephrine is most commonly given via an IV route).
• Peripheral IV epinephrine is safe, so a central line is neither required nor recommended.

advantage of IV epinephrine infusion

• Faster onset (if the patient has an IV placed and if IV epinephrine is available, this is the fastest way to get the medication into circulation).
• Smoother tapering – the infusion can be gradually weaned off in a controlled fashion.
• Ability to withdraw the epinephrine if problems are encountered (e.g., hypertension). This is unlike IM epinephrine, where the epinephrine cannot be immediately withdrawn.
• Patients who are already shocked may not perfuse their muscle tissue well, so they may have poor absorption of IM epinephrine.

dosing of IV epinephrine for anaphylaxis

• A regimen for using IV epinephrine in anaphylaxis is shown in the figure below. Further discussion of the pharmacology of IV epinephrine is here.

“Dirty Epi Drip”

• If a pre-mixed bag of epinephrine isn't immediately available, one may be created as follows:
• Inject a 10-ml syringe of cardiac epinephrine (1:10,000) into a 1-liter bag of normal saline or lactated ringers. (Or a 1-ml vial of 1:1,000 epinephrine – either form will work perfectly here, since both contain a total of 1 mg of epinephrine). Shake it up. This creates a 1 microgram/ml solution of epinephrine.
• Titrate infusion:
  • 2 micrograms/min = 120 ml/hour.
  • 5 micrograms/min = 300 ml/hour.
  • 10 micrograms/min = 600 ml/hour.
  • 16 micrograms/min = 960 ml/hour.
• Push doses of epinephrine:
  • 20 mcg = 20 ml bolus (using a 20 cc syringe).
• 💡 Diluting epinephrine in a liter of saline makes it difficult to give it fast enough to kill someone. Even if this solution is run in wide open, it will result in administration of ~20-30 mcg/min infusion – which shouldn't be dangerous in a monitored setting and might be an appropriate dose during the first few minutes.

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fluid resuscitation

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• Large volumes of crystalloid may be required for hemodynamic stability (e.g., several liters of lactated Ringers).
• Aggressive fluid resuscitation is particularly important for:
  • Patients requiring high doses of epinephrine to maintain hemodynamic stability.
  • Patients about to be intubated.
• Bedside echocardiography may guide fluid resuscitation (if available).

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antihistamines

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• Antihistamines don't appear to improve respiratory or cardiovascular compromise, or to improve survival.(33895231)
• Antihistamines may reduce erythema and pruritus.
• 🛑 Administration of antihistamines should never delay key interventions (e.g., epinephrine administration and volume resuscitation). Furthermore, administration of antihistamines alone should not be misconstrued as representing adequate therapy for anaphylaxis.

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steroid

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• The main potential role of steroid is to reduce late-phase inflammatory responses (e.g., recurrent or biphasic reactions). However, there is no strong evidence that steroids accomplish this task.
• Some guidelines recommend against the routine use of steroids.(33895231) However, this is based on retrospective correlational data, which may be subject to confounding.
• Situations where steroids may be more beneficial include:
  • Anaphylaxis refractory to two IM doses of epinephrine (most patients admitted to ICU would probably meet this definition).
  • Anaphylaxis in the context of asthma (it may be difficult to clearly differentiate between the two entities).
• If steroid is utilized, there is no need for a prolonged steroid regimen. A reasonable approach could be a single dose of 10 mg dexamethasone, which will auto-taper itself off over a course of a couple days (obviating the need for any sort of steroid taper).

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inhaled beta-2 agonists

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• For patients with persistent respiratory symptoms, epinephrine is the front-line therapy. Inhaled beta-2 agonists shouldn't be used alone as an alternative to epinephrine.(33895231)
• Inhaled beta-2 agonists may be useful as an adjunctive, add-on therapy for patients who are receiving epinephrine and continue to have bronchospasm.

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anaphylaxis in the beta-blocked patient

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Start with standard therapy as shown above.

• Epinephrine remains the front-line therapy.
• For most patients who are on low or moderate-dose beta-blockers, epinephrine should still work fine.
• 🔑 Key concept – The usual treatment strategies for anaphylaxis will generally still work in patients who are on beta-blockers. So don't get too fancy – stick to the basics.

If the patient fails to respond adequately to standard treatment (and particularly if bradycardic), then try:

• Glucagon
  • Start with 1-5 mg IV over five minutes.
  • If there is a response, may infuse at 0.3 – 0.9 mg/hour.
  • This will often elicit vomiting, so use caution if the patient has borderline ability to protect their airway.
• Isoproterenol infusion (2-10 micrograms/minute) if available
  • Isoproterenol is a pure beta-agonist.

