Red blood cell transfusion in infants and children: Administration and complications

INTRODUCTION — Transfusions of red blood cells (RBCs) are given to children for a wide range of indications, including anemia due to congenital or acquired disease or blood loss from trauma, surgery, and/or frequent blood sampling. RBC transfusion has significant risks, including volume overload, transmission of infectious agents, and various immunologic consequences including transfusion reactions. Many of these complications can be avoided with careful administration of RBC transfusions.

The administration and complications of RBC transfusion in infants and children will be reviewed here. Other aspects of RBC transfusion in infants and children are discussed in separate topic reviews:

●(See "Red blood cell transfusion in infants and children: Indications".)

●(See "Red blood cell transfusion in infants and children: Selection of blood products".)

●(See "Red blood cell (RBC) transfusions in the neonate".)

●(See "Pretransfusion testing for red blood cell transfusion".)

INFORMED CONSENT — Except in emergency situations, specific informed consent for transfusion should be obtained and is required by the Joint Commission [1]. Parents or guardians are generally able to give this consent, although the additional assent of the child should also be considered. Teenagers in some states are able to give consent for their own medical treatment under certain circumstances.

The informed consent process should include all of the following components (see "Patient education: Blood donation and transfusion (Beyond the Basics)"):

●Discussion of the expected benefits of transfusion

●Disclosure of the risks of transfusion (see 'Complications' below)

●Disclosure of the alternatives to transfusion, including no transfusion or, when appropriate, the option of medications such as iron or erythropoietin (EPO)

When the parent or guardian is unable or unwilling to give consent and clinicians feel that transfusion is medically necessary, guidance of the courts is often sought, with the appointment of a guardian specifically to give this permission.

The treatment of children of Jehovah's Witnesses should be individualized [2]. In general, the church is opposed to storage of blood for transfusion, but local groups and individuals within these groups take different positions about what kinds of hematologic support may be acceptable. In cases in which the child is placed at substantial medical risk because of parental nonconsent, court approval is often sought for transfusion. (See "Approach to the patient who declines blood transfusion".)

ADMINISTRATION

Patient identification — As the infectious risks of transfusion continue to decline, more attention is being paid to other preventable hazards of transfusion, including known causes of transfusion-related deaths [3]. High on this list is a hemolytic transfusion reaction due to a misidentified patient or specimen, which occurs with a frequency greater than that of transfusion-associated transmission of HIV or hepatitis C [3,4]. (See "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)

It is not uncommon to have two patients on the same hospital floor with the same first and last name but different blood types who both require blood transfusion. As a result, all patients in the hospital, including children, should have armbands or similar methods of identification. These should be examined explicitly at the time specimens are drawn for blood bank testing and again immediately before each unit of blood is transfused. Careful attention should be paid to the labeling requirements of specimens for the blood bank [5,6]. Hospitals are increasingly using either a two-sample process (both drawn independently) for ABO/Rh typing prior to transfusion or electronic patient identification for sample labelling to decrease the risk of transfusion errors [7,8].

Infusion pumps and catheter size — Ordinary infusion pumps or roller infusion devices can be used to administer RBC transfusions without risk of causing hemolysis [9]. However, one practical concern in administering blood to children, particularly small infants, is the slow flow of blood products through small intravenous (IV) catheters. Blood under minimal pressure can be transfused through a 22-gauge catheter but will flow very slowly. Higher rates of flow can be achieved with pressure devices. Minimal hemolysis is caused by pressures of up to 300 mmHg and catheter sizes as small as 22 gauge [10].

Filters — Blood must always be administered through a filter to remove small aggregates and blood clots that may have formed during storage [11]. The usual filter is 170 to 260 microns. These devices do not provide leukoreduction.

Many blood centers in the United States and other countries have adopted a policy of "universal leukoreduction," in which all RBC and apheresis platelet products are leukoreduced using a filtration process. Leukocyte reduction is usually performed at the time of collection. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Leukoreduced red blood cells'.)

Volume — The volume of blood to be transfused varies with the clinical situation. The usual transfusion volume is 10 to 15 mL/kg. Because infants have higher blood volume per kg compared with children, they tend to need transfusion volumes on the higher end of this range to achieve the desired hemoglobin concentration. If the hematocrit in the selected RBC product is approximately 65 percent, this volume will usually raise the hemoglobin concentration by 2 to 3 g/dL or the hematocrit by 6 to 9 percent [12]. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Red blood cells'.)

