What is the risk of rebound anaphylaxis after epinephrine (adrenaline) administration?

Risk of Biphasic (Rebound) Anaphylaxis After Epinephrine

Biphasic anaphylaxis occurs in up to 20% of patients after initial symptom resolution, though the actual risk is likely closer to 5% based on more recent data, with the vast majority of reactions occurring within 1-78 hours after the initial episode. 1

Overall Incidence

• The reported incidence ranges from 5% to 20% of all anaphylaxis cases, with the lower estimate (approximately 5%) being more consistent with contemporary data 1, 2
• Biphasic reactions can occur anywhere from 1 to 78 hours after resolution of initial symptoms, creating uncertainty about optimal observation periods 1
• Fatal biphasic anaphylaxis is extremely rare, with overall anaphylaxis fatality rates estimated at only 0.002 deaths per million person-years 2

High-Risk Features for Biphasic Reactions

Strongest Risk Factors (Requiring Extended Observation)

Patients with severe initial anaphylaxis or requiring multiple epinephrine doses have substantially elevated risk and warrant extended observation:

• Requiring >1 dose of epinephrine: OR 4.82 (95% CI, 2.70-8.58) - the strongest predictor 1
• Severe initial anaphylaxis symptoms: OR 2.11 (95% CI, 1.23-3.61) 1
• Wide pulse pressures: OR 2.11 (95% CI, 1.32-3.37) 1
• Initial presentation with hypotension: OR 2.18 (95% CI, 1.14-4.15) 1

Additional Risk Factors (Moderate Evidence)

• Unknown anaphylaxis trigger: OR 1.63 (95% CI, 1.14-2.33) 1
• Cutaneous manifestations: OR 2.54 (95% CI, 1.25-5.15) 1
• Drug-induced anaphylaxis in children <18 years: OR 2.35 (95% CI, 1.16-4.76) 1
• Glucocorticoid use in children <18 years: OR 1.55 (95% CI, 1.01-2.38) - likely a marker of severity rather than causative 1

Protective Factor

• Food as the trigger: OR 0.62 (95% CI, 0.4-0.94) - associated with decreased biphasic risk 1

Evidence-Based Observation Recommendations

For High-Risk Patients

Extended observation (≥6 hours) is recommended for patients with:

• Severe initial anaphylaxis (hypotension, wide pulse pressure) 1
• Requirement for >1 dose of epinephrine 1
• Significant comorbidities (severe asthma, cardiovascular disease) that increase fatality risk 1, 3

The number needed to monitor with extended observation to detect one biphasic episode is:

• 41 patients (range 18-195) for severe initial presentation 1
• 13 patients (range 7-27) for those requiring multiple epinephrine doses 1

For Lower-Risk Patients

A 1-hour observation may be reasonable for patients who:

• Had nonsevere anaphylaxis 1
• Responded promptly to a single dose of epinephrine 1
• Have no significant comorbidities 1
• Have reliable access to medical care following discharge 1
• Have been educated about biphasic risk and have epinephrine autoinjectors 1

Evidence supporting shorter observation:

• 1-hour observation has a 95% negative predictive value for biphasic anaphylaxis 1
• 6-hour observation increases this to 97.3% negative predictive value 1
• The incremental benefit of extended observation is only 2.3% 1

Timing of Biphasic Reactions

• Recent data shows biphasic reactions occur either within 150 minutes (2.5 hours) of initial symptom resolution or many hours later (10-33 hours post-discharge) 4
• Six of 10 biphasic reactions (60%) occurred within 150 minutes, while four occurred 10-33 hours after discharge 4
• This bimodal distribution suggests that extending observation periods within reasonable parameters (4-6 hours) may not capture late biphasic reactions 4

Critical Discharge Requirements

All patients must receive before discharge:

• Two epinephrine autoinjectors with hands-on training 1, 5, 3
• Written anaphylaxis emergency action plan 1, 3
• Education about biphasic reaction risk and when to use epinephrine 1
• Referral to allergist for comprehensive evaluation 1, 3

Important Clinical Caveats

Limitations of Preventive Medications

Antihistamines and corticosteroids do NOT reliably prevent biphasic reactions:

• No clear benefit demonstrated for H1 antihistamines (OR 0.71; 95% CI, 0.47-1.06) 1
• Evidence for glucocorticoids preventing biphasic reactions is very low certainty 1, 3
• These medications may be used for symptom relief only, not prevention 1, 3

Confounding Factors

• The association between multiple epinephrine doses and biphasic reactions is likely a marker of severity rather than epinephrine causing biphasic reactions 1
• Similarly, glucocorticoid use in children likely reflects more severe initial reactions 1

Quality of Evidence

All recommendations are based on very low-certainty evidence due to:

• Moderate to substantial heterogeneity (I² 30-90%) 1
• Low number of events (<250 biphasic reactions in meta-analysis) 1
• Different definitions of severity and cutaneous symptoms across studies 1
• Wide confidence intervals 1