Apheresis: Complications

• Reported per-procedure complication rates in pediatrics vary widely (12-55%), but are usually minor and the procedure is generally well tolerated [PMID 17880609, 31852113, 32949283]

  • Most common complications include: access/circuit/device problems, hypotension, hypocalcemia/hypocalcemic symptoms, allergic reactions (especially urticaria/pruritus), minor bleeding

Complications that occur during apheresis can be broadly categorized into one of the following:

• Access/circuit/device

• Transfusion of blood products

• Removal of clotting factors, immunoglobulins

• Metabolic

• Unintended removal of therapeutic agents

• Citrate anticoagulation

  • Citrate chelates calcium, an essential cofactor in the coagulation cascade, forming calcium citrate

    • Assuming normal liver function, metabolized in the liver within 1.5 hours

• Fresh frozen plasma (FFP) replacement, which contains a substantial citrate load

  • A bag of FFP is ~15% citrate by volume (~7 mmol of citrate per unit) [PMID 22532037]

• Albumin replacement, likely due to the binding of ionized calcium to the infused albumin

• Hypocalcemic symptoms may be related to a rapid decrease in ionized calcium rather than the absolute value of the level [PMID 12423519]

• Ensure the ionized calcium is normal before starting the procedure

  • If hypocalcemic, replenish with calcium before starting

• Monitor for symptoms of hypocalcemia

  • Consider cardiac monitoring and intraprocedural ionized calcium measurement, especially in patients with altered mental status or who are too young to report symptoms

  • Patients with underlying cardiac conditions (e.g., arrhythmias, history of transplant) may be particularly sensitive to lowering of ionized calcium and warrant extra attention

Citrate anticoagulation (or citrate+heparin): administer continuous IV calcium infusion

• Calcium gluconate (CaGluc) 10%

  • 10 mL in 50 mL NS: 1 mL/kg/h

• Calcium chloride (CaCl₂)

• Intermittent IV calcium (e.g., PRN for symptoms) is rarely used in children undergoing apheresis

  • Calcium gluconate (CaGluc) 10%

    • 100-200 mg/kg IV over 5-10 min (max rate of 5 mL/min)

Other anticoagulation: consider an oral calcium regimen or continuous IV calcium infusion

• Oral calcium regimen:

  • Calcium carbonate (CaCO₃)

    • 10 mg/kg before the procedure, then every hour [PMID 17880609]

    • For children >11 years, 1500 mg before the procedure, then 1500 mg every 30-60 minutes (max of 7500 mg) [CNMC]

      • 1500 mg calcium carbonate is 2x 750 mg tablets (300 mg elemental calcium each)

  • Calcium gluconate (CaGluc) 10%

    • 100-200 mg/kg 1 hour after starting the procedure [PMID 9180913]

  • A calcium-containing isotonic sports drink

• Intravenous continuous infusion:

  • Calcium chloride 8000 mg in 1000 mL of 0.9% NS (0.8 mg/mL): start at 5 mg/kg/h (4 mL/kg/h) and titrate to a goal iCa (typically 1.1-1.3 mmol/L)

    • Example titration parameters:

      • ≥20 kg: for iCa >1.3, ↓ rate by 10 mL/h. For iCa 1.1-1.3, no change. For iCa 0.9-1.09, ↑ rate by 10 mL/h. For iCa <0.9, ↑ rate by 20 mL/h.

      • <20 kg: for iCa >1.3, ↓ rate by 5 mL/h. For iCa 1.1-1.3, no change. For iCa 0.9-1.09, ↑ rate by 5 mL/h. For iCa <0.9, ↑ rate by 10 mL/h.

