Transfusion Complications, Emergency Medicine

Basics

Epidemiology

Of 39 million hospital discharges in US, 5.8% (2.3 million) were associated with blood transfusions (2004).
In 2011 there were 30 deaths in US fully attributable to transfusion complications.
Some type of transfusion reaction occurs in 2% of units transfused within 24 hr of use.
Noninfectious complications:
- Febrile nonhemolytic reaction: RBCs 1 in 500 transfusions, platelets 1 in 900
- Allergic reaction (nonanaphylactic): 1 in 3 to 1 in 300
- Anaphylaxis: 1 in 20,000 to 1 in 50,000
- Acute hemolytic reaction: 1 in 38,000 to 1 in 70,000
- Delayed hemolytic reaction: 1 in 4,000 to 1 in 11,000
- Transfusion-associated circulatory overload (TACO): 1 in 100, but as high as 10% in susceptible populations
- Alloimmunization: 1 in 10 to 1 in 100
- Graft-versus-host disease: 1 in 400,000; rare but has >90% mortality.
- Transfusion-related lung injury (TRALI): 1 in 5,000 to 1 in 190,000; represents 13% of reported transfusion-related deaths
- Iron overload: Unknown incidence, depends on volume of blood, often occurs after >100 RBC units
- Hypocalcemia: Unknown incidence
- Hyperkalemia: Unknown incidence
Infectious complications:
- Bacterial contamination: RBCs 1 in 65,000 to 1 in 500,000; platelets 1 in 1,000 to 1 in 10,000:
  - Most common bacterial agents: Yersinia enterocolitica, Pseudomonas spp, Serratia spp.
  - Leading cause of mortality among infectious complications; 17 " “22% of all cases
- Hepatitis C: 1 in 1.6 million
- Hepatitis B: 1 in 100,000 to 1 in 400,000
- HTLV I and II: 1 in 500,000 to 1 in 3 million
- HIV: 1 in 1.4 million to 1 in 4.7 million
- HAV: 1 in 1,000,000
- B19 parvovirus: 1 in 40,000; post-transfusion anemia rare with scattered case reports
- Parasites: Babesia and malaria: <1 in 1 million
- Parasites: Trypanosoma cruzi: 1 in 42,000
- Case reports of Epstein " “Barr virus, Lyme disease, brucellosis, human herpesvirus, Creutzfeldt " “Jakob disease

Acute Intravascular Hemolytic Transfusion Reaction

Mortality and morbidity correlate with amount of incompatible blood transfused (symptoms can occur with exposure to as little as 5 " “20 mL)
Occurs immediately from:
- ABO incompatibility
- Blood type identification error
- Incompatible transfused cells immediately destroyed by antibodies
Intravascular hemolysis causing activation of coagulation system, leading to inflammation, shock, and DIC
Mediators (cytokines) released during inflammatory response
Renal failure:
- Cytokines cause local release of endothelin in kidney, causing vasoconstriction.
- Leads to parenchymal ischemia and acute renal failure
Respiratory failure owing to pulmonary edema/adult ARDS:
- Free hemoglobin (Hb) causes vasoconstriction in pulmonary vasculature.

Other Transfusion-related Complications

Hemolysis because of Rh incompatibility:
- Mild, self-limiting
- 1:200 U transfused
Febrile nonhemolytic transfusion reaction:
- Most common transfusion reaction, diagnosis of exclusion.
- Temperature increases at least 1 ‚ °C with chills within 6 hr
- Antigen " “antibody reaction to transfused blood components (WBCs, platelets, plasma)
- Usually mild
- Occurs more often with multiparous women or multiple transfusions
- Recurs in 15% of patients
- Acetaminophen may be used prophylactically; its use as premedication is controversial, though not harmful.
Allergic transfusion reaction:
- Occurs in 1% of transfusions
- Usually seen with immunoglobulin A (IgA) " “deficient patients
- Urticaria alone is not a reason to stop transfusion.
- Antihistamine may be used as therapy or prophylactically.
Premedicating with acetaminophen and diphenhydramine found to have no effect on incidence of transfusion reaction compared with placebo in some trials.

