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Approach to the patient with a suspected acute transfusion reaction

Approach to the patient with a suspected acute transfusion reaction
Aaron Tobian, MD, PhD
Section Editor:
Steven Kleinman, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Nov 2022. | This topic last updated: Nov 11, 2022.

INTRODUCTION — Acute transfusion reactions range from bothersome yet clinically benign to life-threatening reactions. The nature of the reaction may not be immediately apparent, because severe reactions begin with nonspecific symptoms such as fever or chills. In addition, patients receiving transfusions often have complex underlying clinical conditions, the symptoms of which may mimic a transfusion reaction. Thus, a patient experiencing symptoms or signs consistent with an acute transfusion reaction must be evaluated promptly, with input from the transfusion service, and treated as expeditiously as possible to minimize the impact of the reaction.

This topic describes our approach to determining the nature of a suspected acute reaction (the type of reaction and likely causes) following transfusion of blood products.

Specific acute transfusion reactions and details of their management are discussed more extensively in separate topic reviews listed below. (See 'Types of acute transfusion reactions' below.)

Delayed transfusion reactions, which may occur in the days to weeks following a transfusion, are discussed separately.

Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions – (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

Post-transfusion purpura – (See "Immunologic transfusion reactions", section on 'Post-transfusion purpura'.)

Transfusion-associated graft-versus-host disease (ta-GVHD) – (See "Transfusion-associated graft-versus-host disease".)

Reactions to other plasma-derived products, such as intravenous immune globulin (IVIG), are presented separately. (See "Intravenous immune globulin: Adverse effects".)


The following list summarizes types of acute transfusion reactions and provides links to topics that discuss evaluation and management in more detail:

Transfusion-related acute lung injury – (See "Transfusion-related acute lung injury (TRALI)".)

Transfusion-associated circulatory overload – (See "Transfusion-associated circulatory overload (TACO)".)

Acute hemolysis – (See "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)

Anaphylaxis – (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

Sepsis – (See "Transfusion-transmitted bacterial infection".)

Allergic transfusion reactions – (See "Immunologic transfusion reactions", section on 'Allergic reactions'.)

Febrile nonhemolytic transfusion reactions – (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

Distinguishing features are discussed in the following sections.

Potentially life-threatening reactions — Potentially life-threatening reactions are listed below in order of greatest contribution to transfusion-associated mortality. (See 'Mortality' below.)

Transfusion-associated circulatory overload (TACO) — TACO is a form of pulmonary edema due to volume excess or circulatory overload; it typically occurs in patients who often have a preexisting positive fluid balance, receive a large volume of a transfused product over a short period of time, and/or have underlying cardiovascular disease. Management includes diuresis and supplementary oxygen; ventilatory support may rarely be required. TACO is a relatively common reaction. (See "Transfusion-associated circulatory overload (TACO)" and 'Frequency of reactions' below.)

Transfusion-related acute lung injury (TRALI) — TRALI is a life-threatening form of acute lung injury that occurs when recipient neutrophils are activated by the transfused product in an appropriately primed pulmonary vasculature, due to the transfused product having either anti-HLA or anti-neutrophil antibodies. Presenting findings include fever, chills, and respiratory distress. Therapy is largely supportive and may include intubation and mechanical ventilation. A subsequent evaluation is directed at identifying an implicated donor so that individual does not continue to donate and potentially cause TRALI in other patients. The patient can receive blood products from other donors without restrictions but should not receive any remaining untransfused portion of the implicated product. Any other products from the implicated donor should be quarantined and not transfused to any patients until TRALI is excluded. Prior to mitigation strategies, TRALI was among the more common acute transfusion reactions despite being historically under reported. (See "Transfusion-related acute lung injury (TRALI)" and 'Frequency of reactions' below.)

Acute hemolytic transfusion reaction (AHTR) — AHTR is a life-threatening reaction caused by acute intravascular hemolysis of transfused red blood cells (RBCs). This may be due to ABO incompatibility or caused by a reaction to alleles in other RBC antigen systems. ABO incompatible transfusion reactions are often the result of a clerical error leading to transfusion of a product not intended for the recipient. Presenting symptoms and/or signs include fever, chills, flank pain, and oozing from intravenous sites. It is critical to immediately stop the transfusion and communicate with the transfusion service; this allows for appropriate record checking, which may prevent administration of a wrongly labeled unit to another patient. Treatment involves aggressive hydration and diuresis. AHTRs are rare. (See "Red blood cell antigens and antibodies" and "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions' and 'Frequency of reactions' below.)

Transfusion-associated sepsis — Transfusion-associated sepsis (or bacterial infection) is caused by transfusion of a product that contains a microorganism. Initial findings may include fever, chills, and hypotension. Unlike sepsis from an underlying localized infection, transfusion-associated sepsis may involve a large intravenous inoculum, which in the case of gram-negative organisms, could include an infusion of endotoxin, leading to high fever. Treatment includes broad-spectrum antibiotics and hemodynamic support. Transfusion-associated sepsis is relatively rare. (See "Transfusion-transmitted bacterial infection" and 'Frequency of reactions' below.)

Anaphylactic transfusion reaction — Anaphylactic reactions are severe allergic reactions that include angioedema, wheezing, and/or hypotension. Anaphylactic reactions may occur in IgA-deficient individuals who produce anti-IgA antibodies that react with IgA in the transfused product, or patients who have allergies to another constituent in the transfused product. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

Management may include epinephrine, antihistamines, and vasopressors, depending on the degree of allergic symptoms. Anaphylactic reactions are relatively rare. (See 'Anaphylaxis' below.)

