Plain language summary
White blood cells reduction in packed red blood cell transfusions for preventing adverse reactions
A blood transfusion is when blood is taken from one person and given to another person. Blood transfusions are given to solve life and health-threatening medical conditions on a short-term basis. However, blood transfusions have adverse events, some of them potentially related to an immune system response or due to the transmission of infectious agents (e.g. Human Immunodeficiency Virus). Leukoreduction is a process in which the white blood cells are intentionally removed from donated blood in order to reduce the risk of adverse reactions in people receiving the blood transfusion. The benefits of removing white blood cells with the intent of reducing infectious and non-infectious complications in all types of transfused patients remains unclear. Removing white blood cells is costly. The USA and UK spend tens of millions each year on the procedure. In the USA, the procedure costs approximately USD $30 for each unit of blood product. It may not be worth spending so much money if there is no clear benefit to patients.
What are the benefits and harms of removing white blood cells from donated blood for people receiving a blood transfusion?
We searched medical journals for reports of clinical trials which examined the effects of removing white blood cells from donated blood. We were interested in finding out whether the removal of white blood cells from donated blood resulted in patients receiving a blood transfusion having few complications such as transfusion-related acute lung injury, death, infectious and non-infectious complications, or any other adverse event. We included people of any age or sex, who received a blood transfusion for any reason. The evidence is based on studies retrieved up to 05 December 2014.
We found 13 studies which included people who received a blood transfusion during heart or cancer surgery, or because they were injured, had cancer, HIV or sepsis.
We found no clear evidence showing either benefits or harms for removing white blood cells from donated blood. For all of the outcomes examined (transfusion-related acute lung injury, death from any cause, infection from any cause, non-infectious complication or any other adverse event), there was no sign of benefit or harm.
Quality of evidence
The overall quality of evidence of the included studies ranges from very low to low. None of the studies included enough people to give a definitive answer about the usefulness of removing white blood cells from donated blood. New high-quality studies, involving a few thousand people, are needed to enable us to know the true benefits and harms of this procedure.
Резюме на простом языке
Редукция (уменьшение содержания) белых клеток крови в пакетированной эритроцитарной массе для предотвращения неблагоприятных реакций при её переливании
Переливание крови - это введение крови и ее компонентов от одного человека (донора) другому (реципиенту). Переливания крови проводят для сохранения жизни при жизнеугрожающих состояниях кратковременно. Однако, при переливании крови возможны неблагоприятные события, некоторые из них потенциально связаны с реакцией иммунной системы или передачей инфекционных агентов (например, Вирус Иммунодефицита Человека). Лейкоредукция представляет собой процесс, при котором белые клетки крови намеренно удаляют из донорской крови, для того чтобы уменьшить риск неблагоприятных реакций у людей, получающих переливание крови. Польза от удаления белых кровяных клеток с целью сокращения инфекционных и неинфекционных осложнений у пациентов при всех типах переливания, остается неясной. Удаление белых кровяных клеток является дорогостоящей процедурой. На эти процедуры США и Великобритания тратят ежегодно десятки миллионов. В США процедура стоит около 30 $ США за каждую единицу продукта (препарата) крови. Может быть, такие затраты без ясной пользы для пациентов не стоят того.
Каковы польза и вред удаления из донорской крови белых кровяных клеток для людей, получающих переливание крови?
Мы провели поиск в медицинских журналах на предмет отчетов о клинических испытаниях, которые изучали эффекты удаления белых кровяных клеток из донорской крови. Нам было интересно выяснить, является ли уменьшение таких трансфузионных осложнений, как острая травма легких, смерть, инфекционные и неинфекционные осложнения, или любых других неблагоприятных событий, результатом удаления белых клеток крови из донорской крови, переливаемой пациентам. Мы включили людей любого возраста и пола, которые получили переливания крови по любой причине. Доказательства основаны на исследованиях, полученных к 5 декабря 2014.
Мы нашли 13 исследований, которые включали людей, получавших переливания крови во время сердечной хирургии или хирургии по поводу рака, или по поводу травм, имели рак, ВИЧ или сепсис.
