Official reprint from UpToDate

www.uptodate.com 2016 UpToDate

Approach to the patient with a suspected acute transfusion reaction

Author
Arthur J Silvergleid, MD

Section Editor
Steven Kleinman, MD

Deputy Editor
Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2016. | This topic last updated: Aug 09, 2016.
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 many 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 cause of a suspected acute reaction to transfusion of red blood
cells, platelets, or plasma.
Specific acute transfusion reactions and details of their management are discussed more extensively in separate topic
reviews.
Volume overload (See "Transfusion reactions caused by chemical and physical agents".)
Acute lung injury (See "Transfusion-related acute lung injury (TRALI)".)
Febrile nonhemolytic reactions (See "Immunologic blood transfusion reactions", section on 'Febrile nonhemolytic
reactions'.)
Sepsis (See "Transfusion-transmitted bacterial infection".)
Urticaria (See "Immunologic blood transfusion reactions", section on 'Urticarial (allergic) reactions'.)
Anaphylaxis (See "Immunologic blood transfusion reactions", section on 'Anaphylactic reactions'.)
Acute hemolysis (See "Transfusion-associated immune and non immune-mediated hemolysis".)
Air embolism (See "Air embolism".)
Delayed transfusion reactions, which may occur in the days to weeks following a transfusion, are also discussed in detail
separately.
Delayed hemolysis (See "Immunologic blood transfusion reactions".)
Thrombocytopenia (See "Immunologic blood transfusion reactions", section on 'Post-transfusion purpura'.)
Graft-versus-host disease (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".)
POTENTIAL REACTIONS
Acute hemolytic transfusion reaction (AHTR) AHTR is a life-threatening reaction caused by acute intravascular
hemolysis of transfused red blood cells (RBCs), often caused by a clerical error that results in transfusion of a product
not intended for the recipient. Presenting symptoms include fever, chills, flank pain, and oozing from intravenous sites.
Immediate communication with the transfusion service is critical to allow for appropriate record checking, which may
prevent administration of a wrongly labeled unit to another patient. Treatment involves aggressive hydration and
diuresis. (See "Immunologic blood transfusion reactions".)
Anaphylactic transfusion reaction Any allergic reaction other than hives constitutes an anaphylactic transfusion
reaction. This includes 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. Management may include epinephrine, antihistamines, and
vasopressors, depending on the degree of allergic symptoms. (See "Immunologic blood transfusion reactions", section
on 'Anaphylactic reactions'.)
Febrile non-hemolytic transfusion reaction (FNHTR) FNHTRs are common; these reactions 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. In the case of platelet
transfusion, a similar reaction characterized by chills and/or rigors can occur in the absence of a temperature change.
Management is symptomatic. High quality evidence to support the prophylactic use of premedication with
acetaminophen or antihistamines is lacking; this subject is discussed in more detail separately. (See "Immunologic blood
transfusion reactions", section on 'Febrile nonhemolytic reactions'.)
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 receive a large volume of a transfused product over a short
period of time, or in those with underlying cardiovascular disease. Management includes diuresis and supplementary
oxygen; ventilatory support may rarely be required. (See "Transfusion reactions caused by chemical and physical
agents".)
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. Treatment includes broad-spectrum antibiotics and
hemodynamic support. (See "Transfusion-transmitted bacterial infection".)
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.
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. The patient can receive blood products from other donors without restrictions, but
should not receive any remaining untransfused portion of the implicated product or any other products from the
implicated donor. (See "Transfusion-related acute lung injury (TRALI)".)
Urticarial transfusion reaction (UTR) Urticarial reactions are associated with hives but no other allergic findings (ie,
no wheezing, angioedema, hypotension). 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. UTR 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. (See "Immunologic blood transfusion reactions", section on
'Urticarial (allergic) reactions'.)
FREQUENCY OF REACTIONS Acute transfusion reactions (ATRs) range in frequency from relatively common
reactions, such as urticaria 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, except for TACO, which is expressed as reactions per transfused recipient) [1]:
Common reactions:
Urticaria 1 to 3 percent.
Febrile nonhemolytic transfusion reaction (FNHTR) 0.1 to 1 percent. The frequency of FNHTR is higher
with platelet transfusion than with red blood cell (RBC) transfusion; 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.
Transfusion-related acute lung injury (TRALI) <0.01 percent.
Relatively rare reactions:
Anaphylaxis 1:20,000 to 1:50,000.
Acute hemolytic transfusion reaction (AHTR) 1:76,000, virtually all occurring with RBC transfusion.
Sepsis 1:50,000 for platelets; 1:5,000,000 RBCs.
Frequency too rare to calculate:
Primary hypotensive reactions associated with angiotensin converting enzyme [ACE] inhibitors.
Non-immune hemolysis.
Air embolism.
The frequency of reactions varies among different patient populations. As an example, a review of reactions to over
100,000 transfusions at a single institution found that children had a greater frequency of reactions than adults (0.6
versus 0.2 percent), especially allergic reactions (0.3 versus 0.1 percent) and FNHTRs (0.2 versus 0.05 percent) [2].
Ratios of the types of components transfused were similar in children and adults.
The severity of ATRs 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 urticaria, hypothermia, hypocalcemia, non-immune hemolysis, and FNHTR.
Importantly, early signs and symptoms of an ATR may not distinguish between benign and more serious transfusion
reactions; thus, all ATRs 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 [3]. 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
[3]. Practices implemented since that time including limiting the use of Fresh Frozen Plasma to male donors and
bacterial detection of apheresis platelets may have reduced the overall mortality rates and altered the relative
contributions of different types of reactions.
The acute transfusion reactions most likely to be fatal, in decreasing order of lethality, include TRALI, TACO, AHTR,
sepsis, and anaphylaxis. Transfusion-associated graft-versus-host disease (ta-GVHD) is 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 (ATR)
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.
The most common signs and symptoms are fever (a 1C 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. Disseminated bleeding or
oozing from intravenous sites may be the only indication that an anesthetized patient is experiencing an ATR.
The possibility of an ATR 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.