In neonates, the small volumes require the use of special equipment, which is discussed separately. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Administration'.)

Infusion duration — Blood issued for transfusion should be infused within four hours. More rapid infusion is appropriate when there is acute blood loss resulting in compromised tissue perfusion. (See "Trauma management: Approach to the unstable child", section on 'Blood products'.)

If the transfusion will take longer than four hours because of slow flow or other issues, the blood bank can divide the unit into smaller aliquots so that each can be transfused within four hours. In special circumstances, such as for the operating room or a remote clinic, the blood bank may issue RBC units in coolers that have been validated to maintain the appropriate storage temperature.

A transfusion rate of approximately 2.5 mL/kg/hour usually avoids circulatory overload. Thus, an RBC transfusion of 10 mL/kg usually is transfused over a four-hour period. Patients deemed to be at risk for volume overload (such as those with impaired cardiac function) can be transfused at a slower rate of 1 mL/kg/hour.

Compatible fluids — IV normal saline (0.9% sodium) is compatible with RBCs and can be given concomitantly through the same tubing if IV fluid is required for hydration or to maintain the patency of the catheter. ABO-compatible plasma and albumin are also compatible with RBCs. No other IV solutions or medications should be administered through the same tubing concurrently with the RBC units [11]. Exceptions can be made for products that have explicit approval for compatibility with RBCs in the package insert approved by the US Food and Drug Administration. Such approval has been granted for some isotonic, calcium-free electrolyte solutions.

Commonly used IV solutions that are incompatible with RBCs include:

●Hypotonic solutions (including 5% aqueous dextrose and 5% dextrose in 0.225% saline) because they can cause hemolysis

●Lactated Ringer solutions or other calcium-containing solutions because calcium in these products reverses the anticoagulation in the RBC preparation, causing clotting

If a single line is being used, the tubing should be flushed carefully before and after blood administration if a potentially incompatible fluid has been infused.

Additional discussion regarding compatibility of IV fluids and medications with RBC transfusion is provided separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Compatible fluids'.)

Blood warmers — RBCs are preserved in the blood bank at 1 to 6°C. For a slow transfusion, this temperature may not pose a problem. However, the use of a blood warmer is recommended in the following clinical settings:

●Unstable infants

●Patients who require rapid transfusion of a large amount of blood (>15 mL/kg/hour)

●Patients who require exchange transfusions

●Patients with cold agglutinin disease (see "Cold agglutinin disease", section on 'Transfusions')

If the blood requires warming, it is warmed at the time of transfusion using an approved and calibrated device. These devices must be monitored since excessive warming can cause hemolysis. Blood should never be warmed in an uncontrolled way.

Exchange transfusion — RBC exchange can be performed with an automated apheresis instrument, unless the patient is very small. The automated controls of these instruments are quite accurate in providing the desired target hemoglobin value, and their utility has been demonstrated in a number of studies [13,14]. RBC priming of the instrument is recommended if the extracorporeal volume is more than 10 to 15 percent of the estimated total blood volume (eg, children weighing <10 kg and those with severe anemia) [15].

Most instruments require two sites of vascular access for draw and return; this can be problematic in children who have poor venous access. In emergency settings, double-lumen central catheters, commonly used for hemodialysis, can be placed in the femoral vein. For long-term venous access for repeated exchanges, a surgically implanted port or central venous catheter may be required.

Exchange transfusion in neonates is discussed separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care", section on 'Exchange transfusion'.)

COMPLICATIONS — Undesirable sequelae of transfusion may be divided into infectious and noninfectious categories. As transfusion-transmitted infections have dramatically decreased since the 1980s and 1990s, the most common adverse events in the modern era are noninfectious transfusion reactions [16,17].

The following is a brief review of the different complications from blood transfusions, each of which is discussed in detail elsewhere.