Non-life-threatening reactions — Non-life-threatening reactions are listed in order of frequency. (See 'Frequency of reactions' below.)

Allergic transfusion reaction (ATR) — Allergic transfusion reactions are most often associated with itching and hives. These reactions can be due to both recipient predisposition to allergic reactions and donor factors. The most common cause is an antigen-antibody interaction that occurs between patient and the product; commonly implicated antigens include a number of donor serum proteins. An allergic transfusion reaction is not a contraindication to continuing the transfusion as long as it is clear there are no other allergic symptoms. Antihistamines can be given, but are not indicated prophylactically. Allergic transfusion reactions are common. (See 'Frequency of reactions' below and "Immunologic transfusion reactions", section on 'Allergic reactions'.)

Febrile non-hemolytic transfusion reaction (FNHTR) — FNHTRs are characterized by fever, usually accompanied by chills, in the absence of other systemic symptoms. Because the development of other symptoms is not known at the time of the initial fever, FNHTR is a diagnosis of exclusion; the possibility of other febrile transfusion reactions must be eliminated, including AHTR, sepsis, and TRALI. The most common cause of FNHTR is release of cytokines from white blood cells (WBCs) in a product that has not been leukoreduced. Management is symptomatic, generally with acetaminophen. High quality evidence to support the prophylactic use of premedication with acetaminophen or antihistamines is lacking; this subject is discussed in more detail separately. FNHTRs are common. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions' and 'Frequency of reactions' below.)

With platelet transfusion, a similar reaction to FNHTR can occur, with chills and/or rigors in the absence of fever.

Hypotensive transfusion reactions — Hypotensive transfusion reactions are characterized by a drop in blood pressure without other causes of hypotension. Systolic blood pressure decreases by 30 mmHg or more and may fall to <80 mmHg within minutes of onset of transfusion and returns to baseline once the transfusion is stopped. Other types of transfusion reactions associated with hypotension (eg, acute hemolytic reaction, transfusion-related acute lung injury [TRALI], sepsis, anaphylaxis), and underlying disease must be excluded before a diagnosis of primary hypotensive reaction is made.

Hypotensive transfusion reactions have been reported most commonly with platelet transfusion; they have also occurred during therapeutic apheresis procedures and in patients on extracorporeal circuits [1-3]. Predisposing factors include use of an angiotensin converting enzyme (ACE) inhibitor by the recipient, or filtration through a negatively charged leukocyte reduction filter (which are no longer commonly used) [1,4,5]. The mechanism is thought to involve vasoactive kinins (eg, bradykinin). The reactions are rapidly reversible and generally do not require specific treatment or prevention, except for possible avoidance of ACE inhibitors prior to planned transfusion or apheresis. Hypotensive transfusion reactions are rare. (See 'Frequency of reactions' below.)

FREQUENCY OF REACTIONS — Acute transfusion reactions range in frequency from relatively common reactions, such as allergic and febrile nonhemolytic reactions, to rare complications including anaphylaxis, fatal intravascular hemolysis due to ABO incompatibility, and sepsis.

The approximate frequency of reactions is as follows (expressed as reactions per number of transfused blood components) [6]:

Common reactions:

Allergic – 1 to 3 percent with platelet and plasma components; 0.1 to 0.3 percent with red blood cell (RBC) components.

Febrile nonhemolytic transfusion reaction (FNHTR) – 1 percent. The frequency decreases when leukoreduced products are used.

Relatively common reactions:

Transfusion-associated circulatory overload (TACO) – <1 percent of transfused patients, although this may represent underreporting, and the frequency may be higher in hospitalized patients, especially patients in the intensive care unit.

Relatively rare reactions:

Transfusion-related acute lung injury (TRALI) – <0.01 percent.

Anaphylaxis – 1:20,000 to 1:50,000.

Acute hemolytic transfusion reaction (AHTR) – 1:76,000, virtually all occurring with RBC transfusion.

Hypotensive transfusion reactions – <0.01 percent.

Sepsis – 1:50,000 for platelets; 1:5,000,000 for RBCs.

Frequency too rare to calculate:

Non-immune hemolysis.

Air embolism.

A practice guideline from the Association for the Advancement of Blood & Biotherapies (AABB) has compared the risks for RBC transfusions with other dangers such as a motor vehicle accident or being struck by lightning (figure 1) [7].

The frequency of reactions varies among different patient populations. As an example, reactions are more common in children than adults. This was illustrated in a meta-analysis of three comparative studies that altogether evaluated >1.3 million transfusion reactions (>300,000 in children and >1 million in adults) [8]. The overall rate of transfusion reactions was higher in children (risk ratio [RR] 1.75; 95% CI 1.27–2.41). The higher risk was most significant for cellular components (RR 3.54 for RBCs and 3.62 for platelets) and was not seen with plasma or cryoprecipitate. The higher risk persisted for different types of reactions (allergic, FNHTR). The only types of reactions that were more common in adults were delayed hemolytic transfusion reactions and delayed serologic transfusion reactions. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

The severity of acute transfusion reactions also varies, although the discomfort of the patient may not always parallel the risk of adverse outcomes. Potentially fatal acute reactions include TRALI, TACO, AHTR, sepsis, and anaphylaxis (see 'Mortality' below). Relatively benign reactions include FNHTR, allergic transfusion reaction (ATR), and non-immune hemolysis. Importantly, early signs and symptoms of an acute transfusion reaction may not distinguish between benign and more serious transfusion reactions; thus, all acute transfusion reactions must be considered potentially serious and evaluated accordingly until demonstrated to be otherwise.

