Transfusion Reactions In The ED

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Author: Jim Kenny, MD (EM Resident Physician, PGY-2, NUEM) // Edited by: Samia Farooqi, MD (EM Resident Physician, PGY-4, NUEM) // Expert Commentary: Sarah Choi, MD PhD & Paul Lindholm, MD

Citation: [Peer-Reviewed, Web Publication] Kenny J, Farooqi S (2016, May 3). Transfusion Reactions In The ED. [NUEM Blog. Expert Commentary by Choi S & Lindholm P]. Retrieved from http://www.nuemblog.com/blog/transfusion-reactions

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Introduction

While the incidence of severe transfusion reactions is 0.09% (1/1111), the total incidence of all transfusion reactions is approximately 0.25% (1/400). Therefore, the likelihood that each emergency physician will see one is high, and we should all know the presentation, evaluation, and management of these complications. We will focus mainly on acute reactions here, as they are the most likely to occur in the ED.  However, if you rotate through an ICU, or practice in an institution where you are likely to see patients who present a few days after transfusions, it is important to recognize delayed reactions as well. 

Types of Transfusion Reactions

• Severe Acute Reactions

• Minor Acute Reactions

• Delayed Reactions

• Massive Transfusion Effects

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Severe Acute Reactions

• C: CHF (aka Transfusion-Associated Circulatory Overload)

• H: Hemolysis, acute

• A: Anaphylaxis

• T: TRALI (Transfusion-Related Acute Lung Injury)

• S: Sepsis

Congestive Heart Failure (CHF)/Transfusion-Associated Circulatory Overload (TACO)

Presentation/Background

• Risk factors include advanced age, known heart failure/diastolic dysfunction, and renal failure
• Patients typically develop acute dyspnea, crackles, and hypoxemia during the transfusion or soon after it finishes
• Their underlying cardiomyopathy is unable to handle the increased volume/preload, leading to cardiogenic pulmonary edema (think flash pulmonary edema)
• More likely to develop this after a transfusion than with crystalloid due to the stronger oncotic pressure in blood products
• Synonymous with transfusion-associated circulatory overload (TACO)

Evaluation

• Quickly assess vital signs, mental status, work of breathing, and degree of hypoxemia
• Assess for signs of volume overload such as crackles, an S3, jugular venous distention (JVD) and peripheral edema
• STAT portable chest X-ray (or bedside lung ultrasound) to assess for signs of pulmonary edema with cardiomegaly
• EKG
• Consider resending labs, including a troponin and brain natriuretic peptide (BNP)

Management

• Support with supplemental oxygenation and ventilation as needed
• Medical management includes diuresis and afterload reduction (nitrates to start) in those who are hypertensive
• In patients at high risk for CHF/TACO, transfuse each unit slowly over 3-4 hours and diurese at the same time. 
• Patients with end-stage renal failure can also be transfused during hemodialysis in order to ensure a safer volume status. 

Hemolysis, acute

Presentation/Background

• Perhaps one of the most serious and potentially fatal complications of transfusions with an incidence between 1/75,000-600,000 and a mortality of 1/1.5-1.8 million
• Classically present as the rapid onset of fever, chills, back/flank pain, tachycardia, hypotension, nausea and vomiting
• Can occur up to 24 hours after the initiation of a transfusion, but more commonly occurs during or immediately afterwards
• Acute intravascular hemolysis occurs as a result ABO incompatibility, which leads to recipient antibody-mediated fixation of ABO antigens on donor cells (aka PATIENT ANTIBODIES ATTACK DONOR BLOOD)
• Pathophysiologic effects include the resultant hemolytic anemia, acute renal failure and disseminated intravascular coagulation (DIC)
• Acute hemolysis can occur and be fatal from incompatible non-ABO antibodies as well
• Signs and symptoms may be obvious in an alert patient, but a higher degree of suspicion must be present in those who are unresponsive or sedated. 

Evaluation

• The volume of blood transfused correlates with a more severe reaction, so when an acute hemolytic reaction is suspected: STOP THE TRANSFUSION
• Get the vital signs, and question/examine the patient
• Look at the patient labels/blood type and compare to the labels on the blood product bag
• A mislabeling error is the most common cause of an acute hemolytic reaction and is the reason behind repetitive checks prior to dispensing and administering blood products
• Immediately resend a type and screen from the patient’s blood and from the blood product bag, and simultaneously notify the blood bank that you are doing this
• Check for signs of hemolysis by sending a peripheral smear, LDH (will be high in hemolysis), haptoglobin (will be low in hemolysis), bilirubin (indirect will be high), direct Coombs test, repeat CBC and chemistry (to check creatinine), urinalysis (to check for hemoglobinuria) and a coagulation panel

Management

• Management is mainly supportive
• Give IV fluids in order to maintain renal perfusion, and if the labs indicate that hemolysis is occurring, give loop diuretics (first line is furosemide 40-80 mg IV) concomitantly to force diuresis
• For hypotension refractory to IV fluids, place a central line if vasopressors are needed. The first line vasopressor is norepinephrine.