The possibility of a transfusion reaction in an anesthetized patient receiving a transfusion should be considered if the
patient develops fever, hypotension, wheezing, hypoxia, hives/angioedema, hemoglobinuria, oliguria/anuria, or
disseminated bleeding, including oozing from intravenous sites.
IMMEDIATE ACTIONS (ALL PATIENTS) The following steps should be taken without delay in a patient with a
suspected ATR (algorithm 1):
Immediately stop the transfusion; save the remaining bag and tubing for potential analysis.
Maintain a patent intravenous line with normal saline.
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.
Contact the transfusion service to discuss the appropriate evaluation and initial management.
If the clerical check reveals that the patient received a product intended for a different patient, the transfusion service
must be notified urgently because another patient may also be at risk of receiving an incorrect product.
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.)
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.
Reactions in which transfusion of the same product may be possible include urticaria without other allergic symptoms,
fever due to an underlying illness rather than the transfusion, and transfusion-associated circulatory overload (TACO)
that has resolved with diuresis or other measures. 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).
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 transfusional volume overload 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 is
used to confirm or refute the suspected diagnosis.
Fever/chills Fever (ie, increase in temperature of >1C), with or without a chill, is a critical sign of an ATR (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 ATR is warranted.
Significant ATRs not accompanied by fever include: urticaria, anaphylaxis, primary hypotensive reactions caused by
angiotensin converting enzyme (ACE) inhibitors, and transfusion-associated circulatory overload (TACO). Non-immune
hemolysis, air embolus, hypocalcemia, and hypothermia also 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,
hemolysis 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 'Moderate to severe reactions'
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
'Respiratory distress' below and 'Respiratory distress: TACO versus TRALI' below.)
FNHTR is characterized by fever without evidence of other acute transfusion reaction; fever with a chill 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 >1C 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.
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.
TRALI is more often accompanied by fever.
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".)
Hypotension A significant drop in blood pressure (eg, by >20 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 patients intravenous line and
angiotensin converting enzyme inhibitor (ACE inhibitor) medications. (See "Air embolism" and "Therapeutic apheresis
(plasma exchange or cytapheresis): Complications", section on 'Angiotensin converting enzyme (ACE) inhibitor-related
complications'.)
ACE inhibitor reactions are rare [4]. The mechanism(s), although incompletely understood, may involve concomitant
ACE inhibition in combination with increased bradykinin levels in the transfused product. This has occurred more
frequently with certain brands of leukoreduction filters, which are no longer commonly used. Recurrent hypotension with
subsequent transfusions is not likely because products from different donors may not have high kinin levels. However,
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 urticaria alone, increase in temperature of
<1C, fever related to the patient's underlying illness, 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)
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; all of which can be done within minutes:

 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
Exceptions include settings in which a specific type of non-hemolytic reaction is occurring (eg, anaphylaxis, TACO or
TRALI). (See '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 transfusional
volume overload; 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.
Moderate to severe reactions
Suspected acute hemolytic reaction 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. 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, we obtain laboratory testing first and begin vigorous hydration only if laboratory
testing is positive.
If the reaction is due to ABO incompatibility as a result of transfusing a unit of cells not intended for the patient, the
transfusion service must be notified immediately that another patient may also be at risk.
Laboratory testing for AHTR includes the following, which is done in consultation with the transfusion service:
Repeat ABO compatibility testing
Additional antibody studies 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 disseminated intravascular coagulation (DIC) if the patient has increased bleeding
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
A nephrologist may be consulted for advice on prophylactic measures to prevent or reduce renal damage; a
hematologist may be consulted if the patient has evidence of DIC.
Of note, it is possible, although unlikely, that red blood cells (RBCs) may be damaged or hemolyzed prior to transfusion,

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 A patient with an apparent anaphylactic reaction (eg, hypotension, wheezing, angioedema) should
receive epinephrine (0.2 to 0.5 mL of a 1:1000 solution) subcutaneously or intramuscularly. In severe cases, 0.5 mL of a
1:10,000 aqueous solution may be administered intravenously. Antihistamines are also administered. Other therapies,
such as inhaled bronchodilators, may be appropriate in some patients. 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 as well as the
presence of antibodies to immunoglobulin A (anti-IgA). This testing is not indicated in patients with isolated urticaria.
(See 'Isolated hives/itching' below.)
Suspected septic reaction A septic reaction may be suspected based on an abnormal appearance of the
transfused product (purple or brown discoloration of RBC components; bubbles in a platelet component) or 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 posttransfusion blood sample from the patient. 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
obvious abnormal appearance of the transfused product. 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.
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) (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 'Respiratory distress' above.)
The initial evaluation includes 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, elderly individuals,
very young individuals, or those with underlying cardiac disease. TACO is also supported by findings of hypertension,
heart failure, or elevated pulmonary artery wedge pressure. Hypoxemia and 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. Patients
with apparent TACO who do not respond to diuresis can also be treated with phlebotomy. Laboratory testing for TACO
may include an NT-Pro BNP measurement, which is supportive of TACO if elevated. (See "Treatment of acute
decompensated heart failure: Components of therapy", section on 'Initial therapy' and "Transfusion reactions caused by
chemical and physical agents".)
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.