Delayed Reactions

Infection:
- HIV, hepatitis B, hepatitis C
  - Blood screened for viruses
  - Blood treated to inactivate viruses
  - Blood donors with recent history of travel or poor health are deferred from donating.
Delayed extravascular hemolytic reaction:
- Occurs 7 " “10 days after transfusion
- Antigen " “antibody reaction that develops after transfusion
- Coombs test positive
- Usually asymptomatic
- Blood bank analysis detects antibody
Electrolyte imbalance:
- Hypocalcemia: Calcium binds to citrate
- Hyper/hypokalemia: Citrate metabolized to bicarbonate, which drives potassium intracellularly; prolonged storage of blood may cause hemolysis and hyperkalemia
Graft-versus-host disease:
- Fatal in >90%
- Immunologically competent lymphocytes transfused into immunocompetent host
- Host unable to destroy new WBCs
- Donor WBCs recognize host as foreign and attack hosts tissues.
Anaphylactic reaction:
- Can occur with <10 mL of exposure
- Generalized flushing, urticaria, laryngeal edema, bronchospasm, profound hypotension, shock, or cardiac arrest.
- Treat with subcutaneous epinephrine, supportive hemodynamic and respiratory care.
TRALI:
- Symptoms typically begin with 6 hr of transfusion.
- Acute onset of respiratory distress, bilateral pulmonary edema, fever, tachycardia, hypotension, with normal cardiac function
- 3rd most common cause of fatal transfusion
- Difficult to distinguish from ARDS and TACO; often misdiagnosed and underreported
- Provide supportive care.
- Disease is typically self-limited within 96 hr.
- Mortality is 5 " “10%.
- Diuretics contraindicated

Blood can be transfused through 22G peripheral catheter under pressure (but <300 mm Hg) with minimal hemolysis. ‚

Diagnosis

Signs and Symptoms

General:
- Fevers
- Chills
- Burning at infusion site
- Urticaria/pruritus/skin erythema
Pulmonary:
- Dyspnea
- Bronchospasm
- Respiratory distress/failure
Cardiovascular:
- Tachycardia
- Hypotension
- Substernal chest pain/tightness
GI:
- Nausea
- Vomiting
- Diarrhea
Hematologic:
- Bleeding
- Hemoglobinuria
- Oozing from surgical wounds
- Jaundice
- DIC
Miscellaneous:
- Low back pain
- Renal failure (oliguria/anuria)
- Classic triad of fever, flank pain, and red-brown urine of acute hemolytic reactions is rarely seen.

Essential Workup

Recognize clinical findings of transfusion reaction.
Recheck identifying information of blood and patient compatibility.
Recognize evidence of hypotension/shock, severe respiratory distress, sepsis, fever, and urticaria; intervene appropriately.

Diagnosis Tests & Interpretation

Lab

CBC
Electrolytes, BUN, creatinine, glucose:
- For electrolyte abnormalities
PT, PTT
Serum calcium
Fibrinogen, fibrin degradation products
Bilirubin (direct/indirect)
Coombs test
Hemoglobinemia:
- Pink or red supernatant of plasma or serum indicates hemolysis.
Urinalysis:
- Hemoglobinuria: Dipstick-positive blood without RBCs on micro
Lab findings indicating hemolysis:
- Thrombocytopenia (<100,000)
- Fibrinogenopenia (<150 mg/L)
- Fibrin degradation products
- Prolonged activated PTT (aPTT)
- Spherocytosis
Lab findings indicating hemolysis due to Rh incompatibility:
- Positive Coombs test
- Elevated indirect bilirubin
- Post-transfusion Hb/hematocrit not showing expected rise

Imaging
Chest radiograph: Diffuse patchy infiltrates without cardiomegaly if TRALI. ‚
Diagnostic Procedures/Surgery
ECG for dysrhythmia, sign of electrolyte abnormality ‚

Differential Diagnosis

Sepsis
Anaphylaxis/allergic reaction to medication

Treatment

Pre-Hospital

Routine stabilization ‚

Initial Stabilization/Therapy

Immediately stop infusion:
- Severity of reaction proportional to amount of blood transfused
ABCs
Supplemental oxygen " ”intubation and mechanical ventilation if needed
Recheck blood-identifying information " ”patients bracelet, blood labels, call blood bank