Albumin replacement:

• Calcium can be added (by pharmacy, using sterile syringes) directly to the albumin bottles:

  • CaGluc 10%:

    • 2-3 mL per 250 mL bottle of albumin [1]

    • 1 mEq (~2.15 mL) per 500 mL bottle of albumin [PMID 17722047]

      • [PMID 17722047] cites the above reference as the source for the recommendation of 1 g CaGluc (10 mL) per 1 L albumin (5 mL per 500 mL bottle)

  • CaCl₂ 10%:

    • 2 mmol/L (4 mEq/L, 2.94 mL) added to albumin (0.5 mmol per 250 mL bottle of albumin) [PMID 17647024]

Plasma replacement:

• Calcium bolus can be infused at regular intervals as FFP is given:

  • CaGluc 10%:

    • 2-3 mL IV bolus administered over 10 minutes (or as continuous infusion) for each 100 mL of FFP [1]

    • E.g., for FFP replacement volume of 1500 mL, 2-3 mL CaGluc per 100 mL FFP yields 30-45 mL total

      • If estimated treatment time is 90 minutes, CaGluc infusion rate would be 20-30 mL/h

Severe reactions:

• Hypocalcemic tetany, iCa <0.75 mmol/L, arrhythmias, EKG changes, hypertension:

  • CaGluc 10%: 0.5-1 mL IV over 10 minutes

    • May use peripheral line, but avoid scalp veins or small (hand/foot) veins to limit risk of extravasation, which can cause skin necrosis and sloughing

  • CaCl₂ 10%: 20 mg/kg (0.2 mL/kg) IV over 10 minutes via central line

  • If cardiac symptoms do not improve with calcium replacement, also correct hypomagnesemia

Hypokalemia

• 2 mEq per 500 mL bottle of albumin [PMID 17722047]

• 
  

• Drugs that are primarily intravascular are removed more effectively with plasma exchange

  • Typically, higher protein binding and lower volume of distribution (V_D) result in higher intravascular levels and therefore greater removal with plasmapheresis

  • Also impacted by a wide variety of other factors:

    • Patient variability in V_D

    • Drug half-life (t_1/2)

    • Timing of drug administration

    • Serum levels may not correspond to biological effects

    • Duration and frequency of treatment

    • Replacement fluid used

• Where possible, medications should be timed to be given after the plasma exchange procedure

• https://academic.oup.com/ajcp/article/148/3/190/4057092

• 2007: https://pubmed.ncbi.nlm.nih.gov/17963462/

• Associated with circuit/access

  • Pressure problem (insufficient inflow or outflow)

  • Circuit clotting

  • Catheter clotting

  • Catheter infection

    • Increased risk in femoral lines compared to neck

  • Hematoma/bleeding

    • Typically minor, at the catheter site

  • Pain

  • Air in circuit (rare, <1%)

• Associated with transfusion of blood products

  • Allergy/anaphylaxis to plasma

  • Febrile reactions

  • Hemolytic reactions

  • Transfusion-transmitted diseases

  • Hypocalcemia

• Metabolic

  • Citrate-related

  • Hypocalcemia

  • Hypokalemia: due to dilution (particularly with albumin replacement [PMID 6159932]) and/or citrate-induced alkalemia

  • Alkalosis

    • ↑ risk in kidney failure (inability to excrete the

• Hematologic

  • Anemia

  • Dilutional

  • E.g., clotting of the circuit and loss of the extracorporeal blood volume

• Procedural anxiety

  • Anxiety, agitation

  • Fever, chills

  • Hypoxemia

  • Significant anemia

• Unintended removal of drugs (e.g., antibiotics, vasopressors)

• Lack of efficacy

• Loss of platelets

• Heparin

• Low fibrinogen, especially with multiple treatments

Complication rates

• Relatively common complications (5-15%) include:

  • Hypotension

• • • ↑↑ risk if on vasopressors

    • ↑ risk if low preprocedure hematocrit or if albumin replacement is used

    • If using a membrane filter in a patient on an ACEi (and potentially ARB), hold the medication for at least 24 hours prior to the procedure

  • Hypocalcemia, with or without symptoms

  • Allergic reactions (4.4%)

• Urticaria/rash, pruritus

  • ↑ risk if using FFP replacement

• Hypertension

• Chills and fever

• Rash/urticaria

• Pruritus

• Agitation, anxiety

• Chest pain, palpitations

• Lightheadedness

• Angioedema, shock

• Nausea, vomiting (5.3%)

• Abdominal pain (6.6%)

• Paresthesias (4%)

• Pallor (1.8%)

• Diaphoresis (0.4%)

• Headaches (1.9%)

• Hypoxemia

• Bleeding

• Life-threatening adverse effects are uncommon:

  • Angioedema

  • Anaphylaxis

  • Shock

  • Respiratory failure

  • Seizure