Мы не нашли четких доказательств пользы или вреда от удаления белых кровяных клеток из донорской крови. По всем изученным исходам (трансфузионные острые травмы легких, смерть, инфекции от любых причин, не-инфекционные осложнения или любые другие неблагоприятные события) не было признаков пользы или вреда.
В целом качество доказательств во включенных исследованиях колебалось от очень низкого до низкого. Ни в одно из исследований не было включено достаточно людей, чтобы дать определенный ответ о целесообразности удаления белых кровяных клеток из донорской крови. Необходимы новые исследования высокого качества, с участием нескольких тысяч человек, которые позволили бы узнать истинные пользу и вред этой процедуры.
Заметки по переводу
Перевод: Худайбергенова Махира Сейдуалиевна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: firstname.lastname@example.org
Uklanjanje bijelih krvnih stanica iz upakiranih crvenih krvnih stanica namijenjenih transfuziji za sprječavanje nuspojava
Transfuzija krvi predstavlja postupak u kojem se krv dobivena od jedne osobe daje drugoj osobi. Transfuzija krvi se koristi za liječenje po život i zdravlje opasnih medicinskih stanja na kratkoročnoj osnovi. Međutim, transfuzije krvi imaju svoje nuspojave, od kojih su neke potencijalno vezane uz odgovor imunološkog sustava ili se događaju uslijed prijenosa uzročnika zaraznih bolesti (npr. virus humane imunodeficijencije, HIV). Leukoredukcija je proces u kojem se bijele krvne stanice ciljano uklanjaju iz donirane krvi kako bi se smanjio rizik od nuspojava kod ljudi koji bi trebali primiti transfuziju krvi. Prednosti uklanjanja bijelih krvnih stanica s ciljem smanjenja zaraznih i nezaraznih komplikacija kod svih tipova transfuzija, ostaju nejasne. Uklanjanje bijelih krvnih stanica je skupo. SAD i Velika Britanija troše desetke milijuna svake godine na ove postupke. U SAD-u, postupak košta otprilike 30 USD za svaku jedinicu proizvoda od krvi. Ukoliko ne postoje koristi za pacijente, na ovaj postupak ne vrijedi trošiti toliko novaca.
Koje su prednosti i štete od uklanjanja bijele krvne stanice iz donirane krvi za osobe koje primaju transfuziju krvi?
Pretražili smo medicinske časopise kako bi se pronašli znanstveni radovi koji opisuju kliničke studije koje su ispitivale učinke uklanjanja bijelih krvnih stanica iz donirane krvi. Cilj ovog Cochrane sustavnog pregleda bio je saznati da li je uklanjanje bijelih krvnih stanica iz donirane krvi kod pacijenta koji su primili transfuziju krvi utjecao na pojavu nekoliko komplikacija kao što su akutno oštećenje pluća povezano s transfuzijom, smrt, zarazne i nezarazne komplikacije, ili bilo koju drugu nuspojavu. Uključili smo ljude bilo koje dobi ili spola, koji su primili transfuziju krvi iz bilo kojeg razloga. Dokazi se temelje na istraživanjima objavljenim do 5. prosinca 2014.
Pronašli smo 13 studija koje su uključivale ljude koji su primili transfuziju krvi uslijed operacije srca ili raka, uslijed ozljede, liječenja raka, HIV-a ili sepse.
Nismo pronašli jasne dokaze koji potvrđuju bilo koristi bilo štetu od uklanjanja bijelih krvnih stanica iz donirane krv. Za sve ispitane ishode (akutno oštećenje pluća povezano s transfuzijom, smrt od bilo kojeg uzroka, infekcije iz bilo kojeg razloga, nezarazne komplikacije ili bilo koja druga nuspojava), nije bilo znaka koristi ili štete.