MORTALITY — Mortality from acute transfusion reactions is a rare event, with rates estimated at approximately 0.6 per million (commonly cited as 1 in 1.8 million) to 2.3 per million [9]. These data come from various surveillance systems that may not be directly comparable, and mortality rates may differ depending on the patient population and local transfusion practices.

The reactions associated with the greatest number of deaths in the late 1990s and early 2000s were TRALI and AHTR [9]. Practices implemented since that time, including using Fresh Frozen Plasma and other plasma products from male donors exclusively (as part of an aggressive TRALI mitigation strategy), as well as testing of apheresis platelets for bacterial pathogens, have reduced the overall mortality rates and altered the relative contributions of different types of reactions [10]. (See "Transfusion-related acute lung injury (TRALI)", section on 'Prevention'.)

The acute transfusion reactions with the greatest likelihood of fatality appear to have shifted. In the United States, TRALI was the most likely to be fatal until approximately 2016, when TACO became the most likely to be fatal. Of the 192 deaths from transfusion reported to the US Food and Drug Administration (FDA) in the five years from 2013 to 2017, the numbers of deaths (and percentages of total deaths) attributed to each type of reaction were as follows [11]:

TACO – 65 (34 percent)

TRALI – 45 (23 percent)

AHTR – 39 (20 percent)

Non-ABO incompatibility – 26 (14 percent)

ABO incompatibility – 13 (7 percent)

Sepsis – 25 (13 percent)

Anaphylaxis – 14 (7 percent)

Hypotensive reactions – 2 (1 percent)

Transfusion-associated graft-versus-host disease (ta-GVHD) is extremely rare and almost uniformly fatal; this presents as a delayed (rather than acute) reaction. (See "Transfusion-associated graft-versus-host disease".)

WHEN TO SUSPECT AN ACUTE TRANSFUSION REACTION — The potential of an acute transfusion reaction should be considered in any patient who develops adverse signs and symptoms during or within 24 hours after completion of a transfusion. Many of the most severe reactions occur within the first 15 minutes of initiating the transfusion.

The most common signs and symptoms are fever (a 1°C rise in temperature above baseline), chills, pruritus, and urticaria. Often, these resolve promptly without specific treatment or complications. Other findings that may be an indication of a more severe, potentially fatal reaction include respiratory distress, hemoglobinuria, loss of consciousness, hypertension, hypotension, flank or back pain, jaundice, abnormal bleeding, or oliguria/anuria. A patient receiving general anesthesia cannot inform the clinician about pain or respiratory distress, but they may show fever, hypotension, hypoxia, hemoglobinuria, oliguria/anuria, or disseminated bleeding, including oozing from intravenous sites. Disseminated bleeding or oozing from intravenous sites may be the only indication that an anesthetized patient is experiencing an acute transfusion reaction.

The possibility of an acute transfusion reaction should be considered in any patient receiving a transfusion who develops any of these symptoms, or in patients developing mental status changes, including feelings of anxiety and/or dread.


Stop the transfusion; assess and treat — The following steps should be taken without delay in a patient with a suspected acute transfusion reaction (algorithm 1):

Immediately stop the transfusion; save the remaining bag and tubing for potential analysis.

Maintain a patent intravenous line with normal saline. (See 'Suspected acute hemolytic reaction' below.)

Confirm the correct product was transfused to the intended patient based on product labeling and patient identification; also assess the product for gross color changes or bubbles suggestive of bacterial contamination.

Assess the patient, including symptoms of fever, respiratory distress, chest pain, back pain, itching, angioedema; measure vital signs; perform a limited physical examination guided by symptoms. (See 'Initial patient assessment' below and 'Additional testing and management' below.)

Additional assessments may include pulse oximetry or telemetry. If the reaction appears to be moderate to severe, immediate decisions about management can be made and implemented without delay. These may include (but are not limited to) oxygen for patients with respiratory distress; epinephrine for a patient with obvious anaphylaxis; intravenous fluids for a patient with an AHTR or hypotension; and diuretics for a patient with TACO or an AHTR.

Contact the transfusion service — The transfusion service should be contacted immediately to discuss the appropriate evaluation and initial management.

The transfusion service may request return of the remaining (untransfused) component, associated intravenous bags and tubing, and blood and urine testing. (See 'Initial laboratory testing' below.)

The transfusion service laboratory will perform a clerical check to assess whether the patient received a product intended for a different patient. In addition to helping with the diagnosis, the check will determine whether another patient may also be at risk of receiving an incorrect product.

Can the transfusion be restarted? — Additional transfusion of the remaining product or another product is usually deferred until a preliminary evaluation has been conducted. If the symptoms subside and the correct product is confirmed, a decision regarding administration of further transfusions must be reached with input from both the treating physician and transfusion service.

Transfusion of the original product should not be continued in cases of suspected acute hemolytic transfusion reaction (AHTR), anaphylaxis, sepsis, or transfusion-related acute lung injury (TRALI).