Infection — All donated blood is extensively screened for transfusion-transmitted infections; as a result, the risk of acquiring infection is extremely low (table 1). The table lists the infectious agents for which donated blood is routinely screened in the United States (table 2). A more complete discussion on the screening for transfusion-transmitted infection is found elsewhere. (See "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)

Residual risk remains largely from "window period" donations, during the time when antigens and/or antibodies are of such low level as to be undetectable by current techniques.

The risk of bacterial contamination of blood products is greater than the risk of viral transmission, especially for platelet products since they are stored at room temperature [16,18]. Bacterial contamination of blood products can occur at the time of collection or because the donor had occult bacteremia at the time of donation. Temperature elevation, hypotension, or other signs of sepsis should be investigated carefully in a patient who has received a transfusion. (See "Blood donor screening: Medical history", section on 'General symptoms of active infection' and "Transfusion-transmitted bacterial infection".)

Transfusion reaction — Transfusion reactions occur in approximately 1 percent of children who received RBC transfusions [19].

These reactions are briefly reviewed here and are discussed in greater detail elsewhere.

●Acute hemolytic reactions – Acute hemolytic transfusion reactions usually result from transfusion of ABO-incompatible RBCs due to clerical errors. This complication is best prevented, rather than treated, by meticulous attention to patient and sample identification. Treatment is supportive. (See 'Patient identification' above and "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)

●Delayed hemolytic reactions – Delayed hemolysis results when the patient produces an antibody days following a blood transfusion or by anamnestic response. It presents 2 to 10 days following transfusion as jaundice and/or an unexpected fall in hemoglobin. A delayed hemolytic transfusion reaction is confirmed by repeat antibody screening of the patient's plasma, which demonstrates the presence of a specific alloantibody that was not previously present or identified. Positive direct antiglobulin test for immunoglobulin G (IgG) with a positive eluate against the corresponding antigen will confirm the diagnosis. Many RBC antibodies can cause delayed hemolysis, such as anti-C, anti-E, anti-K, anti-Jka and anti-Jkb. Subsequent RBC transfusions should utilize blood that tests negative for the newly identified antigen. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

●Febrile reactions – Febrile reactions not due to hemolysis are usually related to the presence of cytokines produced by passenger leukocytes. Treatment includes stopping the transfusion and excluding a hemolytic reaction or sepsis as the cause of fever. Antipyretic therapy is given for symptomatic relief. These reactions are reduced with leukoreduction. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions' and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Leukoreduced red blood cells'.)

●Allergic and anaphylactic reactions – An anaphylactic, allergic, or anaphylactoid reaction to a blood transfusion can vary in severity from mild hives and itching to fatal anaphylaxis. While more common with plasma and platelet transfusions, these reactions also may occur following RBC transfusion. Treatment is supportive, usually including antihistamines. (See "Immunologic transfusion reactions", section on 'Allergic reactions'.)

●Transfusion-associated acute lung injury (TRALI) – TRALI is an important cause of transfusion-related mortality and should be suspected when dyspnea, bilateral noncardiogenic pulmonary edema, hypotension, and fever occur within six hours of completion of transfusion. It is due primarily to the interaction between leukocytes from the recipient and anti-human leukocyte antigen antibodies or antigranulocyte antibodies from the donor. Treatment is supportive. TRALI is discussed in greater detail separately. (See "Transfusion-related acute lung injury (TRALI)".)

●Transfusion-associated circulatory overload (TACO) – TACO may occur in children, although it is less common in children compared with adults. In the modern era, TACO is the leading cause of transfusion-related mortality [20]. Manifestations may begin near the end or within six hours after the transfusion. Patients should be monitored closely during this time period for suggestive signs and symptoms, including dyspnea, orthopnea, tachycardia, and a wide pulse pressure, often with hypertension. Patients deemed to be at risk for volume overload (such as those with impaired cardiac function) can be transfused at a slower rate (see 'Infusion duration' above). Diuretic therapy (eg, furosemide 0.5 to 1 mg/kg/dose) may be used as a preventive measure and/or for treatment of symptoms. TACO is discussed in greater detail separately. (See "Transfusion-associated circulatory overload (TACO)".)

●Distinguishing between TRALI and TACO – The symptoms of TRALI and TACO are similar. Distinguishing features are as follows:

•TACO usually is associated with transfusion of a large volume of blood or a high rate of infusion; TRALI may occur with relatively small volumes at a slow rate.