Individuals with underlying acute lung injury or an alternative risk factor for acute lung injury are referred to as having
"possible TRALI." Patients with suspected TRALI should have samples sent for HLA typing and possible testing for HLA
and/or neutrophil antibodies, in consultation with the transfusion service. 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. (See "Transfusion-related acute lung injury (TRALI)".)
Analysis of the pulmonary edema fluid may also be helpful in distinguishing TACO from TRALI in rare cases. The
pulmonary edema in TACO is cardiogenic; thus, the fluid in the alveoli is a transudate. The pulmonary edema in TRALI
is non-cardiogenic; the fluid in the alveoli is an exudate.
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 3).
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 a chill 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. Thus, many cases of isolated fever must initially be
managed as an AHTR until evidence to the contrary is obtained. Exceptions include the following:
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 blood transfusion reactions", section on 'Febrile nonhemolytic 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).
Patients who develop additional symptoms (such as hypotension or chest or back pain, or more severe or
prolonged fever) should be managed as if they are having an AHTR, and appropriate laboratory testing should be
obtained. (See 'Suspected acute hemolytic reaction' above.)
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.
Diphenhydramine can be used to relieve pruritus associated with a hives or itching; however, not all patients will require
pharmacologic intervention. The patient 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
100 mg, depending on the severity of symptoms and the size of the patient. In mild cases of isolated hives or itching that
resolve promptly, the transfusion may be restarted with the original unit.
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.)
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 information: Blood donation and transfusion (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Acute transfusion reactions (ATRs) range from bothersome yet clinically benign to life-threatening reactions. The
nature of the reaction may not be immediately apparent, because many reactions begin with nonspecific symptoms
such as fever or chills. Potential ATRs are listed above. (See 'Potential reactions' above.)
The frequency of reactions varies from relatively common reactions, such as urticaria and febrile nonhemolytic
reactions, to rare complications including anaphylaxis, fatal intravascular hemolysis due to ABO incompatibility,
and sepsis. (See 'Frequency of reactions' above.)
The potential of an ATR 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.)
A patient with a suspected ATR should have the following (algorithm 1) (see 'Immediate actions (all patients)'
above):
Transfusion stopped immediately
Patent intravenous line
Confirmation of the correct product
Clinical assessment
Transfusion service involvement
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 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. Fever may also be a component of the patient's underlying illness. (See 'Fever/chills' above.)
Respiratory symptomatology characterizes TACO, TRALI, and anaphylaxis (table 3). TACO and TRALI may
be difficult to differentiate because they both present with pulmonary edema (table 2). (See 'Respiratory
distress' above.)
A significant drop in blood pressure (eg, by >20 mmHg) is characteristic of AHTR, TRALI, and sepsis;
hypotension may also be due to bleeding rather than a transfusion reaction. (See 'Hypotension' above.)
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.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. AABB Technical Manual, 17th, Roback JD, Grossman BJ, Harris T, et al. (Eds), American Association of Blood
Banks Press, Bethesda, MD 2011. p.237.

2. Oakley FD, Woods M, Arnold S, Young PP. Transfusion reactions in pediatric compared with adult patients: a look
at rate, reaction type, and associated products. Transfusion 2015; 55:563.
3. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and
the available strategies for their prevention. Blood 2009; 113:3406.
4. Metcalf RA, Bakhtary S, Goodnough LT, Andrews J. Clinical Pattern in Hypotensive Transfusion Reactions. Anesth
Analg 2016; 123:268.
Topic 95132 Version 10.0

GRAPHICS
Initial approach to a suspected acute transfusion reaction

This graphic includes some of the most common and life-threatening reactions; other reactions are also p
should be pursued if the clinical picture seems inconsistent with one of these. The transfusion service sho
of any severe transfusion reaction and may request samples of the transfused product and patient blood;
product should not be discarded until discussion with the transfusion service has taken place. In cases of
AHTR, the transfusion service must be contacted immediately because another patient may be at risk of r
incorrect blood product. Refer to UpToDate topics on transfusion reactions for further details of the evalua
management of these conditions.

TACO: transfusion-associated circulatory overload; TRALI: transfusion-related acute lung injury; FNHTR: febrile no
transfusion reaction; AHTR: acute hemolytic transfusion reaction; ALI/ARDS: acute lung injury/adult respiratory d
syndrome; DAT: direct antiglobulin test (Coombs test); CBC: complete blood count; CXR: chest x-ray; LDH: lactat
dehydrogenase; DIC: disseminated intravascular coagulation.
Graphic 96323 Version 1.0