Reactions in which transfusion of the same product may be possible include minor allergic reactions and transfusion-associated circulatory overload (TACO) that has resolved with diuresis or other measures.

Even if the patient has a condition in which it is acceptable to restart the transfusion, it is likely in most cases that the four-hour limit for completing the transfusion may have already passed. In such cases, the unit must be discarded. (See "Transfusion-associated circulatory overload (TACO)", section on 'Resuming transfusions'.)

Decisions regarding the need for additional transfusions of products other than the one associated with the reaction depend on the original indication for the transfusion. As an example, a patient who has already received the majority of the transfusion for a less severe anemia or thrombocytopenia without bleeding may not require additional transfusions, whereas a patient with severe bleeding and thrombocytopenia with suspected TACO who is responding to diuresis may benefit from additional transfusions.

INITIAL PATIENT ASSESSMENT — The initial patient assessment and relevant aspects of the clinical history are used to determine the most likely reaction(s). Subsequent laboratory testing and response to management interventions are used to confirm or refute the suspected diagnosis.

Evaluation according to predominant symptoms

Patient with fever/chills — Fever (increase in temperature of >1°C and temperature >38°C), with or without chills/rigors, is a critical sign of an acute transfusion reaction (algorithm 1 and table 1). Fever/chills suggest an acute hemolytic transfusion reaction (AHTR), a septic transfusion reaction, transfusion-related acute lung injury (TRALI), or a febrile nonhemolytic transfusion reaction (FNHTR). AHTR, sepsis, and TRALI are potentially fatal. FNHTR is less serious but is for the most part a diagnosis of exclusion; FNHTR is diagnosed when the more consequential etiologies of fever have been excluded by clinical and laboratory investigation.

Fever may also be a component of the patient's underlying illness. In such cases, consultation between the primary clinician and the transfusion service regarding the likelihood of an acute transfusion reaction is warranted.

Significant acute transfusion reactions not accompanied by fever include: allergic transfusion reaction (ATR), anaphylaxis, hypotensive transfusion reactions, and transfusion-associated circulatory overload (TACO). Non-immune hemolysis (and other transfusion complications such as hypocalcemia or air embolus) are generally are not associated with fever or chills.

Acute hemolytic transfusion reaction (AHTR) often presents with fever as the first sign of the reaction. Therefore, an AHTR must be excluded by a clerical check that the transfused product was appropriate for the patient, and by laboratory evaluation for hemolysis. This evaluation may need to occur simultaneously with consideration of other potential transfusion reactions also associated with fever (eg, TRALI, sepsis). (See 'Suspected acute hemolytic reaction' below.)

Sepsis from a transfused product often presents initially with fever; transfusion-associated sepsis occurs most commonly with platelet transfusion but can also be associated with RBCs or plasma. The transfused product must be inspected for signs of bacterial contamination including cloudiness, and microbiological testing is used to detect if an organism is present and, if so, to identify it. (See 'Suspected septic reaction' below.)

TRALI is often associated with fever, accompanied by respiratory distress and a new infiltrate on chest radiography. Patients with fever who also have respiratory symptoms should be evaluated for TRALI. (See 'Patient with respiratory distress' below and 'Respiratory distress: TACO versus TRALI' below.)

FNHTR is characterized by fever without evidence of other acute transfusion reaction. Fever with chills/rigors is often a hallmark of a FNHTR; however, this is a diagnosis of exclusion, and often other evaluations are indicated before fever is attributed to FNHTR. (See 'Isolated fever/chills' below.)

Patients with a feeling of warmth or chills without a >1°C increase in temperature should be observed for 15 to 30 minutes while the intravenous line is kept open with normal saline. If symptoms subside, transfusion may be restarted slowly.

Hypothermia is occasionally seen in recipients of large volumes of refrigerated blood products. Patients with hypothermia may feel cold but generally do not have shaking chills. Temperature measurements will not show fever. Warming the patient and/or the blood product is the only intervention needed.

Patient with respiratory distress — Respiratory symptomatology characterizes TACO, TRALI, and anaphylaxis (algorithm 1 and table 1). TACO and TRALI may be difficult to differentiate because they both present with pulmonary edema. (See 'Respiratory distress: TACO versus TRALI' below.)

In addition, TACO and TRALI can occur simultaneously. Distinguishing features between TRALI and TACO include the following (table 2):

TACO is more often characterized by hypertension, while TRALI is often associated with hypotension.

The pulmonary artery wedge pressure is usually elevated in TACO but not in TRALI.

TACO is more closely associated with elevated levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-pro-BNP) than TRALI.

TRALI is more often accompanied by fever.

TACO symptoms are more often responsive to diuresis.

Anaphylaxis can be distinguished from TRALI and TACO by the rapidity of its onset, usually within the first few moments of starting a transfusion. Anaphylaxis is also characterized by bronchospasm (with wheezing and respiratory distress) and possibly urticaria and angioedema, all of which are absent in TRALI and TACO. Anaphylaxis may also be associated with hypotension.

Respiratory distress can also be seen with an air infusion in the patient's intravenous line, an exceedingly rare occurrence. (See "Air embolism".)

Patient with hypotension — A significant drop in systolic blood pressure (by >30 mmHg) is characteristic of AHTR, TRALI, and sepsis (algorithm 1 and table 1). Importantly, hypotension may also be due to bleeding rather than a transfusion reaction. Intraoperative bleeding should be assessed by the surgeon; bleeding in a medical patient may be suspected based on the patient's history and the original indication for transfusion.