•Hypertension is commonly seen in TACO but is uncommon in TRALI.

•Fever is typically absent in TACO, whereas TRALI is often associated with fever.

•Brain natriuretic peptide is often elevated in patients with TACO, whereas it may be normal in TRALI [21,22].

•Patients with TACO usually respond well to diuretic therapy; the response to diuretic therapy in patients with TRALI is variable.

Metabolic toxicity — Metabolic toxicities from RBC transfusion include the following [23-29]:

●Hypocalcemia and/or hypoglycemia, which results from the infused citrate in the preservative solution. Newborns are at particular risk for this complication.

●Hyperkalemia in patients who receive large volumes of blood (eg, exchange or massive transfusions) or rapid transfusion of irradiated blood (radiation increases cellular leakage of potassium). Children who receive large quantities of blood infused through a central line, as in exchange transfusions or massive transfusions, are at particular risk for hyperkalemia [30-34]. Some institutions will provide either fresh RBCs or washed RBCs if hyperkalemia is a concern. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Hyperkalemia'.)

●Clinically significant accumulation of mannitol (a component of preservative solutions) in neonates who receive large volumes of blood may result in an osmotic diuresis.

●Clinically significant accumulation of adenine (a component of preservative solutions) in young infants who receive large volumes of blood may cause nephrotoxicity.

Graft-versus-host disease — Transfusion-associated graft-versus-host disease (TA-GVHD) is almost universally fatal and can be prevented by the use of irradiated products. It is caused by viable, competent donor lymphocytes that are transfused into a patient whose immune system either does not recognize the cells as foreign or does not have the capacity to destroy them. To reduce the risk of TA-GVHD in patients requiring RBC transfusion, it is important to consider the immune status of the child and use irradiated products if indicated (table 3). Patients who are at risk for TA-GVHD include premature, low birth weight infants; infants and children with primary immunodeficiencies; organ transplant recipients; and patients receiving chemotherapy or other immunosuppressive therapy. (See "Transfusion-associated graft-versus-host disease" and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Irradiated red blood cells'.)

Iron overload — Iron overload can be a significant problem in children who are transfused chronically. As an example, patients with thalassemia major can develop heart failure or fatal arrhythmia due to deposition of cardiac iron if they are not treated with an iron chelator. The excess iron from transfusions is compounded by increased iron absorption due to ineffective erythropoiesis.

Children who are at risk for iron overload can be treated with iron chelation therapy. Iron chelation therapy can reduce the damage produced by the lifelong need for RBC transfusions in these children. In addition, exchange transfusion rather than simple transfusion has been used in children with sickle cell disease, partly to reduce the risk of iron overload. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

MEASURES TO REDUCE TRANSFUSION

Erythropoietin — Use of recombinant human erythropoietin (EPO) to increase the patient's endogenous production of RBCs has been investigated, but its role in reducing blood transfusions in infants and children remains limited.

The possible efficacy of EPO has been studied in the following clinical settings:

●Premature infants – Although EPO has been reported to reduce the number of transfusions in premature infants, it does not generally eliminate the need for transfusion. This is discussed separately. (See "Anemia of prematurity (AOP)", section on 'Erythropoiesis stimulating agents (ESAs)'.)

●Children with cancer – Reports vary on whether EPO is effective in reducing blood transfusions in children with cancer [35-38].

●Children with chronic renal failure – EPO is a standard therapy for the anemia associated with chronic renal failure, which is due to reduced EPO production by the kidney. This is discussed separately. (See "Chronic kidney disease in children: Complications", section on 'Anemia'.)

●Myelodysplastic syndrome and bone marrow failure syndromes – EPO plays a role in the management of patients with anemia due to myelodysplastic syndrome, but it is not effective in treating the anemia associated with bone marrow failure syndromes (eg, aplastic anemia, Diamond-Blackfan anemia). These conditions are discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents' and "Diamond-Blackfan anemia" and "Treatment of acquired aplastic anemia in children and adolescents".)

