Transfusion of Packed Red Cells
Indications, Triggers and Adverse Events
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Background: About four million units of packed red cells are transfused in Germany every year. The safety of blood transfusions is further improved by modern production methods and molecular diagnostic techniques.
Methods: This review is based on selected publications, including the German guidelines and regulations and the German Transfusion Act.
Results: Packed red blood cells are transfused to prevent tissue hypoxia. As the clinical manifestations of anemia are nonspecific, the indication for transfusion is based on surrogate parameters, such as the hemoglobin (Hb) concentration, in addition to clinical criteria. For patients with unimpaired cardiopulmonary and vascular function, transfusion is generally indicated at hemoglobin values of 6 g/dL (3.7 mmol/L) or less. Randomized controlled trials have shown that a restrictive transfusion strategy (trigger: Hb 7–8 g/dL) in certain patient groups is as effective as a more liberal strategy (trigger: Hb about 10 g/dL). The most frequent causes for transfusion errors are lack of informed consent, lack of identity checking and/or AB0 identity testing, and the drawing of blood samples in unlabelled tubes.
Conclusion: Overtransfusion, undertransfusion, as well as other transfusion errors can be markedly reduced by means of appropriate organizational measures and training.
The risk of viral transmission via transfusion of packed red blood cells in Germany has reached an all-time low. The reasons comprise the selection of donors and the screening for pathogens such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV) by molecular and serological methods. Transmission of transfusion-relevant viruses via blood products is nowadays a rare event, found only in isolated cases (1). For example, since the introduction of mandatory HCV-PCR (polymerase chain reaction) in Germany in 1999, there has been one single case of transfusion-related HCV transmission in 16 years. At an annual rate of about 4 million units of packed red cells, over 60 million units were transfused in this period (1).
Modern production methods using closed blood bag systems and “inline” leukocyte depletion also contribute towards the safety of modern blood products. All steps of production are subject to quality controls to ensure good manufacturing practice (GMP).
The use of blood preparations is closely regulated by:
- European Union directives
- The German Transfusion Act (TFG; )
- The German Medical Association (GMA) guidelines on collection of blood and blood components and use of blood products (hemotherapy) (3)
- The “Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives“ of the Scientific Advisory Board of the GMA (4).
Germany as well as other member states of the European Union have carried EU directives over into their own laws and guidelines, so that these regulations and recommendations are largely similar in EU member states. Nevertheless, in English-speaking countries, for example, the bedside test and certain laboratory tests are not mandatory, but there is a compulsory ID check by means of the patient’s wrist band.
After studying this article, the reader should:
- Be acquainted with the indications and triggers for packed red cell transfusion
- Be able to recognize, name, treat, and prevent the adverse events that may occur during transfusion
Indications for the transfusion of packed red cells
The transfusion of packed red cells is carried out to prevent manifest anemia-related tissue hypoxia. The administration of packed red cells is the “ultima ratio” of anemia treatment, employed to achieve the primary treatment goal in cases where causal treatment of the anemia is either not feasible or inadequate.
Preoperative anemia is a risk factor for a poor postoperative outcome in a patient (5). With the exception of emergencies and urgent indications for intervention, anemia should be diagnosed and treated before elective surgery. A retrospective analysis showed a fourfold risk of perioperative mortality for patients with mild anemia (hematocrit between 29% and 36% in women and between 29% and 39% in men) compared with those without anemia (30-day mortality: 3.52% for mild preoperative anemia versus 0.78% for hemoglobin/hematocrit in the normal range) (5). The diagnosis and causal treatment of preoperative anemia are not within the scope of this article. Because of the low specificity of clinical symptoms of anemia, surrogate parameters such as hemoglobin (Hb) concentration or hematocrit are used as transfusion triggers in addition to clinical criteria. Box 1 shows the clinical criteria, while Box 2 describes the so-called physiological transfusion triggers. The procedures described here are based not on the results of randomized studies, but on clinical observation and experience.
When determining the indications for administration of packed red cells, it is important to distinguish between acute hemorrhage and chronic anemia, e.g., in myelodysplastic syndrome (MLS).
In the case of an acute bleeding event, an important treatment goal is the maintenance or restoration of homeostasis, particularly normovolemia by means of volume replacement. Furthermore, along with the surgical treatment, management of coagulation is crucial to stop bleeding. Together with normothermia, physiological pH and ionized Ca2+ within the physiological range, the erythrocytes—particularly in the arterial circulation—contribute to laminar flow and thus to spatial proximity of thrombocytes and von Willebrand factor to the endothelium or endothelial defects, localizing them towards the vessel wall. In acute hemorrhagic shock and in manifest tissue hypoxia, timely administration of packed red cells is a life-saving measure. The dosage depends on the patient’s clinical status and on current and anticipated blood loss (4).
The administration of packed red cells has never been systematically investigated in double-blind controlled studies, e.g., in comparison with crystalloid volume replacement.
In a patient with normal cardiopulmonary and vascular performance, an Hb level of 6 g/dL or less (Hb <3.7 mmoL/L or hematocrit <18%) is seen as an “absolute“ indication for transfusion (4). In individual cases, particularly in the presence of chronic adaptation to anemia, the transfusion trigger may be lower (e.g., Hb 5.5 g/dL).
A patient with a stable Hb concentration of over 10 g/dL (Hb >6.2 mmoL/L or hematocrit >30%) without acute blood loss will generally gain no benefit from further administration of packed red cells. Here too, however, exceptions may be justified in individual patients. In such cases, the (physiological) transfusion trigger must be documented in the medical record (Table 1).
In an adult patient without an increase in red cell destruction, administration of one unit of packed red cells increases the hematocrit or Hb concentration by about 3% or 1 g/dL respectively (4). The standard transfusion rate is one bag per hour. In patients with cardiac or renal insufficiency, transfusion volumes and rates have to be individually adapted or reduced (4, 15).
Clinical studies on restrictive versus liberal transfusion triggers
Judging by the prospective randomized studies published to date, a restrictive transfusion strategy with transfusion triggers at 7 to 8 g Hb/dL seems to be non-inferior to a liberal treatment strategy with higher triggers—usually around 10 g/dL (6–11) in the following patient groups:
- Intensive care patients
- Pediatric and geriatric high-risk patients, the latter before total hip replacement
- Patients with upper gastrointestinal bleeding and moderate liver cirrhosis
- Patients in septic shock.
In special situations, e.g., in upper gastrointestinal bleeding, a restrictive strategy may even be slightly superior (6-week survival rate 95% versus 91% for a liberal strategy) (10). However, a pilot study came to the conclusion that a liberal transfusion strategy achieves a significantly lower 30-day mortality rate in patients with symptomatic coronary heart disease, with a trend towards fewer cardiac events, compared with a restrictive transfusion regimen (12). The findings of a recent study in post cardiac surgery patients are similar (25).
Further prospective randomized studies on restrictive transfusion regimens are required to confirm these early results (13), even though some experts already see a transfusion trigger of 7 g/dL as the new standard for almost all groups of patients (14).
Choice of packed red cells and order details
Packed red cells are usually transfused in an AB0-identical manner. In rare cases, packed cells that are AB0 non-identical but AB0 compatible can be transfused (Table 2).
Other blood group characteristics and blood group–specific serological findings have to be taken into account, in particular the following: the Rhesus (Rh) D factor; in certain groups of patients (e.g., regularly transfused patients, patients with known antierythrocytic antibodies, females of child-bearing age) other antigens of the Rh system (C, c, E, e) and the Kell blood group antigen K as well; the results of a recent antibody screening test; relevant data from emergency ID cards and maternity booklets; and the results of serological tolerance testing (cross-matching).
With the exceptions of acute emergencies, particular immunohematological constellations, or acute scarcity of resources, AB0-identical and Rh D–identical packed red cells are transfused (3, 4). Deviations from this rule must be documented. In the event of an acute bleeding crisis in a previously unknown person, packed cells of blood group 0 must be transfused until the patient’s blood group has been established by the laboratory. Even in emergencies, blood samples should be taken and sent for blood group determination and an antibody screening test before the transfusion of packed red cells is initiated. As soon as the results are received, transfusion should be switched to packed cells of the patient’s own AB0 blood group.
Rh D–negative patients should not receive Rh D–positive packed red cells. In an acute bleeding crisis or in the lack of Rh D–negative packed cells, however, Rh D–negative, non-Rh D–sensitized recipients may well have to be given Rh D–positive transfusions. There must be no evidence of Rh D–specific antibodies (anti-D) in the patient’s medical history (emergency ID card, maternity booklet) or in the antibody screening test.
In the event that Rh D–positive packed red cells have to be administered to an Rh D–negative recipient, this must be documented in the patient’s medical record, the patient must be informed, and the discharge letter should include the recommendation for antibody screening within the next 2 to 4 months. If antibodies relevant to transfusion are then demonstrated, the patient must be informed and counseled, and an emergency ID card must be issued. For the rest of his/her life, such antibodies must be considered whenever packed red cells have to be transfused. While such antierythrocytic allo-antibodies are rare in the general population (about or less than 1%), they may be found in up to 10% of regularly transfused patients.
With the exception of life-threatening situations in which no Rh D–negative blood can be obtained quickly enough, Rh D–negative girls and women of child-bearing age must not receive Rh D–positive packed red cells because of the risk of immunization and the subsequent danger of hemolytic disease of the newborn (HDN) (4). Furthermore, the danger of immunization to principal components of the Rh system such as C, c, D, E, or e and to antigen K with subsequent risk of HDN should always be avoided in girls and women of this age group.
Administration of packed red cells
Before the planned administration of packed red cells—with the exception of emergency transfusion—the treating physician must document the recipient’s transfusion history (Box 3). The patient should receive written and oral information about the possible necessity for blood transfusion as early as possible before standard interventions. Standardized information sheets are suitable for this purpose; they are amended to include details discussed between patient and physician, signed by both parties, and the patient receives a copy. The information given to the patient must always include how a transfusion takes place, the risks, potential complications and adverse effects involved, and potential alternatives to transfusion. If the likelihood of perioperative transfusion is estimated as ≥10%—according to local experience—the patient should be informed of the options for autologous hemotherapy, such as preoperative collection of the patient’s own blood for transfusion.
The written agreement of the patient or his/her legal representative—in children, the parent or legal guardian—must be obtained. Early discussion of transfusion gives the patient enough time to come to a decision. If information cannot be given in advance of transfusion, e.g., in an emergency or if the patient is unconscious, it must be provided at the earliest possible time thereafter.
If there is a realistic chance that a planned invasive or operative procedure will involve a transfusion, the patient’s blood group must be known and an antibody screening test carried out (no more than 3 days before the procedure). This “type and screen” strategy is particularly helpful if bleeding complications occur. In this event, the blood group and antibody status are known and the patient’s blood is available in the laboratory. If no transfusion-relevant antibodies are currently present or recorded in the patient’s medical history, unmatched packed red cells of the patient’s AB0 blood group can be used in such a case of emergency. This saves the scarce resources of blood group 0 packed red cells for emergencies in which the recipient’s blood group is initially unknown.
A positive antibody screening test is followed by identification of the antibodies present. If any transfusion-relevant antibodies are found or were already known, planned interventions must be preceded by allocation of a quantity of compatible, i.e., antigen-negative packed red cells sufficient not only for the anticipated perioperative requirements but also for potential complications. This necessitates close cooperation between the laboratory staff and the treating physicians.
If the planned intervention has a high likelihood of perioperative administration of packed red cells (according to local hospital data), the serological compatibility of the patient’s plasma and the packed cells provided should be tested before the intervention (cross-matching).
Ordering packed red cells
The order for packed red cells should generally be placed in writing or electronically. In Germany, blood products require a prescription. This requirement is fulfilled by the physician signing the request form. Requests for emergency transfusions can be made by telephone or fax. The steps involved in an emergency transfusion must be laid down in the local regulations governing transfusion and should be regularly practiced by all parties involved.
The following information should be given on the request form or in the blood bank’s electronic module for ordering blood products:
- Patient’s family name, given name, date of birth, and treatment number
- Ward and location for delivery (e.g., operating theater)
- Patient’s diagnosis and transfusion history (Box 3).
- Type and number of blood products required
- Any special requirements (e.g., irradiated blood products)
- Urgency of transfusion; anticipated further requirements, if any
- Date, physician’s signature (legible!), and telephone number.
Preparation and execution of transfusion, with practical tips
The collection tubes to be filled with blood samples for blood group testing, antibody screening test, and cross-matching must be labeled in advance. Preprinted patient labels can be used for this purpose. The information on each tube must include at least the patient’s family name, given name, and date of birth. Should identification be impossible, another means of labeling must be agreed, e.g., the use of sets of labels with serial numbers. Collection of blood samples in unlabeled tubes is one of the principal causes of error and must be avoided.
The patient’s identity must be clearly established at the bedside before withdrawal of blood. The person taking the samples must ask the patient for identifying details such as date of birth, address, family name, and given name. These data are then compared with the labels on the collection tubes and the request form. After collection of the required samples the date and time of withdrawal is added to the request form and the form is signed. If the person who collects the samples is not the physician ordering the blood products, the latter must also sign the request form. The physician always bears responsibility for the request and for the withdrawal of blood, whether delegated or not, and thus for the identity of the sample. Before the administration of packed red cells the checks detailed in Box 3 must be carried out.
AB0 identity testing
AB0 identity testing (bedside testing), important for patient safety, must be carried out and documented by the physician at the patient’s bedside. Checking the recipient’s AB0 blood group is mandatory. The result must be compared with the AB0 blood group of the packed red cells and the blood group recorded in the accompanying documentation. The results of the patient AB0 bedside and identity check must be entered in the medical record with the date, time, and physician’s initials. Only for autologous blood products do the packed red cells also have to be tested; for allogeneic transfusions the AB0 bedside testing of the recipient suffices. The AB0 bedside test must be performed every single time packed red cells are given—even in emergencies. The bedside test should be repeated whenever one of the four crucial parameters—physician, patient, place, time—changes.
Administration of packed red cells
Transfusion of packed red cells should always be carried out using a standard transfusion set with a filter (pore diameter 170–230 μm), never with a system that does not include a transfusion filter. Two or more units of packed cells should be given consecutively, not in parallel, with the exception of massive or emergency transfusions. The transfusion should be given via an exclusive venous port; drugs or other infusates should not be mixed with the packed red cells or administered simultaneously through the same port. In the case of transfusion via a central venous catheter, it must be ensured that no other parenteral solution is administered simultaneously via the same lumen.
The transfusion is initiated by the physician. He/she is responsible for ensuring that the patient is continuously monitored during the administration of packed red cells and thereafter. During and after transfusion a physician must be immediately available for swift intervention should any adverse events occur. Outpatient recipients must be advised of the risk of delayed adverse events. All patients should be observed for about an hour after transfusion.
In the rare event that packed red cells have to be heated to body temperature before transfusion, only certified blood heaters may be used for this purpose. The heated packed cells should then be transfused as soon as possible. Opened bags must be used within 6 h. Following transfusion, the transfusion set has to be closed in sterile fashion and retained, together with the empty bag, for 24 h at a temperature of + 1°C to + 10°C.
Documentation of packed red cell transfusion
The following information should be documented in the patient’s medical record:
- Patient information and clinical indication for transfusion
- Results of identity check and AB0 bedside test
- Product designation
- Manufacturer and batch number—together with the product designation, these are summarized in the bar code on the bag
- Date and time of packed red cell transfusion
- If applicable, adverse events and transfusion-related effects such as amelioration of symptoms or increase in Hb concentration.
In parallel with the patient-related documentation, product-related documentation is also required. Nowadays this product-associated batch documentation is often accomplished with the aid of an IT system or in the laboratory. These records are to be preserved for 30 years to enable later reconstruction.
Irradiated packed red cells
Despite leukocyte depletion, bags of packed red cells may contain a small number of vital donor lymphocytes that can lead to transfusion-associated graft-versus-host disease (ta-GvHD) in immunocompromised recipients (e.g., patients with Non-Hodgkin lymphoma [NHL]). For this reason the packed cells to be used in such circumstances must be irradiated with at least 30 Gy before transfusion. This information has to be included on the request form sent to the blood bank. Because the irradiation elevates the potassium concentration of the packed red cells, irradiated bags have a reduced shelf life and—especially in children and patients with renal insufficiency—should only be ordered from the blood bank when transfusion is scheduled within the ensuing 24 h. The maximum storage time for irradiated packed red cells depends on the terms of licensing for the individual product and is provided in the manufacturer’s product information accompanying every unit of packed cells (eBox 1).
Washed packed red cells
Washed packed red cells are rarely indicated. Early contact with the responsible transfusion specialist is recommended.
Cryopreserved packed red cells
Cryopreserved packed red cells are required in extremely rare cases in patients with multiple transfusion-relevant antibodies or antibodies to high frequent antigens. Particularly early contact with the responsible transfusion specialist is essential.
Contraindications, risks, and adverse events
Provided transfusion is indicated and the transfusion triggers are observed, there are no contraindications to the administration of packed red cells. Serological tolerance should be assured by means of the investigations described above. In patients scheduled for hematopoietic stem cell transplantation, administration of packed red cells donated by blood relatives or potential stem cell donors must be strictly avoided. Members of some religious faiths follow particular rules regarding blood and transfusion, and in such cases the patient’s wishes must be respected.
Transfusion of cellular blood products, seen as transplantation of the fluid organ blood, represents an immunological challenge for the recipient organism. Whether transfusion-related immunomodulation (TRIM) has a negative influence on the postoperative outcome is currently being investigated. The results of these studies will show whether the connection between TRIM and unfavorable outcome postulated from retrospective observation withstands prospective scrutiny. It must be remembered that preoperative anemia represents an independent correlation factor for elevated perioperative morbidity and mortality. This has been shown for coronary bypass surgery (16), major non-cardiosurgical interventions (5), and colorectal surgery (17).
Studies from the past 2 years (18–20) show that both preoperative anemia before coronary bypass surgery and transfusion seem to contribute to the perioperative risk. A meta-analysis of the prospective trials on restrictive transfusion triggers (18) concluded that restrictive transfusion strategies appear to lead to fewer periprocedural infections than liberal transfusion strategies. Acute transfusion reactions can be distinguished from delayed reactions, and immunological from non- immunological reactions (eTable). The estimated frequencies of occurrence of transfusion-related adverse events together with their pathophysiology, treatment, and prophylaxis are given in Table 3a, b.
- If they are suspected of a causal connection with the administration of packed red cells
- If they occur at the time of administration of packed red cells, with or without suspicion of a causal connection.
Conflict of interest statement
Dr. Müller has received consulting fees from Novartis Pharmaceutical Corporation. He has received payments from Fresenius KABI and Cerus for the preparation of scientific training courses. Furthermore, he has received funding from Cerus for research that he initiated.
Prof. Seifried and Dr. Geisen have received funding from Cerus for research that they initiated.
Prof. Zacharowski has received consulting fees from Vifor Pharma. He has received reimbursement of travel costs and attendance fees for training courses as well as honoraria for the preparation of scientific training courses from B. Braun, CSL Behring, Fresenius KABI, and Vifor Pharma. He has received funding from Fresenius KABI, B. Braun, Vifor Pharma, and CSL Behring for research that he initiated.
Prof. Tonn declares that no conflict of interest exists.
Manuscript received on 13 June 2014, revised version accepted on
6 May 2015.
Translated from the original German by David Roseveare.
Dr. med. Markus M. Müller
Institut für Transfusionsmedizin und Immunhämatologie
DRK-Blutspendedienst Baden-Württemberg – Hessen gemeinnützige GmbH
Sandhofstr., 60528 Frankfurt am Main, Germany
eTable and eBoxes:
|1.||Paul-Ehrlich-Institut (PEI, Langen; Hrsg.): Hämovigilanzbericht des Paul-Ehrlich-Instituts 2011/12 – Auswertung der Meldungen von schwerwiegenden Transfusionsreaktionen nach § 63 c AMG: www.pei.de/haemovigilanzbericht (last accessed on 19 December 2014)|
|2.||Gesetz zur Regelung des Transfusionswesens (Transfusionsgesetz – TFG); Geltung ab 01. 07. 1998, Stand: zuletzt geändert durch Art. 12 des Gesetzes zur Änderung arzneimittelrechtlicher und anderer Vorschriften vom 17. 07. 2009 (BGBl. I S. 2012).|
|3.||Bundesärztekammer: Richtlinien zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Hämotherapie) – Aufgestellt gemäß Transfusionsgesetz von der Bundesärztekammer im Einvernehmen mit dem Paul-Ehrlich-Institut; Gesamtnovelle 2005 – mit Richtlinienanpassung 2010; Deutscher Ärzte-Verlag, Köln; 2010.|
|4.||Wissenschaftlicher Beirat der Bundesärztekammer: Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten – Herausgegeben von der Bundesärztekammer auf Empfehlung ihres Wissenschaftlichen Beirats; 4. überarbeitete Auflage; Deutscher Ärzte-Verlag, Köln, 2014.|
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