Anaphylaxis

Presentation/Background

• The incidence is estimated to be between 1/20,000-150,000
• Similar in presentation to anaphylaxis from all other causes and usually occurs early on during the transfusion
• You know the signs and symptoms: urticaria, pruritus, bronchospasm, hypotension, stridor, flushing
• More likely to occur in patients with a history of anaphylaxis, particularly to blood transfusions, and in those who are IgA-deficient. 
• Patients react to the proteins in the plasma, so washed cells are preferred in order help prevent it. IgA-deficient donor blood is also available for those with a known IgA deficiency. 

Evaluation

• Back to basics: ABCs, IV (probably already have this if you are giving blood), O2, monitor. Evaluate as you would any other anaphylactic reaction. 

Management

• STOP THE BLOOD, epinephrine, corticosteroids, bronchodilators, H1-blockers, IV fluids, supplementary oxygenation and ventilation as needed. 

Transfusion-Related Acute Lung Injury (TRALI) 

Presentation/Background

• The incidence is quoted as being between 1/10,000-50,000, and is considered to be the leading cause of transfusion-related mortalities
• Can be difficult to distinguish from acute CHF/TACO
• Both present with progressive dyspnea, crackles, bilateral infiltrates on chest X-ray and hypoxemia within 6 hours after the onset or end of a transfusion
• Classically, patients with TRALI will not show signs of volume overload (as in TACO), and they will be hypotensive rather than hypertensive. However, this is not always the case and the patient should be treated clinically
• The pathophysiology behind TRALI is different in that it is non-cardiogenic pulmonary edema due to anti-leukocyte antibodies from the donor that attack the patient’s white blood cells and release pro-inflammatory cytokines. This results in increased vascular permeability within the pulmonary capillary membranes, essentially causing adult respiratory distress syndrome (ARDS)

Evaluation

• The evaluation is similar to those with CHF, but the following features favor a diagnosis of TRALI: absence of clinical signs of volume overload (peripheral edema, JVD, an S3, left atrial enlargement on EKG), and grossly adequate cardiac function on a bedside echocardiogram. 
• Hypotension is more likely associated with TRALI, rather than TACO; however, relying on this finding can be dangerous if there are signs of cardiogenic shock. 
• The chest X-ray may show a more diffuse interstitial pattern of pulmonary edema without cardiomegaly, but this is unreliable as well
• Given that TRALI is technically ARDS, an arterial blood gas will aid in the diagnosis in order to calculate the PaO2/FiO2 ratio, but this is less clinically important in the acute setting
• Ultimately, the same initial measures of evaluation should be taken for both TACO and TRALI 

Management

• Same as for CHF including supplemental oxygenation and ventilation
• Central line should be placed for hemodynamic support and invasive monitoring if there is hypotension
• Diuretics will not help in true TRALI, but if there is any concern that the hypoxemia and respiratory distress is due to CHF, diurese the patient. Some state that TRALI is ultimately a diagnosis of exclusion, and failure to improve with diuresis helps make the diagnosis
• There is some data to support only transfusing plasma from males in order to prevent TRALI, as females produce more antibodies during pregnancy

Sepsis

Presentation/Background

• Occurs due to bacterial contamination of blood products
• Acute onset of infectious symptoms including fever, chills, rigors, sweats, nausea, tachypnea, tachycardia, hypotension, altered mental status
• Can be confused with initial symptoms of an acute hemolytic reaction
• Rare in red blood cell transfusions; however, if this does occur think of Yersinia enterocolitica, as this bacteria can continue to grow at refrigerated temperatures
• More likely in platelet transfusion (approximately 1/700,000), as these are stored at room temperature; the multiple species implicated including S. aureus, Klebsiella and Streptococcus spp. 
• Single-donor platelets less likely to be contaminated than pooled platelets
• Gram-negative transfusion-related sepsis has the highest fatality

Evaluation

• ABCs first
• Assess need for hemodynamic support
• Blood cultures from blood product and patient, CBC, Chemistry, Lactic Acid
• Also need to evaluate for acute hemolysis as many of the initial signs and symptoms overlap

Management

• Same as you would manage any other presentation of sepsis: IV fluids, broad-spectrum antibiotics, central line and vasopressors as needed
• Anti-staphylococcal agents and third-generation cephalosporins in platelet transfusions
• Third-generation cephalosporins or fluoroquinolones in RBC transfusions

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Minor Acute Reactions

The two reactions that are more common than severe reactions: Isolated fever and simple allergic reaction. In order to remember this, make believe you grew up in Staten Island and pronounce it as "FevA."