Artificial oxygen carriers — "Artificial blood" (ie, oxygen therapeutics or oxygen carriers) are substances that can fulfill some of the oxygen-carrying function of the RBC and have been under investigation as a measure to reduce transfusion. They consist of either noncellular hemoglobin solutions stabilized to prevent immediate removal by the kidneys or perfluorocarbon emulsions capable of transporting dissolved oxygen. There are no artificial oxygen carriers that are approved by the US Food and Drug Administration, but they can be used on compassionate use. (See "Oxygen carriers as alternatives to red blood cell transfusion".)

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".)

SUMMARY AND RECOMMENDATIONS

●Informed consent – Except in emergency situations, specific informed consent for transfusion should be obtained prior to administration of red blood cell (RBC) transfusion. The informed consent process should include disclosure of the expected benefits of transfusion; potential risks; and alternatives, including no transfusion or, when appropriate, the option of medications such as iron or erythropoietin (EPO). (See 'Informed consent' above.)

●RBC transfusion volume and infusion duration – The usual RBC transfusion volume in children is 10 to 15 mL/kg; this volume is expected to raise the hemoglobin concentration by 2 to 3 g/dL. To avoid volume overload, the transfusion should be given slowly, at approximately 2.5 mL/kg/hour (10 mL/kg over four hours). If the transfusion will take longer than four hours because of slow flow or other issues, the blood bank can issue the transfusion in smaller aliquots so that each can be given over less than four hours. (See 'Volume' above and 'Infusion duration' above.)

●Infectious screening – In the United States, each unit of blood is screened for a number of infections, as summarized in the (table 2) and discussed separately. (See "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)

Residual risk remains largely from "window period" donations, during the time when antigen and/or antibody are of such low level as to be undetectable by current techniques. This risk is very low. (See 'Infection' above.)

●Transfusion reactions – Transfusion reactions occur in approximately 1 percent of children who received transfusions. Types of transfusion reactions include (see 'Transfusion reaction' above):

•Acute hemolytic reactions, which usually result from the mistransfusion of ABO-incompatible RBCs and are best prevented by meticulous attention to patient and sample identification. (See 'Patient identification' above.)

•Delayed hemolytic reactions, which present 2 to 10 days following transfusion as jaundice and/or an unexpected fall in hemoglobin. These reactions result when the patient produces an antibody during the days following a blood transfusion or by anamnestic response. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

•Febrile reactions are usually related to the presence of cytokines produced by passenger leukocytes and can be reduced with leukoreduction. Treatment includes stopping the transfusion, excluding a hemolytic reaction or other causes of fever, and administering antipyretic therapy for symptomatic relief. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions' and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Leukoreduced red blood cells'.)

•Allergic and anaphylactic reactions can vary in severity from mild hives and itching to fatal anaphylaxis. Treatment is supportive and often includes antihistamines. (See "Immunologic transfusion reactions", section on 'Allergic reactions'.)

•Transfusion-associated acute lung injury (TRALI) is an important cause of transfusion-related mortality and should be suspected if a patient develops dyspnea, pulmonary edema, hypotension, and fever within six hours of a transfusion. (See "Transfusion-related acute lung injury (TRALI)".)

•Transfusion-associated circulatory overload (TACO) may occur, particularly in children with impaired cardiac function. Symptoms typically begin near the end of the transfusion or within the subsequent six hours. Patients should be monitored closely during this time period for suggestive signs and symptoms, including dyspnea, orthopnea, tachycardia, and a wide pulse pressure, often with hypertension. (See "Transfusion-associated circulatory overload (TACO)".)

●Metabolic side effects – Metabolic derangements that can result from RBC transfusion include hypocalcemia, hypoglycemia, and hyperkalemia. Neonates are at risk for accumulation of mannitol and/or adenine, which can cause an osmotic diuresis and/or nephrotoxicity. (See 'Metabolic toxicity' above.)

●Transfusion-associated graft-versus-host disease (TA-GVHD) – TA-GVHD is almost universally fatal and can be prevented by the use of irradiated products. Patients who are at risk for TA-GVHD (and hence should receive irradiated products) include premature, low birth weight infants; infants and children with primary immunodeficiencies; organ transplant recipients; and patients receiving chemotherapy or other immunosuppressive therapy (table 3). (See 'Graft-versus-host disease' above and "Transfusion-associated graft-versus-host disease" and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Irradiated red blood cells'.)