Ukupna kvaliteta dokaza uključenih studija kreće se od vrlo niske do niske. Niti jedna od studija nije uključila dovoljno ljudi kako bi se dao konačan odgovor o koristi uklanjanje bijelih krvnih stanica iz donirane krv. Potrebne su nove visokokvalitetne studije koje uključuju nekoliko tisuća ljudi, kako bi bili u mogućnosti utvrditi pravu korist i štetu ovog postupka.
Prevela: Jasna Safić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: email@example.com
Reduktion weißer Blutkörperchen in Transfusionen von roten Blutkörperchen zur Vorbeugung von Nebenwirkungen
Eine Bluttransfusion bedeutet, dass das Blut von einer Person an eine andere Person gegeben wird. Bluttransfusionen werden verabreicht, um kurzfristig lebens- und gesundheitsbedrohliche medizinische Zustände zu lösen. Dennoch haben Bluttransfusionen Nebenwirkungen, von denen manche möglicherweise mit einer Reaktion des Immunsystems zusammenhängen oder aufgrund von Übertragungen von Infektionserregern auftreten (z.B. das Humane Immundefizienz-Virus). Leukozytendepletion ist ein Verfahren, in dem die weißen Blutkörperchen absichtlich aus dem gespendeten Blut entfernt werden, um das Risiko für unerwünschte Reaktionen bei den Spendenempfängern zu reduzieren. Der Nutzen der Entfernung von weißen Blutkörperchen mit dem Ziel bei verschiedensten Spendenempfängern infektiösen und nicht-infektiösen Komplikationen zu reduzieren, bleibt unklar. Die Entfernung weißer Blutkörperchen ist teuer. Die USA und das Vereinigte Königreich geben für dieses Verfahren jedes Jahr viele Millionen Dollar bzw. Pfund aus. In den USA kostet dieses Verfahren ungefähr $30 USD für jede Blutprodukteinheit. Möglicherweise zahlt es sich nicht aus, so viel Geld auszugeben, wenn durch dieses Verfahren kein eindeutiger Nutzen für die Patienten entsteht.
Was sind Nutzen und Schäden einer Entfernung der weißen Blutkörperchen aus gespendetem Blut für Blutspendeempfänger?
Wir durchsuchten medizinische Zeitschriften nach Berichten zu klinischen Studien, die die Wirkungen der Entfernung von weißen Blutkörperchen aus gespendetem Blut untersuchten. Wir wollten herausfinden, ob eine Entfernung von weißen Blutkörperchen aus gespendetem Blut zu weniger Komplikationen bei Empfängern einer Bluttransfusion führt, wie z.B. weniger transfusionsbezogene akute Lungenschädigungen, Tod, infektiöse und nicht-infektiöse Komplikationen oder weitere unerwünschte Ereignisse. Wir schlossen Personen jeglichen Alters oder Geschlechts ein, die aus unterschiedlichen Gründen eine Bluttransfusion erhielten. Die Evidenz basiert auf Studien, die bis zum 5. Dezember 2014 gefunden wurden.
Wir fanden 13 Studien, die Personen einschlossen, die eine Bluttransfusion während einer Herz- oder Krebsoperation erhielten oder weil sie verletzt waren oder Krebs, HIV oder eine Sepsis hatten.
Wir fanden keine eindeutige Evidenz, die entweder Nutzen oder Schäden der Entfernung von weißen Blutkörperchen aus gespendetem Blut zeigt. Für alle untersuchten Endpunkte (transfusionsbezogene akute Lungenschädigung, Gesamtsterblichkeit, Infektionen aufgrund jeglicher Ursache oder nicht-infektiöse Komplikationen oder andere unerwünschte Ereignisse), gab es keine Anzeichen von Nutzen oder Schaden.
Qualität der Evidenz
Die Gesamtqualität der Evidenz der eingeschlossenen Studien variiert von sehr niedrig bis niedrig. Keine der Studien umfasst genügend Personen, um eine definitive Aussage über die Zweckmäßigkeit einer Entfernung von weißen Blutkörperchen aus gespendetem Blut zu treffen. Neue Studien von hoher Qualität, die einige tausend Personen umfassen, sind nötig, um uns zu ermöglichen, den wahren Nutzen und Schaden dieses Verfahrens zu erkennen.
