What is the recommended protocol to prevent and manage reactions during intravenous immunoglobulin (IVIG) infusion?

Management of IVIG Infusion Reactions

Stop the infusion immediately at the first sign of any reaction, maintain IV access with normal saline, and manage based on reaction severity using a graded approach with slower restart rates for mild-to-moderate reactions and permanent discontinuation for severe reactions. 1

Immediate Recognition and Initial Response

When any infusion reaction is suspected, execute the following steps without delay:

• Stop the IVIG infusion immediately and keep the IV line patent with normal saline for medication administration and potential fluid resuscitation 1, 2
• Assess airway, breathing, circulation, and level of consciousness rapidly 2
• Take early warning signs seriously—patients reporting vague discomfort, feeling "odd," or urgency to urinate/defecate require immediate vital sign measurement (blood pressure and pulse) 2
• Position the patient appropriately: Trendelenburg for hypotension, upright/sitting for respiratory distress, or recovery position if unconscious 1, 3
• Administer supplemental oxygen if clinically indicated 1, 2
• Call for medical assistance immediately 1, 2

Prevention Strategies

Premedication and infusion protocols significantly reduce reaction rates but do not eliminate them entirely:

• Administer acetaminophen 650-1000 mg orally 30-60 minutes before infusion 4, 5, 6
• Consider adding antihistamines (diphenhydramine 25-50 mg) especially in patients with prior reactions 4, 5, 6
• Corticosteroid premedication may be considered for high-risk patients or those with previous severe reactions, though evidence is mixed 4, 6
• Start infusion at a slow rate (0.5-1.0 mL/kg/hour) and increase gradually only if tolerated 4, 5, 6
• Ensure adequate hydration before and during infusion, particularly in high-risk patients (elderly, diabetic, renal disease, dehydrated) 4, 5

Important caveat: Despite widespread premedication use, adverse events still occur in approximately 25-26% of patients, suggesting premedication reduces but does not eliminate reactions 7, 8

Grade-Based Management Algorithm

Grade 1 Reactions (Mild)

Symptoms: Mild headache, flushing, mild fever, fatigue, myalgia

• Slow the infusion rate to 50% of current rate 1, 6
• Administer symptomatic treatment: acetaminophen for fever/headache, antihistamines for pruritus 4, 6
• Monitor vital signs continuously 6
• Resume infusion at 50% of original rate once symptoms resolve, then gradually titrate upward as tolerated 1, 6

Grade 2 Reactions (Moderate)

Symptoms: Moderate headache, chills, nausea, vomiting, urticaria, blood pressure changes, tachycardia

• Stop the infusion temporarily 1, 6
• Administer combined H1 and H2 antihistamines (diphenhydramine 25-50 mg IV plus ranitidine 50 mg IV), which is superior to H1 antagonists alone 1
• Consider corticosteroids (methylprednisolone 40-100 mg IV) for persistent symptoms 1, 6
• Monitor vital signs until complete symptom resolution 1, 6
• Restart infusion at 50% of the previous rate only after all symptoms have resolved 1, 6
• If symptoms recur, stop permanently for that session 1

Grade 3 Reactions (Severe)

Symptoms: Symptomatic bronchospasm, significant dyspnea, hypoxia, severe hypotension, chest pain

• Stop the infusion permanently for that session 1, 2
• Provide aggressive symptomatic treatment:
  • Epinephrine 0.3-0.5 mg (1:1000) intramuscularly into lateral thigh if anaphylaxis criteria met 1
  • Fluid resuscitation: 1-2 liters normal saline rapidly at 5-10 mL/kg in first 5 minutes 1
  • Combined H1/H2 antihistamines (diphenhydramine 25-50 mg IV plus ranitidine 50 mg IV) 1
  • Corticosteroids (methylprednisolone 1-2 mg/kg IV every 6 hours) 1
  • Bronchodilators for bronchospasm 1
• Treat bradycardia with atropine 0.6 mg IV 1
• For refractory hypotension despite epinephrine and fluids, initiate vasopressors (dopamine 2-20 mcg/kg/min) 1
• Do not rechallenge during the same session 1, 2
• Future IVIG may require desensitization protocols at specialized centers 1