Each of these hypotensive transfusion reactions has characteristic clinical and laboratory findings, making discrimination among them relatively straightforward in most cases:

AHTR may be accompanied by fever, chills, back pain, pain along the infusion vein, and disseminated bleeding/oozing from intravenous catheters. Dark urine and/or oliguria may also occur, but these are often seen later in the course of the reaction (eg, hours later). Laboratory evaluation will show evidence of intravascular immune hemolysis. (See 'Suspected acute hemolytic reaction' below.)

TRALI is accompanied by fever/chills, respiratory distress, rales on lung exam, and hypoxemia; chest radiography shows bilateral pulmonary edema. (See 'Respiratory distress: TACO versus TRALI' below.)

Sepsis may be accompanied by fever/chills and other findings of shock. Laboratory evaluation will reveal the infectious organism, although this may take hours to days. (See 'Suspected septic reaction' below.)

Additional, less-common causes of hypotensive reactions include air infusion from the patient's intravenous line and angiotensin converting enzyme (ACE) inhibitors. (See "Air embolism" and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'ACE inhibitor-related complications'.)

Hypotensive transfusion reactions are rare [1,2,12]. The Centers for Disease Control and Prevention (CDC) Biovigilance Network criteria for a hypotensive transfusion reaction requires other transfusion reactions to be excluded and the systolic blood pressure to decrease by at least 30 mmHg and to be below 80 mmHg [13]. The mechanism(s), although incompletely understood, may involve concomitant ACE inhibition in combination with increased bradykinin levels in the transfused product (see 'Hypotensive transfusion reactions' above). This has occurred more frequently with patients on extracorporeal circuits and with certain brands of leukoreduction filters that are no longer commonly used. For patients with recurrent hypotensive transfusion reactions, there is a theoretical possibility that withholding the ACE inhibitor for 24 hours prior to transfusion might decrease this risk. This intervention must be weighed against the benefits of ACE inhibition for the individual patient, and the certainty that all other possible explanations for hypotension have been eliminated (eg, atypical allergic transfusion reaction, reduced intravascular volume).

Initial laboratory testing — The decision to order laboratory testing should be made in discussion between the treating physician, who knows the patient's underlying illness, and transfusion service personnel, who know additional details of the transfused product and the appropriate testing needed. Individuals with minor allergic transfusion reactions (isolated urticaria) and transfusion-associated circulatory overload (TACO) may not require laboratory evaluation. In contrast, all patients with suspected AHTR, anaphylaxis, sepsis, and TRALI will require laboratory or other testing (eg, chest radiography) to evaluate the cause of the patient's symptoms (algorithm 1).

Laboratory samples for evaluating a suspected transfusion reaction should be accompanied by information regarding the patient history and the reaction; in most institutions a specific form for this information is provided.

Relevant information about the patient includes:

Unique patient identifying information

Underlying diagnosis and reason for the transfusion

Recent febrile course

Previous transfusion reactions

Administration of any pre-transfusion medications (eg, acetaminophen, antihistamines, glucocorticoids) or new medications to which the patient might have an allergic reaction or drug-induced hemolysis

Important information about the reaction includes:

Time the transfusion was initiated

Time symptoms began

Time the transfusion was stopped

Patient symptoms including fever, chills/rigors, respiratory distress, chest pain, back pain, pain/burning at the intravenous site, and hematuria

Patient vital signs

The transfusion service and/or hospital laboratory should be consulted regarding where to send the blood component container and associated tubing, as well as which other specimens are required.

The hospital blood bank or laboratory will do the following, which generally are not time-consuming:

A clerical check of the component container, label, paperwork, and initial patient sample used for typing and crossmatching

Repeat ABO testing on the post-transfusion patient sample

A visual check of both pre-and post-transfusion patient samples for evidence of hemolysis

A direct antiglobulin (Coombs) test (DAT) on the post-transfusion patient sample

An antibody screen

As exceptions, the items above to evaluate for hemolysis are not needed when a specific type of non-hemolytic reaction is occurring (allergic transfusion reaction, anaphylaxis, TACO or TRALI). (See 'Isolated hives/itching' below and 'Anaphylaxis' below and 'Respiratory distress: TACO versus TRALI' below.)

Additional testing and preliminary management will depend on the type of reaction suspected. Stabilization of the patient may need to occur simultaneously with the laboratory evaluation. Of note, none of the urgent interventions needed to stabilize the patient will interfere with the evaluation, and in some cases, response to these interventions may be helpful in determining the cause of the reaction as well as improving patient symptoms (eg, diuresis for presumed TACO, epinephrine for presumed anaphylactic reaction). Once the likely diagnosis is determined, consultation with other clinicians may be appropriate.

ADDITIONAL TESTING AND MANAGEMENT — Management of symptoms is initiated while awaiting results of initial laboratory testing and other evaluations. The aggressiveness of interventions depends on the severity of the reaction and the suspected diagnosis.

Suspected acute hemolytic reaction — After immediately stopping the transfusion, we initiate aggressive hydration if any of the clinical findings suggest the diagnosis of acute hemolytic transfusion reaction (AHTR), including evidence that the patient received the incorrect unit of blood, flank pain and/or significant hypotension, oozing from intravenous sites, or oliguria/anuria. Aggressive hydration is used to minimize complications of free hemoglobin in the circulation, which may include acute kidney injury; disseminated intravascular coagulation; and symptoms of vasospasm (eg, chest pain). Hydration with normal saline should be used to maintain renal output of >1 mL/kg/hour; an intravenous diuretic such as furosemide is often used. Aggressive hydration should be maintained until there is no further evidence of adverse effects from hemolysis, such as hemoglobinemia/hemoglobinuria, hypotension, oliguria, and/or disseminated intravascular coagulation (DIC). If DIC is suspected, additional blood component transfusion may be necessary, including platelets, plasma, and/or cryoprecipitate, depending on the degree of bleeding and laboratory findings.

If the diagnosis of AHTR is less clear because none of the highly suggestive clinical findings mentioned above are present (ie, there is no evidence that an incorrect unit of blood was administered and there is no flank pain, hypotension, oliguria, or evidence of DIC), we obtain laboratory testing first and begin vigorous hydration if necessary. The hospital transfusion service evaluation plays a critical role in making the initial diagnosis of AHTR.

Laboratory testing for AHTR includes the following, which is done in consultation with the transfusion service:

Repeat ABO compatibility testing on both a pre-transfusion and a post-transfusion sample

Additional antibody studies (antibody screen and identification) if ABO incompatibility is excluded

Repeat crossmatch with pre-and post-transfusion specimens using an indirect antiglobulin (IAT) method

Direct antiglobulin (Coombs) testing (DAT)

Observation of the serum for pink color and analysis for free hemoglobin

Serum haptoglobin, lactate dehydrogenase (LDH), and unconjugated bilirubin levels to document hemolysis

Coagulation testing for DIC if the patient has increased bleeding, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, and D-dimer

Observation of the urine for pink color and analysis for free hemoglobin

Serial hemoglobin levels to determine the severity of hemolytic anemia and possible need for additional red blood cell (RBC) transfusions

If it is clear that intravascular hemolysis has occurred (eg, if there is pink plasma or urine), a nephrologist may be consulted for advice on prophylactic measures (beyond intravenous hydration and diuresis) to prevent or reduce renal damage; a hematologist may be consulted if the patient has evidence of DIC.

It is possible, although unlikely, that red blood cells (RBCs) may be damaged or hemolyzed prior to transfusion, from thermal, mechanical, or osmotic injury, resulting in transfusion of free hemoglobin rather than hemolysis of transfused cells within the patient. Causes may include thermal injury to the cells from inappropriate warming or from rapid thawing of frozen products. This condition is less severe than AHTR because the amount of free hemoglobin is limited, and hemolysis is not ongoing; however, if large amounts of free hemoglobin are transfused, symptoms can be significant. Typical findings include pink serum, pink urine, negative DAT, negative IAT, and a compatible crossmatch. Analysis of the remaining (untransfused) product will also reveal a pink supernatant after centrifugation. In this setting, brisk diuresis induced by infusion of 500 mL normal saline per hour or as tolerated is usually adequate. Hydration is continued until hemoglobinuria resolves.

Anaphylaxis — The management of an anaphylactic emergency is reviewed in detail elsewhere (see "Anaphylaxis: Emergency treatment"); the main treatments are summarized here:

A patient with an apparent anaphylactic reaction (eg, hypotension, wheezing, angioedema) should promptly receive intramuscular (IM) epinephrine, preferably to the mid-outer thigh. The recommended dose of IM epinephrine for patients of any age is 0.01 mg/kg (maximum 0.5 mg), which requires use of a 1 mg/mL solution. The dose may be repeated every 5 to 15 minutes (or more frequently) if needed. Patients weighing >50 kg can be given 0.5 mg IM (0.5 mL of the 1 mg/mL solution). In some countries other than the United States, 1 mg/mL solution may be labeled as 1:1000.

In many settings use of an autoinjector may be preferred for speed, reliability, and ease of use. IM epinephrine autoinjector is dosed as follows:

Patients >25 kg – 0.3 mg

Infants and children 10 to 25 kg – 0.15 mg

If epinephrine is injected promptly by the IM route, most patients will have a response to one, two, or at most, three doses. The IM route is preferred to subcutaneous administration because it consistently provides a more rapid increase in blood and tissue concentrations of epinephrine.

In severe cases such as impending cardiovascular collapse refractory to IM epinephrine and volume resuscitation, a slow intravenous bolus of epinephrine is indicated, ideally with hemodynamic monitoring while an epinephrine infusion is prepared. In adults, the intravenous epinephrine dose is 0.05 to 0.1 mg, which requires 0.5 to 1 mL of a 0.1 mg/mL solution; this preparation is typically stocked on resuscitation carts as a syringe (1 mg epinephrine in 10 mL). In some countries other than the United States, the 0.1 mg/mL solution may be labeled as 1:10,000.

Intravenous fluids (saline) and an H1-antihistamine (loratadine or cetirizine, 10 mg orally, or diphenhydramine, 25 or 50 mg orally or intravenously, for itch or angioedema) may also be administered.

The dose of H1-antihistamine (25 versus 50 mg of diphenhydramine) is at the discretion of the clinician treating the reaction and depends on the size of the individual and severity of the reaction. A repeat dose (eg, 15 or 30 minutes after the first dose) can be given if needed for persistent itching or hives. The maximum dose of diphenhydramine is 100 mg in a one-hour period. (See 'Isolated hives/itching' below.)