Anmerkungen zur Übersetzung
I. Nolle, freigegeben durch Cochrane Deutschland.
Description of the condition
Blood transfusion is the infusion of both soluble and cell-associated forms (red blood cells (RBCs), white blood cells (WBCs) and platelets) into a recipient (Vamvakas 2001). A blood transfusion is an acute intervention, implemented to solve life and health-threatening conditions on a short-term basis; and in general, its long-term effects tend to be of secondary importance (Tsai 2010).
However, blood transfusion is associated with an increasing risk of infectious and non-infectious adverse events (Wagner 2004; Hendrickson 2009; Sachs 2010). The incidence of non-infectious transfusion reactions is greater than that of infectious complications (Lavoie 2011). Mortality associated with non-infectious risks is also significantly higher and accounts for 87% to 100% of fatal complications of transfusions (Lavoie 2011).
The main non-infectious adverse events to the patient are transfusion-related acute lung injury (TRALI), which is considered the most severe non-infectious complication (Renaudier 2009; Triulzi 2009; Vamvakas 2009); non-haemolytic febrile transfusion reaction (NHFTR) (King 2004; Blajchman 2006; Hoffman 2008) and allergic reactions (Tenorio 2007). Less frequent are transfusion-associated graft-versus-host disease (TA-GVHD) (Dwyre 2008; Hoffman 2008; Rühl 2009) and transfusion-related with an immunomodulation effect (TRIM) (Vamvakas 2006).
Several approaches have been considered to prevent adverse reactions related to transfusion (Martí-Carvajal 2010; Lavoie 2011; Lindholm 2011; Tobian 2011). Transfusion of leukocyte-reduced RBC concentrates is one of those approaches (Blajchman 2010; Blumberg 2010; Mukagatare 2010). Leukocytes (WBCs) in blood components can mediate febrile transfusion reactions, stimulate human leukocyte antigen (HLA) alloimmunization in transfusion recipients, and transmit some cell-associated pathogens such as cytomegalovirus (CMV). Therefore, it is desirable to remove WBCs from transfusable blood components (Galel 2009).
Appendix 1 shows non-infectious transfusion reaction definitions related to WBCs.
Description of the intervention
Leukoreduction is a process in which the WBCs are intentionally reduced by almost 99.99% in RBC concentrates (Shapiro 2004). There are many methods to conduct this approach; however, this process is currently performed using selective leukoreduction filters (Galel 2009). According to the U.S. Food and Drug Administration (FDA), leukocyte-reduced RBC concentrates contain fewer than 5 × 106 WBCs/unit and at least 85% of the original RBCs (Galel 2009), and according to the Council of Europe < 1 × 106 total WBC/unit. Usually, most RBC leukofiltration is performed by blood collection centres within the first few days after collection (Galel 2009).
Leukoreduction in trauma patients
Safe transfusion products are a necessity for the successful treatment of trauma patients (Tien 2007; Theusinger 2009). It is unclear if leukoreduction of RBC concentrates is the best method of providing blood products for trauma patients (Nathens 2006; Phelan 2007; Watkins 2008). Retrospective studies have shown a reduction of infectious complications in injured patients treated with leukoreduced AlloBT; this effect appears more pronounced in patients receiving massive transfusion (> 6 units of PRBC) (Friese 2008).
Leukoreduction in surgery
Several studies have focused on the advantages of leukoreduced PRBC cells for transfusion in cardiac surgery (van de Watering 1998; Dzik 2002; Wallis 2002; Bilgin 2004; van Hilten 2004; Connery 2005); colorectal surgery (Jensen 1992; Houbiers 1994; Jensen 1996; Titlestad 2001; Dzik 2002; Skånberg 2007); gastrointestinal surgery (Tartter 1998; Dzik 2002; van Hilten 2004); and renal transplantation (Sanfilippo 1985; Opelz 1997; Hiesse 2001). However, some of the findings of these published trials are considered controversial. Furthermore, this approach has been used in patients with AIDS; but, is unclear if this alternative method is beneficial in this population (Collier 2001).