Grade 4 Reactions (Life-Threatening Anaphylaxis)

Symptoms: Anaphylaxis, severe respiratory failure, cardiovascular collapse, myocardial infarction

• Permanently discontinue IVIG 1, 2
• Epinephrine 0.3-0.5 mg IM immediately, repeat every 5-15 minutes as needed 1
• If inadequate response, administer IV epinephrine infusion 1
• Aggressive fluid resuscitation with crystalloids/colloids in 20 mL/kg boluses 1
• Full resuscitative measures per anaphylaxis protocols 1
• For patients on beta-blockers: glucagon 1-5 mg IV over 5 minutes followed by infusion (5-15 mg/min) 1
• Never attempt rechallenge 1, 2

Anaphylaxis Criteria (Any One Triggers Epinephrine)

Administer epinephrine immediately if the patient meets any of these three criteria 1:

1. Acute onset with skin/mucosal involvement (urticaria, angioedema) PLUS respiratory compromise OR hypotension
2. Two or more systems involved rapidly after IVIG exposure: skin, respiratory, cardiovascular, or gastrointestinal
3. Hypotension alone after known allergen exposure (systolic BP <90 mmHg or >30% decrease from baseline)

Post-Reaction Monitoring

• Monitor vital signs continuously until complete symptom resolution 1, 6
• Observe for minimum 24 hours after severe reactions to detect biphasic anaphylaxis 1, 2
• Document reaction grade, specific symptoms, timing of onset, interventions performed, and response to treatment 1
• Assess urine output and renal function, particularly in high-risk patients 4, 5

Special Populations and Risk Factors

High-risk patients requiring extra precautions 4, 5:

• Advanced age (>70 years)
• Pre-existing renal disease or dehydration
• Diabetes mellitus
• Hypertension or cardiovascular disease
• Previous thromboembolic events or immobilization
• IgA deficiency (risk of anaphylaxis)
• Receiving nephrotoxic medications concurrently

For high-risk patients: Use non-sucrose-containing IVIG products, ensure excellent hydration, infuse at slower rates (maximum 1.5 mL/kg/hour), and monitor renal function closely 4, 5

Critical Pitfalls to Avoid

• Never delay epinephrine when anaphylaxis is suspected—it is the only life-saving medication in true anaphylaxis 1, 2
• Do not restart infusion at full rate after any reaction; always resume at 50% of previous rate 1, 6
• Do not discharge patients prematurely after severe reactions—24-hour observation is mandatory to detect biphasic reactions 1, 2
• Corticosteroids do not provide acute benefit in anaphylaxis but help prevent biphasic reactions; never use them as sole therapy 1
• Do not attempt rechallenge after Grade 3-4 reactions without desensitization protocols 1, 2
• Recognize that premedication does not eliminate reactions—maintain vigilance even in premedicated patients 7
• Avoid rapid infusion rates (>1.5 mL/kg/hour), which significantly increase reaction frequency 6
• Ensure adequate hydration before infusion to prevent renal complications, especially with sucrose-containing products 4, 5

Delayed Adverse Events (Hours to Days Post-Infusion)

While most reactions are immediate, monitor for delayed complications 4, 5:

• Acute renal failure (1-10 days post-infusion): Monitor urine output, serum creatinine, especially in high-risk patients
• Thromboembolic events: Higher risk with rapid infusion, high doses, hyperviscosity, or multiple risk factors
• Aseptic meningitis: Severe headache, neck stiffness, photophobia developing 6-48 hours post-infusion
• Hemolytic anemia: Monitor for jaundice, dark urine, falling hemoglobin

Prevention of delayed events: Slow infusion rates, adequate hydration, and avoiding high-risk patients when possible 4, 5