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airway management

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racemic epinephrine & heliox

• Nebulized racemic epinephrine can temporize while preparing for intubation.
• Heliox may also be considered as a stop-gap measure to stabilize the patient sufficiently to organize the material and people required for intubation.

indications for intubation

• Precise indications are unclear. High-quality evidence is impossible to obtain, for the following reasons:
  • (#1) Physicians cannot be blinded to clinical features when they decide whether to intubate a patient.
  • (#2) Intubation is generally used as an outcome variable, but this may simply be a measurement of the decision algorithms which physicians employ when deciding whether to intubate (#1).
  • (#3) Truly determining which patients absolutely require intubation would require a decision to randomized patients and never intubate some patients and see which patients die – which is obviously impossible.
• Potential indications for intubation are as follows:
  • (1) Stridor, dyspnea – especially if worsening & not responding to therapy.
  • (2) Inability to handle secretions.
  • (3) Progressive deterioration of edema (intubation may become more difficult over time if edema worsens).
  • (4) Nasolaryngoscopy shows significant laryngeal edema or impending closure of the posterior pharynx. When in doubt, nasolaryngoscopy may help reveal whether there is significant laryngeal edema. The true threat to the airway is the larynx and posterior tongue – not the lips and anterior tongue.

intubation is fraught with hazard

• Airway manipulation may worsen swelling.
• Laryngeal edema will often preclude the use of a laryngeal mask airway.
• In severe angioedema, orotracheal intubation may simply be impossible.
• There is a high risk of hemodynamic collapse following intubation: start epinephrine & give fluid beforehand.

scenario #1: the crashing anaphylaxis patient (extremely rare!)

• Description
  • Patient is at immediate risk of losing their airway.
  • Patient is stridulous, sitting bolt upright, and struggling for breath.
  • Patient may be unable to lie down.
• Potential management: Ketamine-dissociated cricothyrotomy
  • Place the patient on 100% FiO2 using one of the following:
    • i) High-flow nasal cannula at 100% FiO2 and 60 liters flow.
    • ii) BiPAP mask.
    • iii) 100% Non-rebreather facemask set to flush rate (crank the flow rate well past the 15 liters/min mark).
    • iv) 100% non-rebreather facemask set to 15 liters/minute plus a nasal cannula underneath it running at 15 liters/minute.
  • Provide a dissociative dose of IV ketamine (e.g. 1.5-2 mg/kg) slowly over ~120 seconds. This should fully dissociate the patient, without impairing the respiratory drive. Patients with a history of alcoholism may require more ketamine to fully dissociate.
  • Perform a scalpel-finger-bougie cricothyrotomy. The patient should continue breathing throughout the entire procedure, so you should be able to take your time a bit with this. However, if asphyxiation occurs, the procedure should be achievable very rapidly.

scenario #2: the non-crashing anaphylaxis patient

• Description
  • The patient requires intubation, but isn't actively crashing.
  • There is time to call for help and additional equipment.
• Suggested management: The awake double setup:
  • Obtain an experienced intubator and someone competent at scalpel-finger-bougie cricothyrotomy (Note: it doesn't matter whether this person is a surgeon, what matters is skill in this specific procedure).
  • Perform awake fiberoptic intubation. These patients often have tongue swelling, so the best approach is often nasotracheal intubation (for taller patients, consider obtaining an extra-long ETT for nasotracheal intubation).
  • During the intubation procedure, the second operator should be prepared to perform cricothyrotomy if the airway is lost.

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recovery

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weaning epinephrine

• The one drawback of using an epinephrine infusion is that it tends to stay on forever.
• Aggressive attempts should be made to wean the epinephrine off, ideally within some hours of admission.
• Follow the patient carefully after stopping epinephrine, and resume the infusion if symptoms recur.

steroid

• Prolonged courses are unnecessary (e.g., steroid may be stopped within 2 days).
• If dexamethasone is used initially, there is no need for any additional steroid administration.

extubation

• Patients can generally be extubated reasonably rapidly (e.g. after <24 hours). The primary determinant of readiness to extubate is visual confirmation that airway edema has improved – rather than any arbitrary time interval.(30480175)
• Evaluation of airway patency:
  • Wait for external swelling to subside (if there is observable swelling).
  • Under deep sedation, very gently insert a hyperangulated videolaryngoscope blade (e.g. a glidescope blade or a C-MAC D-blade). This should allow for direct visualization of the airway, including the epiglottis.
  • Presence or absence of cuff leak may provide some adjunctive information.
• When in doubt, consider extubation over an airway exchange catheter:
  • Leave the airway exchange catheter in place temporarily to ensure that the airway is patent.
  • If stridor occurs, re-intubation can be performed immediately over the exchange catheter.

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disposition

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duration of observation in the hospital

• Recurrent (biphasic) reactions can occur, but they are rare and tend to be less severe.
• There is little evidence supporting any specific duration of time to observe the patient prior to discharge.
• The UK Anaphylaxis Working Group recommends the following:(33895231)

discharge instructions

• (1) Patients should be prescribed an EpiPen and taught how to self-administer it.
• (2) Efforts should be made to avoid the causative agent.
• (3) Patients should be instructed to return to the hospital if a recurrent reaction occurs.
• (4) Many patients will be discharged with a short course of steroids (e.g. 1-2 days).

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failing to consider anaphylaxis (this can be a very challenging diagnosis, given the myriad of organ systems which can be involved).
• Delayed initiation of therapy.
• Inadequate use of epinephrine.
• Attempting intubation without sufficient preparation/planning.

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