Guideline on the investigation and management of acute transfusion reactions

Abstract

This guideline was compiled according to the British Society for Haematology (BSH) process at https://b-s-h.org.uk/media/19922/bsh-guidance-development-process-july-2021.pdf. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations.1 The GRADE criteria can be found in Appendix S3 of the above BSH document. The literature search was performed in January 2021 and updated in January 2022. With the assistance of the Oxford Systematic Reviews Initiative (SRI), the following databases were searched for relevant publications in English: MEDLINE (from 1950), EMBASE (from 1980), CINAHL (from 1982), The Cochrane Library, DARE (CRD website) and SRI hand search databases. The initial search and filtering produced 1693 systematic reviews, randomised controlled trials and observational studies from which relevant publications were extracted by the members of the Writing Group. Search terms include Transfusion AND (‘TACO’ OR ‘TRALI’ OR ‘TAD’ OR ‘pulmonary complication’ OR ‘lung’ OR ‘pulmonary oedema’ OR ‘respiratory’ OR ‘ARDS’ OR ‘reaction’ OR ‘anaphylaxis’ OR ‘febrile reaction’ OR ‘allergic reaction’ OR ‘non haemolytic reaction’ OR ‘haemolytic reaction’), wrong blood to wrong person, incompatible transfusion reaction, ABO-related incompatible transfusions. The guideline does not cover the detailed medical management of ATRs such as treatment of cardiac/respiratory failure or bacterial sepsis. Measures that might be employed for primary prevention of ATRs are outside the scope of the guideline. Readers may also find it useful to cross reference to other related British Society for Haematology guidelines such as The Administration of Blood Components and Pre-Transfusion Compatibility Procedures in Blood Transfusion Laboratories; all are available at https://b-s-h.org.uk/guidelines. The full guideline with appendices providing detailed information on symptoms and signs, laboratory investigations, the International Society for Blood Transfusion (ISBT)/International Haemovigilance Network (IHN) classification of ATRs, a table describing differences between transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) and an algorithm for investigating and categorising pulmonary complications of transfusion can also be found on the BSH guidelines website. 2 2 2 2 2 2 B B C C B C 1 2 C C Acute transfusion reactions (ATRs) are defined as those occurring within 24 h of the administration of blood or blood components.2 ATRs vary in severity from minor febrile reactions to life-threatening allergic, haemolytic or hypotensive events. Allergic and febrile non-haemolytic transfusion reactions (FNHTR) are those most commonly reported, but the true incidence of ATR is uncertain as most haemovigilance systems only collect information on the more serious reactions, there are wide variations in institutional reporting rates and the introduction of new processes may differentially alter reaction rates over time (e.g. prestorage leucodepletion reduces the rate of FNHTR but not allergic reactions).3, 4 ATR rates of 0.5–3% of transfusions are commonly quoted.5 The 2020 Serious Hazard of Transfusion (SHOT) report reviewed 10 years of reporting data and calculated the risk of a febrile, allergic or hypotensive reaction as 1:7704 and the risk of a haemolytic reaction as 1:57425. Pulmonary complications were the foremost cause of morbidity and mortality accounting for 65% of reported transfusion-related deaths. Platelets are the components with the highest number of reported reactions per 10 000 transfusions.6 There is uncertainty about the cause of ATRs. There is good evidence, supported by the impact of leucodepletion, that many febrile reactions are caused by reactions to donor white cells or accumulation of biological response modifiers during component storage.7 Except in rare cases, a specific allergen will not be identified in patients with allergic transfusion reactions,8 although plasma reduction may lower their frequency.9 It is increasingly recognised that recipient factors, particularly underlying diagnosis and allergic predisposition, may be paramount in predicting allergic transfusion reactions.10-13 It is possible that genetic polymorphisms play a role.14, 15 Patients' age, physical characteristics and baseline observations may be significant risk factors for development of febrile reactions.16-18 Preventative strategies should be directed at the minority of patients who have a propensity to severe reactions. Although it is useful to categorise ATR for reporting and research purposes and for international comparison,19 patients with severe ATR often present with an overlapping complex of symptoms and signs, the differential diagnosis of which includes potentially life-threatening allergy or anaphylaxis, acute haemolytic transfusion reactions, bacterial transfusion-transmitted infection, transfusion-associated acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO). Transfusion-associated dyspnoea (TAD) may be suspected when respiratory distress has a temporal association with transfusion and does not meet the criteria for allergic reaction, TRALI or TACO. The initial clinical picture is also often obscured by factors related to the patient's underlying medical conditions, such as febrile septic episodes in neutropenic patients who also happen to be receiving a blood component transfusion. For this reason, this guideline will consider all causes of a possible reaction during blood transfusion and focus on initial recognition and general management of the clinical problem, guided in the main by symptoms and clinical signs and assessment of the severity of the problem. This allows appropriate investigation, specific treatment and, where possible, prevention of future episodes. To minimise the risk of harm, early identification of transfusion reactions and rapid clinical assessment are essential. If transfusions are administered at a patient's home, these should only be conducted in accordance with well-developed policies in patients deemed to be at low risk of ATR while otherwise abiding by the above recommendations. Although anaphylactic and haemolytic reactions can present after only a small volume of blood has been transfused,20 reactions can present much later, on occasion several hours after completion of the transfusion.21 Delayed haemolytic reactions can present after days to weeks. Therefore, observation and monitoring are required throughout the transfusion episode and patients should be asked to report symptoms which develop after transfusion, particularly fever, dark urine, jaundice or symptoms suggestive of anaemia.22 Unconscious patients, or those unable to report symptoms, require direct monitoring. The evidence on the use of early warning scores (EWS) to aid recognition of reactions is limited; however, when changes from the baseline are seen in EWS during or post-transfusion, consideration should be given to a possible transfusion reaction. Retrospective analysis has shown that in cases of patient deterioration the link to the transfusion is not always recognised and in particular pulmonary complications may not be identified.23 Patients should be asked to report symptoms which develop following completion of the transfusion. (1C) Initial clinical assessment seeks to quickly identify those patients with serious or life-threatening reactions so that immediate treatment/resuscitation can be initiated. Figure 1 provides a practical guide to recognition and initial management of suspected ATR. In all cases, the transfusion must be stopped temporarily and venous access should be maintained with physiological saline. The patient's airway, breathing and circulation (‘ABC’) must be assessed.24 Their core identification details must be checked to ensure that they correspond with those on the blood component compatibility label—is the reaction due to transfusion of a component intended for another patient?22 The component must be examined for unusual clumps or particulate matter, or discolouration suggestive of bacterial contamination. Provided that the reaction is not severe or life-threatening, as defined in the flow diagram (Figure 1), standard observations on the patient are then performed. If the presumed ATR is severe or life-threatening, a doctor should be called immediately and the blood transfusion should be discontinued. Caution is required in bleeding patients where hypotension may be associated with haemorrhage and continuing the transfusion may be life-saving. If the reaction is mild, for example an isolated rise in temperature without chills, rigors or other change in observations, medical staff should be informed but the transfusion may be restarted under direct supervision. In the case of reactions considered moderate, urgent medical advice should usually be sought before the transfusion is restarted. Exceptions to this would include reactions where there is an obvious alternative explanation for the symptoms/signs or the patient has a history of similar, previously investigated, non-serious transfusion reactions. The patient's pulse rate, blood pressure, temperature and respiratory rate should be monitored,22 and abnormal clinical features such as fever, rashes or angioedema should be frequently assessed. A patient who has experienced a transfusion reaction should be observed directly until the clinical picture has improved. Rapidly developing features of ABC problems, usually associated with skin and mucosal change would suggest anaphylaxis.25 The symptoms and signs of reactions are discussed in more detail in Appendix S1. A table incorporating both the ISBT/IHN and SHOT classifications and gradations of severity can be found in Appendix S3. Both these appendices can be found on the BSH website. Management is guided by rapid assessment of symptoms, clinical signs and severity of the reaction rather than laboratory investigations. Medical support should be given as appropriate for an acutely ill patient.26 In all cases, disconnect the component and giving set from the patient and retain for further investigation, maintaining venous access with intravenous physiological saline. If the patient is severely dyspnoeic, ensure the airway is patent and give high flow oxygen through a mask with a reservoir. If wheeze is present without upper airways obstruction, consider nebulising a short-acting, inhaled, beta-2 agonists such as salbutamol.27 Position hypotensive patients flat with leg elevation, or in the recovery position if unconscious or nauseated and at risk of vomiting. Further management is dependent on expert medical assessment and appropriate specialist support, such as the resuscitation team or critical care outreach team, who should be alerted according to local policies. Prompt treatment may be life-saving, and it may not be appropriate to wait for the results of investigation. A rational outline of management is provided below. This is strongly suggestive of anaphylaxis with airways obstruction, especially if examination reveals angioedema and/or urticaria. This requires immediate intervention to ensure the airway is patent and the administration of adrenaline (epinephrine) is according to the UK Resuscitation Council (UKRC) guidelines.25 Intramuscular (IM) adrenaline is rapidly effective and prevents delay in attempting to get venous access in a patient with peripheral venous shutdown. It should not be prohibited in patients with thrombocytopenia or coagulopathy. Intravenous adrenaline should only be given by expert practitioners such as intensive care specialists or anaesthetists. For adults and children over 12 years, administer IM adrenaline: 0.5 mL of 1:1000 adrenaline (500 μg) into the anterolateral aspect of the middle third of the thigh. For children between 6 and 12 years, give 0.3 mL of 1:1000 IM adrenaline (300 μg). For children less than 6 years, give 0.15 mL of 1:1000 IM adrenaline (150 μg). Adrenaline is repeated, if necessary, at 5-minute intervals according to blood pressure, pulse and respiratory function under the direction of appropriately trained clinicians. Patients who have had an anaphylactic reaction should be discussed with an allergist or immunologist regarding further assessment and investigation if there is uncertainty about the cause (e.g. if other drugs had been administered at the same time as transfusion). A policy for future blood component therapy must be formulated (see section Subsequent Management). Consider ABO blood group incompatibility or bacterial contamination. Both require supportive care with fluid resuscitation, expert evaluation for inotropic, renal and/or respiratory support and blood component therapy for disseminated intravascular coagulation with bleeding. Isolated hypotension can occur in anaphylaxis and severe hypotension can occur in TRALI. In the latter, the clinical picture is usually dominated by dyspnoea. If the identity check suggests ABO incompatibility due to transfusion of a unit intended for another patient, contact the transfusion laboratory immediately. If bacterial contamination is suspected, take blood cultures from the patient (peripheral vein and through central line, if present) and then start broad spectrum intravenous (IV) antibiotics (the local regimen for patients with neutropenic sepsis would be appropriate). Immediately notify the transfusion laboratory staff and haematologist. The blood transfusion should be to the of the unit and for this to be will also and of all other components from the Consider TRALI or where allergic reaction has been as a cause for dyspnoea. the airway is patent and oxygen therapy while urgent expert medical assessment is Initial investigation should include and oxygen investigation and treatment of TRALI pulmonary and due to fluid are the scope of this guideline. The is as the primary treatment of TRALI is support and may be by therapy in patients who have intravascular medical management should be where TRALI is strongly suspected should be discussed with a at the blood as investigation of may be It should be that and TRALI may and may be Appendix provides a of the pulmonary complications of and Appendix provides on TRALI and The differential diagnosis and investigation are to severe ATR. there is an obvious alternative explanation for the symptoms/signs or the patient has a history of previously investigated, non-serious transfusion reactions, transfusion of the unit should only be after full clinical and signs are defined as a temperature or a rise of from baseline and/or symptoms such as chills, or in with ISBT/IHN contamination or a haemolytic reaction is if the reaction is and the patient with only If the reaction is however, these should be Management of bacterial contamination and due to ABO incompatibility due to are above under severe reactions and treatment of febrile reactions is in section reactions. If a patient febrile symptoms or signs of severity OR a rise of from baseline symptoms such as chills, or bacterial contamination or a haemolytic reaction should be (1C) and symptoms may include angioedema and but not severe to be such as or may be effective and in oxygen therapy and a beta-2 agonists such as may be useful for respiratory only to the response and have in acute The to transfusion will on the clinical assessment of the cause of the symptoms, response to initial therapy and the of transfusion. are defined as or change in observations, for example an isolated but and rise of but from baseline and/or or but without other features (Figure In these cases, it is to the transfusion under direct There are randomised controlled trials which consider the treatment of febrile symptoms associated with transfusion. with suggests that it is a useful but less effective for the management of symptoms such as or A systematic of the use of drugs in to transfusion suggests that they may be more effective for this assessment of the of the severity of the reaction should be in Caution would be required in the use of in patients with function or renal There are reported trials of treatment of skin symptoms but clinical suggests that patients with skin reactions such as or with other features may to the transfusion. the rate of transfusion and the use of a may be Appendix for detailed This is by the of symptoms and clinical signs and the severity of the reaction. that all reactions considered to be a of the transfusion, minor allergic or febrile reactions, and without a history of non-serious reactions, be with a standard of with on the complex The of and clinical details must be to the If febrile symptoms of severity are bacterial contamination or a haemolytic reaction should be should be to the laboratory for further investigation and the blood immediately so that associated components from the can be If however, febrile symptoms are and the patient with only further investigation to these is to be If febrile reaction unit to laboratory for compatibility and on both the and If the is or on the studies should be of for Blood cultures from patient oxygen or blood if symptoms are If severe suspected, consider of h and 24 Patients with respiratory symptoms not caused by anaphylaxis or allergy should have for (e.g. and and to the of pulmonary to diagnosis and haemovigilance reporting as for If severe consider of as above a baseline in case of clinical deterioration and may give an early of has Further should be guided by the clinical symptoms and signs, rather than the presumed of reaction. are usually an in patients with ATR and is not (see Appendix for detailed and This section on the management of febrile and allergic reactions. In the small number of patients with reactions, and/or component by or plasma is usually although the evidence is on prevention of with usually in a of are of include both primary and and report a incidence of febrile reactions in patients with are by studies with on patients with a febrile reaction in reaction rates to those with There is information on the of administration of is after studies that does not symptoms such as and was reported to the incidence of FNHTR before the introduction of prestorage but there are publications to support this In the of evidence, if reactions include with given 1 h before the reaction is or the use of blood may be useful in patients with or rigors associated with transfusions but must be used with in patients with thrombocytopenia or renal assessment of the of the severity of reaction should be in There are several studies of that with an as used in the was effective or not patients had experienced a reaction. There are studies which assess the use of The use of components was shown to the incidence of allergic complications in before and after and in a analysis of a investigating transfusion reactions to with prestorage In the of evidence that is patients who have experienced a allergic reaction may further transfusions without intervention and reaction can be by the rate of transfusion and by the use of a such as or which is effective in patients with intervention as for more severe reactions, detailed in may be In patients with severe reactions who urgent transfusion, of standard components with or without with direct monitoring is in are associated with allergic reactions than which have a plasma allergic transfusion reactions to plasma in patients with plasma for such as thrombocytopenia are by the use of For allergic reactions, there is evidence to support with or causes such as allergy to drugs or should be transfusion reactions have been in patients with severe in association with there is a of evidence for a and the link Haemovigilance data not support an incidence of in patients anaphylaxis, and reported reactions in patients more often features with rapid the 15 of levels found on in the of should be by a more and should be checked by the blood Patients with and a history of transfusion reactions should be with cells and in in If is the UK blood a small of plasma available on a If reactions in of the case should be discussed with a transfusion specialist from the blood If transfusion is standard blood components should be with direct observation in a clinical with the and to severe acute There is evidence to guide the management of patients with and transfusion. Serious reactions to standard components are rare in this and patients with history of allergic reactions may be with standard the of clinical in a patient with a history of significant allergic reactions in other might of the case with a transfusion specialist or clinical immunologist may be transfusion must not be components are not immediately There is evidence that the use of or components is of in the incidence of transfusion reactions and these are not required there is evidence of Appendix Patients with otherwise hypotensive reactions should be given a of cells or in In rare cases, it is to be due to should be stopped before transfusion if to and signs of ATR may be less recognised in children or although they may have a than in transfusion A high of by is for management should be in with In the case of anaphylaxis, guidelines should be of adrenaline are given and severe ATRs, as defined in this meet the criteria for serious reactions and there is a to report to the and (the UK under the Blood and should also be reported to the UK SHOT haemovigilance to to analysis of transfusion and for The is not a but is by laboratory and and should be considered a may to the reaction, as set in S3 and as classification can be the SHOT will aid in classification into the appropriate and a of SHOT reporting and to on SHOT This is when bacterial contamination of components may have when TRALI is suspected or there is severe or thrombocytopenia associated with an as associated components from the must be from the blood A transfusion specialist will also be available to give advice on the of components for future transfusion and the for investigation of should have in to ensure and effective with the blood SHOT provides to support reporting and of reaction section of the SHOT of acute transfusion reactions within a and reporting and of transfusions. to and the The would to the BSH Transfusion the BSH and the BSH for their support in this guideline. The BSH the during the of this have a full of to the BSH and which may be on of the have relevant of to of the group will the group if new evidence available that would alter the strength of the in this or it The will be reviewed by the relevant and the literature search will be years to search for new evidence that may have been The will be and from the BSH guidelines if it If new are an will be on the BSH guidelines the advice and information in this is to be true and at the time of to the the BSH the for the of this can be found on the The is not for the or of information by the than should be directed to the for the

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