Other therapies, such as inhaled bronchodilators, continuous positive airway pressure (CPAP), and an H2-antihistamine (eg, famotidine), may be appropriate in some patients with severe bronchospasm. In addition to managing the reaction, the response to these interventions further supports the diagnosis of anaphylaxis. (See "Anaphylaxis: Emergency treatment".)

Laboratory testing for an anaphylactic reaction should include quantitative immunoglobulin A (IgA) levels, which will be absent (level, <7 mg/dL) in individuals with IgA deficiency, as well as the presence of antibodies to immunoglobulin A (anti-IgA). (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis' and "Selective IgA deficiency: Management and prognosis", section on 'Safe administration of blood products'.)

This testing is not indicated in patients with isolated pruritus and/or urticaria. (See 'Isolated hives/itching' below.)

Suspected septic reaction — A septic reaction may be suspected based on severe fever/chills/hypotension without evidence of hemolysis on initial laboratory testing. In such cases, Gram stain should be performed on the returned component, and cultures should be performed on both the remaining component and a post-transfusion blood sample from the patient. Some hospitals perform Gram stains and cultures on all transfusion reactions that present with a fever. A complete blood count (CBC) with white blood cell count (WBC) is also obtained.

Intravenous broad-spectrum antibiotic therapy should be administered based on the severity of clinical symptoms or suspicion of a septic transfusion reaction. Antibiotics may be adjusted based on the results of the Gram stain or culture of the product, but should not be withheld while awaiting these results. An infectious disease clinician may be consulted for advice on appropriate antibiotic therapy. (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Evaluation and management of suspected sepsis and septic shock in adults".)

Respiratory distress: TACO versus TRALI — A patient with respiratory distress may be suspected of having transfusion-associated circulatory overload (TACO) or transfusion-related acute lung injury (TRALI); distinguishing features between the two are summarized in the table (table 2). In some cases the distinction between these reactions is relatively obvious; in others it may be more difficult, or TACO and TRALI may both occur. (See 'Patient with respiratory distress' above.)

The initial evaluation includes imaging (such as chest radiography) and assessment of oxygenation status using pulse oximetry or arterial blood gas measurement. Patients with hypoxia should receive supplemental oxygen regardless of the underlying cause. Severe respiratory compromise may require transfer to an intensive care unit for possible intubation and mechanical ventilation. A cardiologist or pulmonologist may be consulted for cardiovascular and/or ventilatory management.

TACO is more likely in patients who have received a large volume of fluid over a short period of time, older individuals, very young individuals, or those with underlying cardiac disease. TACO is also supported by findings of acute respiratory distress, hypertension, heart failure, elevated central venous pressure, and elevated brain natriuretic protein (BNP) or N-terminal pro-BN (NT-pro BNP) [13]. Pulmonary edema on chest radiography may be seen with TACO. If the clinical evaluation suggests TACO, the patient should be positioned in a seated posture and diuresis should be initiated, and the patient's response may be helpful in confirming the initial assessment. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Initial therapy' and "Transfusion-associated circulatory overload (TACO)", section on 'Evaluation and diagnosis'.)

TRALI is more likely in patients who have respiratory distress out of proportion to the volume of fluid received or early on during the transfusion. Other findings in TRALI include respiratory distress of sudden onset, fever, hypotension, and pink frothy airway secretions. Unlike TACO, a diagnosis of TRALI requires hypoxemia and an abnormal chest radiograph showing bilateral infiltrates and no left atrial hypertension [13]. Until 2019, individuals with underlying acute lung injury or an alternative risk factor for acute lung injury have been referred to as having "possible TRALI" (table 3); a newer classification scheme, proposed in 2019, indicates that data from the individuals in this category be further evaluated and that each case either be classified as acute respiratory distress syndrome (ARDS) or TRALI type II (table 4) [14]. (See "Transfusion-related acute lung injury (TRALI)", section on 'Terminology and diagnostic criteria'.)

The blood collection facility should be informed of a suspected TRALI case so that appropriate specimens may be obtained from the donor (or donors) involved; this notification is done by the transfusion service. Patients with suspected TRALI (either type I or type II) may also have samples sent for HLA typing and possible testing for HLA and/or neutrophil antibodies, in consultation with the transfusion service. (See "Transfusion-related acute lung injury (TRALI)".)

Analysis of the pulmonary edema fluid (obtained from a catheter inserted into a distal airway) may also be helpful in distinguishing TACO from TRALI, although this is rarely done [15,16]. The pulmonary edema in TACO is cardiogenic; thus, the fluid in the alveoli is a transudate (ie, the ratio of protein in the edema fluid to protein in the plasma is <0.65). The pulmonary edema in TRALI is non-cardiogenic; the fluid in the alveoli is an exudate (ie, the ratio of protein in the edema fluid to protein in the plasma is >0.75).

Importantly, if TACO and/or TRALI do not appear to explain the clinical picture, assessment for other causes of respiratory distress should be pursued, including transfusion reactions such as sepsis and other coincident medical conditions such as pulmonary embolism or myocardial ischemia (table 5). The CDC Biovigilance Network includes a transfusion reaction classification of transfusion-associated dyspnea (TAD), which is defined as acute respiratory distress within 24 hours of the transfusion along with exclusion of all other transfusion reactions and underlying medical conditions that might explain the symptoms [13].

Stable patient, mild reaction — The challenge when the patient appears to be having a mild reaction is that the ultimate course of the reaction is initially unknown. Thus, it is important to monitor the patient until the reaction has subsided.