How the intervention might work
Leukoreduction works through multiple mechanisms for preventing adverse reactions:
To prevent TRALI: avoiding the transfer of leukocytes and reducing the cellular antibody interaction complexes that damage the endothelium of the lung (Triulzi 2009; Sachs 2011).
To avoid post-transfusion infections through reducing some cell-associated pathogens, such as CMV (Bilgin 2004; Blajchman 2004; van Hilten 2004; Connery 2005; Friese 2008).
To prevent immunomodulation: donor WBCs may suppress the recipient's immune system by interacting with it, producing susceptibility to many pathological conditions including cancer recurrence and other malignancies (Blajchman 2002; Dellinger 2004; Flohé 2007).
Why it is important to do this review
This Cochrane review is important for the following reasons:
Firstly, leukoreduction is expensive. About EUR 29 million/year are spent on implementing leukoreduction (AETSA 2007). Other studies reported costs ranging from CAD $26 million to 46 million annually (CCOHTA 1998). One study estimated the total cost of implementing leukoreduction was about USD 600 million dollars per year in USA (Shapiro 2004). It has also been reported that leukoreduction results in an increase of approximately USD 30/unit of blood product (Phelan 2007). More recently, Tsantes 2014 reported an incremental cost-effectiveness ratio (ICER) of EUR 6916 to prevent one case of febrile non-haemolytic transfusion reactions (FNHTR). Secondly, the potential role of leukoreduction for decreasing mortality and infection is controversial (AETSA 2007; Mukagatare 2010). Thirdly, several studies and meta-analyses did not report conclusive results about leukoreduction, and showed methodological inconsistencies (Vamvakas 1996; Blumberg 1998; Jensen 1998; Fergusson 2004; Blumberg 2007; Vamvakas 2007). Therefore, it is important to conduct this Cochrane review to determine the potential benefits of leukoreduction procedure in patients requiring RBC concentrates, focused on the prevention of adverse reaction.
To determine the clinical effectiveness of leukoreduction of packed red blood cells for preventing adverse reactions following allogeneic blood transfusion.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
Patients requiring allogeneic packed RBC (PRBC) transfusion. Patients could be of any age.
Types of interventions
We applied no limitations to the leukoreduction procedures used.
Types of outcome measures
Incidence of TRALI.
Death due to any cause.
Infection from any cause (number of patients out of the total randomised).
Non-infectious complications (Appendix 1).
Any other adverse event: “any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment” (Nebeker 2004).
We took the information size for the primary outcome of this Cochrane review from the relative risk reported in Nathens 2006. This study included trauma patients. A total sample size of 8781 participants was defined to assess a relative risk reduction on TRALI events of 25%, from a baseline incidence in the control of 6.31% (alpha level of 5% and power of 90%).
Search methods for identification of studies
In order to reduce publication and retrieval bias we did not restrict our search by language, date or publication status.
The Cochrane Injuries Group Trials Search Co-ordinator searched the following:
Cochrane Injuries Group Specialised Register (10/11/2015)
Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library) (issue 10 of 12, 2015)
MEDLINE (OvidSP) (1950 to November week 1, 2015)
Embase + Embase Classic (OvidSP) (1947 to 10/11/2015)
LILACS (BIREME) (1982 to 10/11/2015)
CINAHL Plus (EBSCO) (1937 to 10/11/2015)
Clinicaltrials.gov (www.clinicaltrials.gov) (10/1/2015)
WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) (10/11/2015)
We have reported the search strategies in Appendix 2. We adapted the MEDLINE search strategy as necessary for the other databases. To the MEDLINE search strategy we added the Cochrane Highly Sensitive Search Strategy for identifying RCTs. To the EMBASE strategy we added the terms of the search strategy and study design terms as used by the UK Cochrane Centre (Lefebvre 2011).
Searching other resources
We also searched the following websites (25 November 2014):
US FDA (http://www.fda.gov).
