What is the recommended management for infusion reactions?

Management of Infusion Reactions

For mild to moderate infusion reactions (Grade 1-2), immediately stop or slow the infusion rate and provide symptomatic treatment with antihistamines; for severe reactions (Grade 3-4), stop the infusion completely, administer epinephrine 0.3-0.5 mg intramuscularly for anaphylaxis, provide aggressive symptomatic treatment including corticosteroids, and permanently discontinue the drug in most cases. 1, 2

Immediate Recognition and Grading

When an infusion reaction occurs, the first critical step is to stop the infusion immediately and assess the severity using a grading system 2:

• Grade 1-2 reactions present with fever, chills, pruritus, flushing, mild rash, mild dyspnea, mild hypotension, or nausea 3
• Grade 3 reactions involve significant bronchospasm, severe hypotension, severe dyspnea, severe urticaria, or angioedema 3
• Grade 4 reactions are life-threatening and include anaphylaxis, cardiac/respiratory arrest, or severe bronchospasm requiring ventilation 3

Evaluate ABCs (Airway, Breathing, Circulation), level of consciousness, position the patient appropriately, and call for medical assistance immediately for severe reactions 2.

Acute Management by Severity

Grade 1-2 (Mild to Moderate) Reactions

• Stop or slow the infusion rate to 50-60 ml/h 1, 4
• Administer symptomatic treatment with H1 antihistamines (e.g., diphenhydramine 50 mg) 1
• Once symptoms resolve, restart the infusion at half the previous rate and titrate to tolerance 1
• Monitor vital signs continuously until complete resolution 2

Grade 3 (Severe) Reactions

• Immediately stop the infusion 1, 3
• Provide aggressive symptomatic treatment including H1/H2 antihistamines and corticosteroids 2
• After complete resolution of symptoms, treatment may be resumed at half the previous rate (drug-specific; see below) 1, 3
• Consider 24-hour observation 2

Grade 4 (Life-Threatening) Reactions

• Permanently discontinue the infusion 1
• Administer epinephrine 0.3-0.5 mg (1 mg/mL) intramuscularly into the lateral thigh muscle immediately 2, 5
• Repeat epinephrine every 5-10 minutes as necessary 5
• Provide adjunctive medications: H1/H2 antihistamines, corticosteroids, and atropine 600 μg IV if bradycardia develops 2
• Consider ICU admission for monitoring 3

Critical pitfall: Never delay epinephrine administration in suspected anaphylaxis—this is the most common error in management 2, 6. Studies show that only 56% of fellows administered epinephrine appropriately in simulated grade-4 reactions 6.

Drug-Specific Management Considerations

Management varies significantly by agent 1:

High-Risk Agents Requiring Premedication

• Rituximab (77% reaction rate): Premedicate with antipyretic and antihistamine; use slow initial infusion rate 1, 3
• Cetuximab (90% reaction rate, 2-5% severe): Premedicate with corticosteroids plus antihistamines 1, 2
• Ofatumumab (61% reaction rate): Premedicate with paracetamol 1g, antihistamine (diphenhydramine 50 mg or cetirizine 10 mg), and IV corticosteroid (prednisolone 50-100 mg) 30 minutes to 2 hours before infusion 1
• Blinatumomab (44-67% reaction rate): Premedicate with dexamethasone 20 mg IV 1 hour before infusion 1

Low-Risk Agents NOT Requiring Routine Premedication

• PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab): <1-5% reaction rate; premedication NOT recommended initially 1, 2, 7
• Panitumumab (4% reaction rate): Premedication NOT recommended 1
• Trastuzumab (20-40% reaction rate, <1% severe): Premedication NOT recommended 1
• Bevacizumab (<3% reaction rate): Premedication NOT recommended 1

Important distinction: Do not confuse drug-specific requirements—applying unnecessary premedication (especially corticosteroids) to low-risk agents like durvalumab exposes patients to steroid-related side effects without benefit 7.

Rechallenge and Subsequent Infusions

When to Permanently Discontinue

• All Grade 4 (anaphylaxis) reactions 1, 2
• Grade 3-4 reactions with PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab) 1, 2
• Grade 4 reactions with panitumumab, ofatumumab, ipilimumab 1

When Rechallenge May Be Considered

For Grade 1-2 reactions and some Grade 3 reactions with certain agents 1, 3:

• Implement premedication with antipyretics and antihistamines for subsequent infusions 1, 2
• Start infusion at slower rate (50-60 ml/h) 4
• Gradually increase infusion rate over subsequent treatments as tolerated 4, 8
• Most patients can resume normal infusion schedules without premedication after 8 weeks to 3.5 years 8

For platinum agents or taxanes with prior Grade 3-4 reactions, consider desensitization protocols 2.

Post-Reaction Documentation and Monitoring

• Record specific symptoms, timing of onset, and treatments administered 2
• Consider measuring tryptase levels 15 minutes to 3 hours after onset if anaphylaxis is suspected 2
• Observe patients for minimum 1-2 hours after infusion completion 3
• Educate patients about potential delayed reactions up to 24 hours after infusion 3
• Establish steps to prevent future episodes based on the precipitating drug and characteristics of the event 1

Common Pitfalls to Avoid

• Never delay epinephrine in suspected anaphylaxis—this is the single most critical error 2, 6
• Do not use corticosteroids alone without antihistamines in acute reactions 2
• Avoid unnecessary premedication with agents that don't require it (PD-1/PD-L1 inhibitors, panitumumab, trastuzumab) 2, 7
• Do not administer repeated epinephrine injections at the same site as vasoconstriction may cause tissue necrosis 5
• Do not confuse first-dose sensitization patterns—ipilimumab reactions occur more frequently after the first dose, while rituximab reactions are most common on first infusion 1, 3