What are the guidelines for managing infusion reactions?

Management of Infusion Reactions

Immediately stop the infusion and assess for anaphylaxis versus cytokine-release/hypersensitivity reaction, as this distinction determines whether epinephrine is administered emergently or whether symptomatic management with rate adjustment suffices. 1

Initial Assessment and Stabilization

When an infusion reaction occurs, take the following immediate steps:

• Stop the medication infusion immediately but maintain IV access with normal saline to keep the vein open 1
• Assess ABCs (Airway, Breathing, Circulation) and level of consciousness 1
• Position the patient appropriately: Trendelenburg for hypotension, sitting upright for respiratory distress, recovery position if unconscious 1
• Administer supplemental oxygen if needed 1
• Call for medical assistance as soon as possible 1
• Monitor vital signs continuously until complete resolution 1

Critical early warning signs: Patients may feel odd, uncomfortable, or express a sudden need to urinate or defecate before an infusion reaction manifests—these symptoms must be taken seriously and prompt immediate blood pressure and pulse rate measurement 1

Distinguish Anaphylaxis from Hypersensitivity Reaction

If Anaphylaxis is Suspected (IgE-Mediated)

Administer epinephrine 0.2-0.5 mg (1 mg/mL) intramuscularly into the lateral thigh immediately, repeating every 5-15 minutes as needed 1

Additional management for anaphylaxis:

• Aggressive fluid resuscitation: Normal saline 1-2 L IV at 5-10 mL/kg in first 5 minutes, then crystalloids or colloids in 20 mL/kg boluses followed by slow infusion 1
• H1/H2 antagonists: Diphenhydramine 50 mg IV plus ranitidine 50 mg IV 1
• Corticosteroids: Equivalent to 1-2 mg/kg IV methylprednisolone every 6 hours (prevents biphasic reactions but not critical for acute management) 1
• If bradycardia develops: Atropine 600 μg IV 1
• If hypotension persists despite epinephrine and fluids: Dopamine 400 mg in 500 mL at 2-20 μg/kg/min OR vasopressin 25 units in 250 mL (0.1 U/mL) at 0.01-0.04 U/min 1
• If patient on beta-blockers: Glucagon 1-5 mg IV infusion over 5 minutes 1

If Cytokine-Release/Hypersensitivity Reaction (Non-Anaphylactic)

Management is graded by severity:

Grade 1 (Mild):

• Slow the infusion rate to 50-60 mL/h 1, 2
• Monitor closely for progression 1
• Most reactions are self-limiting and resolve spontaneously within 15 minutes 1

Grade 2 (Moderate):

• Stop or significantly slow the infusion 1
• Administer H1/H2 antagonists: Diphenhydramine 50 mg IV plus ranitidine 50 mg IV 1
• Corticosteroids: Equivalent to 1-2 mg/kg IV methylprednisolone every 6 hours 1
• After symptom resolution, restart infusion at 50% of original rate and titrate to tolerance 1

Grade 3 (Severe):

• Stop the infusion completely 1
• H1/H2 antagonists: Diphenhydramine 50 mg IV plus ranitidine 50 mg IV 1
• Corticosteroids: Equivalent to 1-2 mg/kg IV methylprednisolone every 6 hours 1
• Rechallenge is discouraged in severe reactions 1
• If symptoms improve to Grade 2, may attempt restart at half rate with extreme caution 1

Grade 4 (Life-Threatening):

• Permanently discontinue the drug 1
• Treat as anaphylaxis with epinephrine and aggressive supportive care 1

Symptom-Directed Treatment

For specific symptoms during mild-moderate reactions:

• Nausea: 5-HT3 antagonist (ondansetron 4-8 mg IV) 1
• Urticaria: Second-generation antihistamine (loratadine 10 mg PO or cetirizine 10 mg IV/PO) 1
• Mild hypotension: Normal saline IV to maintain systolic BP >100 mmHg 1

Critical Pitfalls to Avoid

Never use first-generation antihistamines (diphenhydramine) or vasopressors for mild infusion reactions, as these can convert minor reactions into hemodynamically significant events including exacerbation of hypotension, tachycardia, diaphoresis, sedation, and shock 1

Never delay epinephrine administration if anaphylaxis is suspected—this is the single most important intervention 2

Avoid corticosteroids alone without antihistamines in acute reactions 2

Rechallenge Protocol

After complete symptom resolution in Grade 1-2 reactions:

• Wait approximately 15 minutes after symptoms resolve 1
• Restart infusion at 50% of the initial rate 1
• After 15 minutes of tolerance, gradually increase to desired rate 1
• If symptoms recur, stop infusion and manage as described above 1

Do not rechallenge in cases of suspected IgE-mediated anaphylaxis or Grade 4 reactions 1, 2

Post-Reaction Monitoring

• Monitor vital signs continuously until complete resolution of all symptoms 1
• 24-hour observation is mandatory after severe reactions 1, 2
• Counsel patients about possible delayed reactions (flu-like symptoms, arthralgias, myalgias, fever) occurring hours to days post-infusion, manageable with NSAIDs 1
• Document thoroughly: Record specific symptoms, timing of onset, treatments administered, and response 2

There is no physiological basis for routine 30-minute post-infusion observation in uncomplicated infusions, as IV medications are not associated with severe delayed reactions 1

Drug-Specific Premedication Considerations

Cetuximab: Requires premedication with corticosteroids plus antihistamines 1, 2

Rituximab: Premedicate with antipyretic (paracetamol) and antihistamine (diphenhydramine); use slow initial infusion rate 1, 2

Ofatumumab: Premedicate 30 minutes to 2 hours before with paracetamol 1 g PO, antihistamine (diphenhydramine 50 mg or cetirizine 10 mg), and IV corticosteroid (prednisolone 50-100 mg depending on disease status) 1, 2

Daratumumab: Premedicate 1 hour before every infusion with IV corticosteroid (methylprednisolone 100 mg), oral antipyretic (paracetamol 650-1000 mg), and oral/IV antihistamine (diphenhydramine 25-50 mg) 1

PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, durvalumab): Premedication is NOT routinely recommended; consider only after a prior infusion reaction 1, 2, 3

Panitumumab: Premedication is NOT recommended 1