Isolated fever/chills — Isolated fever with or without chills/rigors is most often caused by a febrile non-hemolytic transfusion reaction (FNHTR); however, the diagnosis of FNHTR cannot be established until it is clear that the patient is not having an acute hemolytic reaction (AHTR), sepsis, or TRALI. All cases of isolated fever (>1°C increase in temperature and temperature >38°C) must initially be managed as an AHTR until evidence to the contrary is obtained. The transfusion should immediately be stopped and the transfusion service should be informed.

For patients whose fever does not resolve quickly or who are uncomfortable from fever, oral acetaminophen may be administered. Aspirin should be avoided because it inhibits platelet function. Severe rigors can be treated with meperidine. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

These medications will not interfere with subsequent laboratory testing should it be necessary (eg, it is not necessary to withhold acetaminophen until cultures are obtained).

Isolated hives/itching — Patients with isolated hives or itching do not require laboratory testing, as long as there are no other allergic symptoms such as angioedema, wheezing, or hypotension. The transfusion should be paused for 15 to 30 minutes until it is clear that additional allergic symptoms are not developing. However, even though no laboratory testing is needed, many hospital transfusion services require reporting of all such reactions to the transfusion service.

Diphenhydramine can be used to relieve pruritus associated with a hives or itching; however, not all patients will require pharmacologic intervention. Outpatients should be queried about driving home before diphenhydramine is administered because this may cause drowsiness. Diphenhydramine can be administered orally or intravenously, at a dose of 25 to 50 mg, depending on the severity of symptoms and the size of the patient. If urticaria persists, additional doses of diphenhydramine (and/or other symptomatic therapies) can be administered as needed, typically after 15 to 30 minutes. The maximum dose of diphenhydramine is 100 mg in a one-hour period.

Data for using other treatments are limited. However, more severe allergic reactions or those refractory to diphenhydramine can be treated with famotidine, 20 mg intravenously, hydroxyzine, 50 mg orally, or methylprednisolone, 125 mg intravenously.

In mild cases of isolated hives or itching that resolve promptly, the transfusion may be restarted with the original unit.

If the hives resolve without medication or with diphenhydramine, an outpatient receiving a transfusion can be discharged. The nature of the reaction, the unlikeliness of serious sequelae, and symptoms that should prompt contacting the physician should be discussed with the patient.

If the patient develops more severe allergic symptoms, such as wheezing, angioedema, or hypotension, the transfusion should be discontinued immediately and additional interventions to treat anaphylaxis should be employed. (See 'Anaphylaxis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Blood donation and transfusion (Beyond the Basics)")


Types of acute reactions – Acute transfusion reactions range from bothersome yet clinically benign to life-threatening reactions. The nature of the reaction may not be immediately apparent, because many reactions, including the most severe reactions, begin with nonspecific symptoms such as fever or chills. Potential types of reactions are listed above. (See 'Types of acute transfusion reactions' above and 'Mortality' above.)

Incidence – The frequency of reactions varies from relatively common reactions, such as allergic transfusion reactions and febrile nonhemolytic transfusion reactions (FNHTRs), to rare complications including anaphylaxis, fatal ABO-incompatible acute hemolytic transfusion reactions (AHTRs), and sepsis (figure 1). (See 'Frequency of reactions' above.)

When to suspect – The potential of an acute transfusion reaction should be considered in any patient who develops adverse signs and symptoms during, or within 24 hours after completion of a transfusion. Many of the most severe reactions occur within the first 15 minutes of transfusion. (See 'When to suspect an acute transfusion reaction' above.)

Immediate actions – For a patient with a suspected acute transfusion reaction (algorithm 1) (see 'Immediate actions (all patients)' above):

Stop the transfusion immediately

Maintain a patent intravenous line

Inform the transfusion service

Confirm the correct product

Assess clinically

Evaluation (bedside) – The initial patient assessment and relevant aspects of the clinical history are used to determine the most likely reaction(s) (table 1).

Fever/chills suggest an AHTR, septic transfusion reaction, transfusion-related acute lung injury (TRALI), or FNHTR. AHTR, sepsis, and TRALI are potentially fatal; FNHTRs are less serious but for the most part are a diagnosis of exclusion. Fever may also be associated with patient's underlying illness. (See 'Patient with fever/chills' above.)

Respiratory symptoms characterize TACO, TRALI, and anaphylaxis (table 5). TACO and TRALI may be difficult to differentiate because they both present with pulmonary edema (table 2). (See 'Patient with respiratory distress' above.)

A significant drop in systolic blood pressure (by >30 mmHg) is characteristic of AHTR, TRALI, and sepsis; hypotension may also be due to bleeding or volume depletion rather than a transfusion reaction. Hypotensive transfusion reactions may also be responsible, although these are very rare. (See 'Patient with hypotension' above and 'Hypotensive transfusion reactions' above.)

Evaluation (blood bank or laboratory) – Laboratory samples for evaluating a suspected transfusion reaction should be accompanied by information regarding the patient history and the reaction. The hospital blood bank or laboratory will do a clerical check, repeat ABO testing, a visual check for hemolysis, and a direct antiglobulin (Coombs) test (DAT). Additional testing and preliminary management will depend on the type of reaction suspected. (See 'Initial laboratory testing' above and 'Additional testing and management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD to earlier versions of this and many other topic reviews.

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