The need to link anaphylaxis signs and symptoms with targeted therapeutic strategies

Anaphylaxis is challenging to diagnose and manage for patients, caregivers, and clinicians alike, largely because there is no reference standard diagnostic test. The diagnosis instead relies on a combination of signs and symptoms from up to 5 organ systems, including the mucosal/dermatologic, gastrointestinal, respiratory, cardiovascular, and neurologic systems.^1,2 Guidelines emphasize epinephrine as the first-line anaphylaxis therapy, and repeat dosing or initiation of an epinephrine infusion is indicated for refractory cases.^3,4 Further confounding management decisions is the lack of randomized controlled trials to evaluate the efficacy of “second-line” therapies, including intravenous fluids, supplemental oxygen, bronchodilators, positive pressure ventilation, racemic epinephrine, antihistamines, and systemic glucocorticoids.⁵ Instead, existing therapeutic approaches are extrapolated from small observational studies and the care of conditions with overlapping clinical presentations, namely intravenous fluids and vasopressors for patients with distributive shock, bronchodilators and systemic corticosteroids for patients with status asthmaticus, and racemic epinephrine or intubation for patients with partial or complete upper airway obstruction.

In this issue of the Annals of Asthma, Allergy & Immunology, Shaker et al⁶ provide an in-depth review of epinephrine prescribing and anaphylaxis management. After reaction onset, the authors suggest a 1-2-3 treatment algorithm beginning with (1) prompt epinephrine administration and proper patient positioning, (2) considering the use of supplemental oxygen with or without intravenous fluids after a second epinephrine dose, and (3) intravenous fluids after the third dose. Although this approach is easy to remember and straightforward, it does not account for the inherent management differences in treating anaphylaxis in the community vs acute care settings (eg, resource allocation, responder training and experience). In addition, it does not address the complexity of treating life-threatening reactions that necessitate simultaneous epinephrine redosing while delivering targeted therapies on the basis of symptom combinations, severity, and evolving reaction features, including worsening, new, or recurrent symptoms.⁷

Although reactions may progress along a 1-2-3 course (initially, no respiratory or cardiovascular involvement, then respiratory, and next cardiovascular), others will not, especially life-threatening reactions that may rapidly progress to respiratory or cardiovascular collapse without emergent interventions.⁸ A patient with immediate onset of hypotension, respiratory distress, and wheezing should receive early and aggressive intravenous fluids to counteract massive fluid shifts and bronchodilators with or without positive pressure ventilation to treat lower airway obstruction and relieve respiratory distress. These life-saving resuscitative efforts should be initiated while simultaneously redosing epinephrine and preparing an epinephrine infusion.

Likewise, although uncommon, a patient presenting to the emergency department with rapidly progressive upper airway obstruction may require, in addition to immediate administration of epinephrine, emergent endotracheal intubation (or cricothyrotomy if the intubation is unsuccessful) given the risk of complete upper airway obstruction and respiratory arrest. In these cases, delaying symptom-targeted therapies until after the second or third epinephrine dose may result in irreversible symptom progression and adverse outcomes. Instead of linking the number of epinephrine doses with therapies (oxygen and intravenous fluids), the use of second-line therapies should be guided by symptom severity and progression, a strategy that is akin to the care of patients with cardiac arrest in which code-dose epinephrine is redosed while trying to rapidly correct hemodynamic, respiratory, or other potential causes of the arrest.⁹

Furthermore, although patients with anaphylaxis who are hypoxemic should receive supplemental oxygen, it is imperative to train health care providers to recognize and manage the underlying etiology of the hypoxemia given supplemental oxygen alone will not correct upper airway obstruction, bronchospasm, or hypoventilation, all of which may progress to respiratory arrest without timely interventions. Similarly, although intravenous fluids are indicated for patients with hypotension or signs of cardiovascular dysfunction (eg, delayed capillary refill, rising heart rate not related to epinephrine, declining mental status), providers must be able to quickly identify patients with life-threatening cardiovascular involvement that may progress to cardiac arrest unless aggressively treated with vasoactive agents and aggressive intravenous fluid resuscitation.⁹

Although the proposed 1-2-3 anaphylaxis algorithm may result in reaction under resuscitation, linking oxygen and intravenous fluids to second and third epinephrine doses may inadvertently result in therapeutic overutilization for patients who require repeat dosing because of nonsevere persistent or recurrent dermatologic/mucosal and gastrointestinal symptoms. To date, and to the best of our knowledge, there is no solid evidence supporting the routine use of supplemental oxygen, intravenous access, or intravenous fluids for patients without respiratory or cardiovascular involvement.^3,5 Linking these therapies to the number of epinephrine doses may result in medication overuse, mounting health care costs, and unnecessarily long observation periods to wean and discontinue these therapies. Instead, a more practical and patient-specific approach is that all patients, especially those who require multiple epinephrine doses, should be closely monitored for examination findings that may signify clinical deterioration or the need for symptom-directed therapies and advanced resuscitative efforts.

In conclusion, although I applaud the authors’ efforts to try and simplify anaphylaxis treatment recommendations into a 1-2-3 algorithm, we should not shy away from the complexity and challenge of targeted anaphylaxis management owing to the risk of both reaction under- and over-resuscitation. Despite the lack of evidence supporting second-line anaphylaxis therapies, randomized controlled trials of these treatments are not feasible because of inherent study design challenges and because there would not be equipoise to withhold intravenous fluids for hypotensive patients, bronchodilators for those with wheezing, or oxygen for patients with hypoxemia or respiratory distress. However, this does not mean that the complexity of anaphylaxis management cannot be allayed. The practical and nuanced review by Shaker et al⁶ highlights the need to develop innovative and intuitive patient and clinician support tools and technologies to optimize anaphylaxis recognition, epinephrine utilization, and the appropriate, personalized, and timely use of symptom-directed therapies and life-saving resuscitative efforts.⁵