Ed Treatment/Procedures

Hypotension:
- 0.9% normal saline (NS) hydration with 2 large-bore IVs
- Avoid Ringer lactate or solutions containing dextrose.
- Trendelenburg position
- Dopamine
Prevention of renal failure:
- Maintain urine output of 1 mL/kg/h
- Adequate hydration
- Furosemide or mannitol if oliguric
- Dopamine infusion at 2 Ž ¼g/kg/min
Febrile reactions:
- Antipyretics (acetaminophen/nonsteroidal anti-inflammatory drugs [NSAIDs])
- Antihistamine (diphenhydramine + ranitidine) IV
- Steroids (methylprednisolone)
Allergic reactions:
- Antihistamine (diphenhydramine + ranitidine) IV
- Epinephrine for respiratory symptoms
- Steroids (methylprednisolone)
Redraw blood sample for repeat ABO/Rh typing, direct antiglobulin testing.
Foley catheter to monitor urine output
Replenish calcium if hypocalcemia develops.
Treat DIC

Medication

Calcium gluconate: 10 mL of 10% (peds: 100 mg/kg/dose) solution slow IV push
Dopamine: 2 " “20 Ž ¼g/kg/min IV
Diphenhydramine: 25 " “50 mg (peds: 1.25 mg/kg) IV or PO
Ranitidine: 50 mg IV (peds: 1 " “2 mg/kg/dose max. 50 mg)
Epinephrine (1 in 1,000): 0.3 " “0.5 mL (peds: 0.01 mL/kg) SC
Methylprednisolone: 125 mg (peds: 2 mg/kg) IV

Follow-Up

Disposition

Admission Criteria

Acute hemolytic transfusion reaction, pulmonary complications, anaphylaxis, sepsis:
- Require ICU monitoring
Delayed hemolytic transfusion reactions for evaluation/treatment
Electrolyte abnormalities requiring cardiac monitoring

Discharge Criteria
Uncomplicated febrile or allergic reaction ‚

Pearls and Pitfalls

Blood transfusion is substantially over utilized and has significant associated risk, such as transfusion reactions, transmission of pathogens, and immune suppression.
Maintaining body temperature during massive transfusion is crucial to correcting coagulopathy.
Failure to properly compare patient identification to labeling on blood or failure to wait for fully cross-matched blood carries significant risks.
Suspect acute intravascular hemolysis if patient develops hypotension, dark urine, or oozing from IV or other puncture sites.

Additional Reading

Bakdash ‚ S, Yazer ‚ MH. What every physician should know about transfusion reactions. CMAJ. 2007;177:141 " “147.
Goodnough ‚ LT, Levy ‚ JH, Murphy ‚ MF. Concepts of blood transfusion in adults. Lancet. 2013;381:1845 " “1854.
Morton ‚ J, Anastassopoulos ‚ KP, Patel ‚ ST, et. al. Frequency and outcomes of blood products transfusion across procedures and clinical conditions warranting inpatient care: An analysis of the 2004 healthcare cost and utilization project nationwide inpatient sample database. Am J Med Qual. 2010;25:289 " “296.
Spahn ‚ DR, Goodnough ‚ LT. Alternatives to blood transfusion. Lancet. 2013;381:1855 " “1865.
Squires ‚ JE. Risks of transfusion. South Med J. 2011;104(11):762 " “769.

Codes

ICD9

780.66 Febrile nonhemolytic transfusion reaction
999.80 Transfusion reaction, unspecified
999.84 Acute hemolytic transfusion reaction, incompatibility unspecified
999.85 Delayed hemolytic transfusion reaction, incompatibility unspecified
276.61 Transfusion associated circulatory overload
279.50 Graft-versus-host disease, unspecified
518.7 Transfusion related acute lung injury (TRALI)
999.83 Hemolytic transfusion reaction, incompatibility unspecified
999.89 Other transfusion reaction

ICD10

R50.84 Febrile nonhemolytic transfusion reaction
T80.910A Acute hemolytic transfusion reaction, unspecified incompatibility, initial encounter
T80.92XA Unspecified transfusion reaction, initial encounter
T80.911A Delayed hemolytic transfusion reaction, unspecified incompatibility, initial encounter
D89.813 Graft-versus-host disease, unspecified
E87.71 Transfusion associated circulatory overload
J95.84 Transfusion-related acute lung injury (TRALI)
T80.919A Hemolytic transfusion reaction, unspecified incompatibility, unspecified as acute or delayed, initial encounter

SNOMED

82545002 Blood transfusion reaction (disorder)
435001000124103 Febrile transfusion reaction without hemolysis (disorder)
36617002 Immediate hemolytic transfusion reaction (disorder)
83250000 Delayed hemolytic transfusion reaction (disorder)
234646005 Graft-versus-host disease (disorder)
361098001 Allergic transfusion reaction (disorder)
389078002 Transfusion related acute lung injury (disorder)
79337003 Anaphylactic transfusion reaction

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