…and the only prescription is giving Tylenol. 

Simple febrile reactions

• Most common transfusion reaction
• Incidence approximately 0.1%
• Possibly from anti-leukocyte antibodies or from cytokines already existing in the blood product bag
• No associated concerning signs such as back pain, hemodynamic instability, nausea
• Work-up consists of ruling out more severe reactions, mainly hemolysis and sepsis
• Can give leuko-reduced or washed cells to patients with a prior history of this
• Treatment is acetaminophen

Simple allergic reactions

• Incidence approximately 0.1%, but may be higher

• More common in fresh frozen plasma (FFP) or platelet transfusions due to transfused plasma proteins

• Symptoms mainly include urticaria, flushing and pruritus without anaphylactic signs or symptoms such as wheezing or hypotension

• H1-blockers such as diphenhydramine are sufficient to treat this

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Delayed Reactions

Can be remembered by the mnemonic: Giving Heme Has Delayed Consequences Occasionally

Graft-Versus-Host Disease

• Occurs 7-10 days after transfusion
• Rare, but nearly 100% fatal
• Symptoms include fever, rash, nausea and vomiting, jaundice
• Due to donor lymphocytes attacking an immunocompromised patient’s cells or when immunologically similar lymphocytes are transfused and not recognized as donor/foreign cells by the patient’s immune system
• Results in transaminitis and pancytopenia
• Neonates and bone marrow transplant patients are at high risk
• No specific treatment
• Use irradiated blood products in high-risk populations

Hepatitis

• Less common than in the 1970-80s
• Hepatitis B risk: 1/200,000
• Hepatitis C risk: 1/2,000,000

HIV

• Risk 1/2,000,000

Delayed Hemolysis

• Occurs 5-10 days after transfusion
• Incidence approximately 1/30,000
• Less severe version of acute hemolytic reaction due to antibodies against minor RBC antigens
• Most commonly leads to minor hemolysis and progressive anemia

Cytomegalovirus

• Benign in immunocompetent patients but clinically significant in premature neonates, bone marrow and solid organ transplant patients, and HIV patients
• Leukocyte-reduced blood products and CMV-negative donors decreases risk of transmission

Other infections

• EBV, syphilis, malaria, West Nile virus, babesiosis, toxoplasmosis

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Massive Transfusion Effects

Remember CAT CaKe: Coagulopathy, Acidosis, Temperature (Hypothermia), Calcium (hypo), Kalemia (hyper). Defined as ≥ 10 units of PRBCs within 24 hours or at least 6 units of PRBCs within 3 hours in the setting of active hemorrhage.

• Coagulopathy occurs from dilutional effect of RBCs alone without clotting factors, but also exacerbated given the underlying clinical situation
  • Prevent by basically replacing platelets and clotting factors with FFP, cryoprecipitate and platelets
  • Many different formulae/practices but can give 1:1:1 ratio or use 10 RBC:4 FFP:1 platelets
  • Correct underlying hypothermia, hypotension and acidosis
• Acidosis occurs from large amounts of lactic acid in stored blood
• Hypothermia occurs with cold blood products
  • Heat up blood or transfuse with warm crystalloid
• Hypocalcemia occurs due to citrate binding (more common in whole blood andless common with more modern storing practices)
  • Can give empiric supplemental calcium gluconate
• Hyperkalemia occurs due to increased potassium in stored RBCs
  • Monitor closely and treat accordingly 

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Summary

• The spectrum of transfusion reactions vary widely from simple reactions to acute hemolysis and the emergency physician should be vigilant in assessing patient with any symptoms that develop during transfusion (or in patients presenting to the ED with recent transfusion) 
• If you suspect a blood transfusion, stop blood immediately and notify blood bank, assess the patient's clinical symptoms for signs of severe transfusion reaction, check blood labeling, and resend a type and screen from both the patient and the blood product 
• If a transfusion reaction is simple, given tylenol for fever and H1-blocker for simple allergic symptoms
• Some numbers for your patients:

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Expert Commentary

Hi Jim,

This is an excellent review of the categories of transfusion reactions, clinical presentation, and management.   To emphasize/modify a few of the topics that were covered:

• Mislabeling errors can occur both at the time of transfusion AND during initial specimen collection for the type and screen.   Both mistakes can have serious consequences, and it’s important to remember that.
• IgA-deficient donor blood is not readily available (it’s a special order) and is quite rare, so only patients with extensive documentation of IgA deficiency are able to obtain this product.
• All plasma products come from males.  The American Association of Blood Banks requires that female donors are not used for plasma.  This is to reduce the risk of TRALI from antibodies that woman can generate during exposure to fetal antigens in pregnancy.
• Hypothermia can be managed using blood warmers (which avoid overheating) or transfusion with warm normal saline, which is the only crystalloid that can be co-transfused (in the same line) with blood products.
• Calcium gluconate should only be given through a separate line to avoid clotting.

From a laboratory standpoint, the most pressing issue that we need to resolve as swiftly as possible, in conjunction with identifying the potential cause of the transfusion reaction, is whether or not it is safe to release additional blood products to the patient.  

While in most cases, waiting an hour or two for a workup to be complete is not a significant issue, one can imagine circumstances where the need for a product might be more urgent.  So it is important to have an efficient process in place and to have good communication with the blood bank about what needs to be done for the workup to happen as safely and swiftly as possible.

A few points about expediting the transfusion workup:

1. The blood product bag should be returned if at all possible.  It will aid greatly in the workup of certain transfusion reactions.
2. A post transfusion blood sample (type and screen) is essential to the workup of a transfusion reaction and should be sent as soon as possible.  This specimen allows the lab to double check the blood type and to re-evaluate for the presence of antibodies that may be responsible for hemolysis.  
   1. Though acute hemolytic transfusion reactions, particularly the fatal ones, are thought of in association with ABO incompatibility and clerical errors, it’s important to keep in mind that there are antibodies to other red cells antigens (e.g. Kidd antigens, Kell, others) that can cause acute hemolysis.  People who’ve been exposed to blood products, especially red cell products, potentially will develop antibodies to other non-ABO antigens in those products.  Women who have had prior pregnancies can also develop antibodies to antigens on their fetus’ cells.
   2. More commonly, though, non-ABO antibodies will cause a more delayed hemolytic reaction.  Delayed reactions tend to lead to minor extravascular hemolysis, progressive anemia, and hyperbilirubinemia.
   3. Identifying these antibodies allows the blood bank to find products that are negative for those antigens and prevent future hemolytic reactions.
3. Additional critical labs to draw for hemolysis workup include urine sample, bilirubin, LDH, and haptoglobin.
4. The workup of a transfusion reaction from the blood bank standpoint consists of answering the following questions:
   1. Was there a clerical error?
   2. What are the pre and post transfusion vitals and symptoms?  Do they fit a pattern for a particular type of reaction?
   3. Is there evidence of antibody mediated hemolysis?
      1. DAT (Coombs) test to be performed on post sample and if necessary, pre sample for comparison.
      2. If antibodies are found, identification of those antibodies will potentially take some time.  The more antibodies the patient has (which tends to occur in people receiving many blood products in the past), the longer it will take to identify them.
   4. Does anything need to be sent for culture?
      1. Platelets, because they are stored at room temperature, are at higher risk for developing bacterial contamination.
      2. The most common signs of septic reaction are high fever and hypotension.
   5. After these questions are answered and resolved satisfactorily, the blood bank will be able to release more products.  The laboratory relies heavily on the information provided by the clinicians and nurses taking care of the patient to make the determination of whether or not additional transfusion is safe.
5. What to do if the transfusion reaction workup is not complete yet and you need more products. 
   1. Discuss the situation and the nature of the reaction with the blood bank pathologist or medical director of the blood bank to assess the risks of additional transfusion.  At Northwestern, a pathologist is available 24/7.
6. Always ask yourself one more time before you give any product whether there is truly an indication for a transfusion.  Blood products, despite what may be commonly believed, are a scarce and valuable resource.  While overall, there are many systems to ensure the safety of the products, any transfusion poses a certain degree of risk.  Just something to keep in mind.

Sarah Choi, MD PhD and Paul Lindholm, MD

Northwestern University, Department of Pathology

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References

• Hendey GW. Harwood-Nuss’ Clinical Practice of Emergency Medicine. 6th ed. Philadelphia: Wolters Kluwer; 2015. Chapter 201, Transfusion Reactions and Complications; pp. 979-984. 
• Osterman JL and Arora S. Blood Product Transfusions and Reactions. Emerg Med Clin North Am 2014; 32(3): pp. 727-738.