Distinguishing findings in the evaluation of suspected transfusion

reactions

Reaction

Clinical findings

Laboratory
findings

Implicated
products and
findings

Acute hemolytic
reaction

Fever, chills,
hypotension, DIC

Hemoglobinemia,
hemoglobinuria,
positive direct antibody
test (may be negative
if all cell have
hemolyzed), findings of
DIC (prolonged PT,
prolonged aPTT, low
fibrinogen,
thrombocytopenia)

RBCs

Anaphylactic reaction

Hypotension,
angioedema, wheezing,
respiratory distress

Hypoxemia, IgA
deficiency

RBCs, platelets, plasma

products

Acute lung injury

(TRALI)

Hypotension,
respiratory distress

Abnormal chest
radiography,
hypoxemia, transient
leukopenia, antineutrophil or anti-HLA
antibodies (only tested
in some cases)

RBCs, platelets, plasma

products

Circulatory overload
(TACO)

Respiratory distress,
rales

Abnormal chest
radiography,
hypoxemia

RBCs, platelets, plasma

products

Sepsis/bacterial
infection

Fever, chills,
hypotension, DIC

Bacteremia,
leukocytosis, findings
of DIC

Platelets most
commonly implicated,
but can be any product

Intended recipient does

not match actual
recipient

Product may show

bacterial contamination
Febrile non-hemolytic
reaction

Fever

None

Urticarial reaction

Hives

None unless specific

investigation is made

The table includes some common findings, but is not comprehensive and does not substitute for
clinical judgment in the patient evaluation. Refer to UpToDate topics on transfusion reactions for
details of evaluation, diagnosis, and management.
DIC: disseminated intravascular coagulation; PT: prothrombin time; aPTT: activated partial thromboplastin
time; RBCs: red blood cells; TRALI: transfusion-related acute lung injury; TACO: transfusion-associated
volume/circulatory overload.

Adapted from: Sazama K, DeChristopher PJ, Dodd R, et al. Practice parameter for the recognition,
management, and prevention of adverse consequences of blood transfusion. College of American
Pathologists. Arch Pathol Lab Med 2000; 124:61.
Graphic 94399 Version 2.0

Helpful features in distinguishing TRALI and TACO

Feature

TRALI

TACO

Body temperature

Fever may be present

Unchanged

Blood pressure

Hypotension may be present

Hypertension may be present

Respiratory symptoms

Acute dyspnea

Acute dyspnea

Neck veins

Unchanged

May be distended

Auscultation

Rales

Rales and S3 may be present

Chest radiograph

Diffuse bilateral infiltrates

Diffuse bilateral infiltrates

Ejection fraction

Normal

Decreased

PAOP

Most often 18 mmHg or less

Greater than 18 mmHg

Pulmonary edema fluid

Exudate

Transudate

Fluid balance

Neutral or negative

Positive

Response to diuretics

Inconsistent

Significant improvement

White cell count

Transient leukopenia may be

present

Unchanged

BNP

<250 pg/mL

>1200 pg/mL

TRALI: transfusion-related acute lung injury; TACO: transfusion-associated circulatory overload; PAOP:
pulmonary artery occlusion pressure; BNP: brain natriuretic peptide.
Modified with permission from: Skeate RC, Eastlund T. Distinguishing between transfusion related acute
lung injury and transfusion associated circulatory overload. Curr Opin Hematol 2007; 14:682. Copyright
2007 Lippincott Williams & Wilkins.
Graphic 86939 Version 4.0

Causes of acute dyspnea

Cardiovascular system
Acute myocardial ischemia
Heart failure
Cardiac tamponade

Respiratory system
Bronchospasm
Pulmonary embolism
Pneumothorax
Pulmonary infection - bronchitis, pneumonia
Upper airway obstruction - aspiration, anaphylaxis
Graphic 82700 Version 1.0

Contributor Disclosures
Contributor Disclosures
Arthur J Silvergleid, MD Nothing to disclose. Steven Kleinman, MD Consultant/Advisory Boards: Cerus Corp.
[pathogen reduction of blood components (Intercept Blood system)]. Equity Ownership/Stock Options: Cerus Corp.
Jennifer S Tirnauer, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy