Reason for admission: Elective aortic valve repair.
History: A 72-year-old man with a history of hypertension, hyperlipidemia, chronic hepatitis C, and cirrhosis came to the hospital for elective aortic valve replacement for symptomatic critical aortic stenosis. He reported no other relevant history. His surgical history included splenectomy and blood transfusion for splenic rupture during a motor vehicle accident 32 years ago. He was a former smoker (30 pack-years) and quit 10 years ago but reported no alcohol or illicit drug use. He retired seven years ago, lives with his family, and has good social support. He had no known drug allergies. His current medications were lisinopril, 20 mg/d, and atorvastatin, 40 mg/d.
Physical examination: Vitals were as follows: blood pressure, 140/70 mm Hg; heart rate, 90 beats/min; temperature, 98.5 °F; respiratory rate, 15 breaths/min; and oxygen saturation, 98% on room air. The patient was sitting comfortably on the bed. No jugular venous distension was observed. Cardiac examination showed normal rate and rhythm and normal S1 and S2 with a grade 4/6 crescendo-decrescendo systolic murmur at the right upper sternal border. Lungs were clear to auscultation bilaterally. Abdominal examination was unremarkable except for a splenectomy scar on the left upper quadrant. He had 1+ bilateral lower extremity pitting edema. The rest of the examination was unremarkable.
Labs: Preoperative workup showed a hemoglobin level of 12 g/dL, a hematocrit of 42%, a white blood cell count of 5,400 cells/µL, a platelet count of 45,000 cells/µL, a prothrombin time (PT) of 13.5 s, an international normalized ratio (INR) of 1.8, and an activated partial thromboplastin time of 33 s. The rest of his labs were unremarkable.
Clinical course: The patient underwent a moderate-risk aortic valve replacement surgery that was complicated by major intraoperative bleeding. Hemostasis was achieved after the patient received five units of packed red blood cells, three units of cryoprecipitate, three units of fresh frozen plasma, and two units of platelets. Postoperatively, the patient was hemodynamically stable and extubated.
Three hours later, he developed a temperature of 101.6 °F and shortness of breath. The use of respiratory accessory muscles was observed. His oxygen saturation was 85% on ambient air, and blood pressure was 98/45 mm Hg. A chest X-ray showed diffuse bilateral pulmonary infiltrates consistent with pulmonary congestion. He was diagnosed with transfusion-associated circulatory overload (TACO), and the transfusion was stopped immediately.
The patient was given 40 mg of IV furosemide. The hypoxia slightly improved with initiation of a 100% nonrebreather mask. The patient continued to be hypotensive. Within the next few hours, his urine output dropped significantly. He was given another 80 mg of IV furosemide. Two hours later, he became more hypoxic and hypotensive and was intubated. He remained on mechanical ventilation for the next 48 hours. He was fluid-resuscitated. His respiratory and hemodynamic status improved, and he was subsequently extubated.
Q: Was our patient diagnosed correctly?
A: No. The patient was diagnosed with transfusion-associated circulatory overload (TACO), but in fact he had transfusion-related acute lung injury (TRALI). TACO is a common transfusion reaction occurring in 0.3% to 8% of patients undergoing transfusion in the hospital setting. TACO is characterized by new-onset respiratory distress, hypertension, and hydrostatic pulmonary edema within six hours of completing a transfusion. TRALI is characterized by sudden onset of severe hypoxemia, fever, and hypotension within six hours of transfusion (1). TRALI is often associated with transfusion of platelets and fresh frozen plasma as occurred in this patient.
Keys to the diagnosis of TRALI in this patient include:
- high-grade fever
- clinical deterioration after diuretic therapy
Q: Was our patient managed appropriately?
A: No. Our patient was not medically optimized prior to surgery. His perioperative platelet count was 45,000 cells/µL. Threshold for platelet transfusion in non-neuraxial surgery is 50,000 cells/µL or lower (1). He should have received a platelet transfusion prior to aortic valve replacement. The patient's acquired coagulopathy (as demonstrated by his PT and INR levels) should have been taken into consideration before surgery. Perioperative transfusion with fresh frozen plasma could have been considered.
In addition, given that the clinical deterioration after transfusion is consistent with TRALI rather than TACO, the patient should have been managed with supportive care, i.e., supplemental oxygen and mechanical ventilation (1-4). The diuretic administration caused worsening of hypoxemia and circulatory collapse. Care should be taken in differentiating TRALI from TACO and treating patients accordingly.
Q: What else could have been done to improve care for this patient?
A: In addition to addressing perioperative coagulopathy and correctly diagnosing transfusion-related adverse reactions, clinicians can reduce the risk of TRALI by using of fresh frozen plasma and single-donor platelets collected exclusively from male donors or female donors without a history of pregnancy (5).
The decision to transfuse has commonly involved only the patient's hemoglobin concentration. However, guidelines have emphasized that the decision to transfuse should also be based on individual patient characteristics, clinical judgment, and symptoms of anemia (chest pain, shortness of breath, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure) (6).
One recommendation supported by the majority of guidelines is that transfusion is not indicated for a hemoglobin level over 10 g/dL. However, the recommended thresholds for transfusion vary from 6 g/dL to 8 g/dL. The 2016 AABB guidelines recommend the following regarding transfusion in hemodynamically stable patients without active bleeding (6):
- Transfusion is recommended if hemoglobin level is below 6 g/dL;
- Transfusion is likely indicated if hemoglobin level is between 6 and 7 g/dL;
- Transfusion may be indicated after clinically evaluating patients undergoing cardiac or orthopedic surgery if hemoglobin level is 7 to 8 g/dL;
- Transfusion is generally not indicated in patients with a hemoglobin level of 8 to 10 g/dL;
- Transfusion should be considered for patients with a hemoglobin level of 8 to 10 g/dL with symptomatic anemia or acute coronary syndrome with ischemia; and
- Transfusion is generally not indicated if hemoglobin level is above 10 g/dL.
Platelet transfusions can be given prophylactically to prevent bleeding or therapeutically during active bleeding. The platelet count serves as the trigger to transfuse when trying to prevent spontaneous bleeding; a threshold of 10,000 cells/µL is the most widely accepted value. It is associated with lower rates of hemorrhage (7), although some data are conflicting. Special considerations include fever, coagulopathy, and a need for prophylactic heparin (8). A minimum platelet count for patients with such considerations should be 20,000 cells/µL (9). It is widely accepted that patients with intracranial hemorrhage should have a minimum platelet count of 100,000 cells/µL. In patients with intracranial hemorrhage taking antiplatelet therapy such as aspirin, transfusion in excess of this amount is indicated. In other, non-central nervous system bleeding, the threshold is 50,000 cells/µL (9).
Per AABB guidelines, platelet transfusion is indicated as follows (6):
- Below 10,000 cells/µL for the hospitalized adult with therapy-induced hypoproliferative thrombocytopenia
- Less than or equal to 10,000 cells/µL for the adult hospitalized patient to reduce the risk for spontaneous bleeding
- Below 20,000 cells/µL prior to central line placement
- Below 50,000 cells/µL prior to lumbar puncture
- Below 50,000 cells/µL prior to nonneuraxial surgery
The guidelines recommend against routine prophylactic platelet transfusion for patients who are non-thrombocytopenic and having cardiac surgery with cardiopulmonary bypass. Platelet transfusion suggested for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. They recommended neither for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous).
For fresh frozen plasma (FFP), a single unit of whole blood usually yields a volume of 200 to 250 mL of standard FFP units. The recommended initial dose of FFP is 10 to 15 mL/kg of body weight.
The American Society of Anesthesiology (ASA) guideline recommendations for FFP transfusion are as follows (10):
- Excessive microvascular bleeding (i.e., coagulopathy) in the presence of an INR above 2, in the absence of heparin;
- Excessive microvascular bleeding secondary to coagulation factor deficiency in patients transfused with more than one blood volume and when PT/INR/activated partial thromboplastin time cannot be obtained in a timely fashion;
- Urgent reversal of warfarin therapy when prothrombin product concentrates (PCCs) are not available; and
- Coagulation factor deficiencies for which specific concentrates are unavailable.
When FFP is thawed at 4°C (39.2°F), a cryoprecipitate remains enriched for factors VIII and XIII, fibrinogen, and von Willebrand factor (vWF). A unit is 10 to 20 mL. Cryoprecipitate is used to treat fibrinogen deficiency, dysfibrinogenemia, and factor XIII deficiency. Cryoprecipitate can be used as a source of vWF for patients with von Willebrand disease, but vWF-containing factor VIII concentrates are preferred.
The ASA guideline recommends cryoprecipitate transfusion for patients with hypodysfibrinogenemia, defined as a fibrinolysis/fibrinogen concentration of less than 80 to 100 mg/dL in the presence of excessive bleeding. It can also be used an adjunct in massively transfused patients when fibrinogen concentrations cannot be measured in a timely fashion or for patients with congenital fibrinogen deficiencies. However, whenever possible, decisions regarding such patients should be made in consultation with the patient's hematologist.
Adverse effects of blood transfusions range from benign to life-threatening. They can be categorized as immunologic or nonimmunologic and further subdivided into acute or delayed.
Acute hemolytic transfusion reactions: These can be immune mediated or non-immune mediated and lead to intravascular hemolysis. Symptoms include fever, chills, renal failure, disseminated intravascular coagulation, and hypotension. ABO incompatibility reactions are the most serious immune-mediated reaction and are most commonly due to clerical error (11). Multiple antigens coat the red-blood cell surface and can lead to acute hemolytic transfusion reactions as well. Non-immune-mediated reactions include, but are not limited to, hot and cold thermal injury, osmotic injury, mechanical injury, drugs, and infection (12).
Delayed hemolytic transfusion reaction: Patients with this reaction usually present to an ED with history of a blood transfusion. Symptoms can include fever and jaundice. Lab results include high lactate dehydrogenase level, reticulocytosis, increased indirect bilirubin level, decreased haptoglobin level, or spherocytosis (12).
Nonhemolytic febrile reactions: In this reaction, the recipients' antibodies react to the donor's white blood cells. Symptoms include fever within two hours of transfusion with associated chills and rigors (13). It is important to notify the blood bank immediately to assess for contamination. Typical fever workup with an emphasis on sending blood cultures is imperative. Infectious processes need to be ruled out. Using leukocyte-reduced products decreases the incidence of this reaction. This is a diagnosis of exclusion.
Allergic (urticarial) reactions: These are IgE mediated. Symptoms include urticaria, pruritus, flushing, and mild wheezing. Premedicating before a transfusion has not been shown to change incidence (14).
Anaphylactoid/anaphylactic reactions: These are caused by antibodies to donor plasma proteins such as haptoglobin and C4 but most commonly occur in IgA-deficient patients. Hypotension, urticaria, bronchospasm, angioedema, and anxiety are common symptoms. Hemolysis should be ruled out before making this diagnosis.
Transfusion-associated graft-versus-host disease: These reactions are rare but almost always fatal. Signs and symptoms include pancytopenia, maculopapular rash, diarrhea, and hepatitis presenting one to four weeks after transfusion. Irradiation of blood products decreases the incidence of this reaction (1).
TRALI: This results from reformed HLA or neutrophil antibodies in donor product. Signs and symptoms include fever within six hours of transfusion, acute dyspnea, hypotension, bilateral pulmonary edema, and transient leukopenia (1). In addition, a pulmonary artery occlusion pressure of ≤18 mm Hg, exudative pulmonary edema fluid, and minimal response or deterioration after diuretic therapy can also be present (1-4). TRALI is the leading cause of transfusion-related fatalities in the United States (15).
TACO: Usually symptoms will occur after a significant portion of blood components or multiple units have been transfused in a patient with positive fluid balance. Symptoms typically include hypertension, respiratory distress (dyspnea, orthopnea) in a patient with known or unknown underlying heart failure and typically occur within six hours of completing transfusion. Vital signs and examination findings may include hypertension, tachycardia, widened pulse pressure, presence of jugular venous distension, rales and or wheezing on lung examination (1-4).
In the event that TRALI or TACO is suspected, care must be given to differentiate the two and take appropriate action. Transfusion should be discontinued in both situations. Supportive care with oxygen supplementation and respiratory support is the mainstay of therapy in TRALI. Administration of intravenous fluids and vasopressors for blood pressure support is essential. Care should be taken to avoid diuretics in TRALI. Treatment of TACO focuses on symptom management. The degree of respiratory distress determines the amount of support necessary to maintain the patient's oxygenation. Excess fluid is treated with administration of diuretics (1-4).
Proper documentation involves specifying transfusion reactions based on duration, symptoms, and specific reaction type. For example, this patient should have been accurately documented as having TRALI. Documenting the severity of a patient's condition along with comorbidities is also crucial for appropriate diagnosis-related group (DRG) and geometric mean length of stay (GMLOS) classification (Table).
In conclusion, this case demonstrates the importance of providing blood transfusions according to guidelines and properly diagnosing and documenting any adverse reactions in order to improve patient outcomes, decrease length of stay, and obtain appropriate reimbursement.