European Medicines Agency (http://www.emea.europa.eu).
American Association of Blood Banks (AABB) (http://www.aabb.org).
Transfusion Evidence Library (http://transfusionguidelines.org).
In addition, we checked the reference lists of all relevant trials and reviews identified.
Data collection and analysis
We summarised data according to standard Cochrane methodologies, including the Cochrane Handbook of Systematic Reviews for Interventions (Higgins 2011) and the Methodological Expectations for Cochrane Intervention Reviews (MECIR) (Chandler 2013).
Selection of studies
Two review authors, Daniel Simancas-Racines (DSR) and Ingrid Arévalo-Rodriguez (IAR), independently assessed for inclusion all the potential studies identified from the literature searches. We consulted a third review author, Arturo Martí-Carvajal (AMC) for any disagreements, which were resolved through discussion and consensus.
Data extraction and management
Two review authors, DSR and IAR, independently extracted data from the included trials. We consulted AMC and Dimelza Osorio (DO) in the event of any disagreements, which we resolved through discussion and consensus. Data were recorded for: eligibility criteria, demographics (age, gender and country), type of surgery, setting of the patients (i.e. cardiac surgery, intensive care unit (ICU)) outcomes. DSR recorded the data into a database. IAR and DO checked the data entered.
We contacted the trial author when a full-text article was unavailable (see Appendix 3 for details).
Assessment of risk of bias in included studies
Two review authors, DSR and IAR, independently assessed the quality of each trial using a simple form following the domain-based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We compared the assessments and discussed any discrepancies between the review authors. We consulted a third review author (AMC) to resolve any disagreement and to reach consensus.
For each included trial, we assessed risk of bias (as low, high or unclear) for each of the following domains:
Generation of random sequence (selection bias).
Concealment of treatment allocation (selection bias).
Blinding of participants and personnel (person delivering treatment) to treatment allocation (performance bias).
Blinding of outcome assessors to treatment allocation (detection bias).
Completeness of the outcome data (including checks for possible attrition bias through withdrawals, loss to follow-up and protocol violations). For the incomplete outcome data domain, we considered as a high risk of bias RCTs that losses participants after transfusion intervention. Additionally, we considered high risk of bias (design bias) as those studies in which the patients were not transfused because inconsistency to determine inclusion criteria adequately or when a premature randomisation was done.
Selective reporting of outcomes (reporting bias).
Other sources of bias (other bias).
Measures of treatment effect
All outcomes in this Cochrane review were binary outcomes. We calculated the treatment effect with risk ratios (RRs) with 95% confidence intervals (CI).
Unit of analysis issues
The unit of analysis was the patient. We collected and analysed a single measurement for each outcome from each patient.
Dealing with missing data
We assessed the percentages of the overall dropouts for each included trial and per each randomisation arm, and we evaluated whether an intention-to-treat (ITT) analysis had been performed or could be performed with the available published information. We defined these dropouts as the percentage of lost patients who received an effective transfusion, over the total of transfused patients reported for each arm of the included studies.
Assessment of heterogeneity
We quantified statistical heterogeneity using the I² statistic. The I² statistic describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error (Higgins 2003). We considered I² statistic between 50% and 74% as a moderate statistical heterogeneity, whereas a value of ≥ 75% represents high heterogeneity. We explored heterogeneity using a sensitivity analysis.
Assessment of reporting biases
We created a funnel plot to assess reporting bias for each outcome (Sterne 2011) where there were data from at least 10 trials (Higgins 2011).
We summarized sufficiently comparable trials using the random-effects model to accommodate the high heterogeneity, and used a fixed-effect model for the sensitivity analysis. We carried out the main analysis based on the number of randomised participants, using an ITT analysis. All the analyses were carried out using RevMan 2014.
Subgroup analysis and investigation of heterogeneity
No data were available to perform the following subgroup analyses for the primary outcome (incidence of TRALI):
By type of post-transfusion complication.
By technique or type of material used.
Immunosuppressed patient versus non-immunosuppressed patient.
Massive transfusion (> 6 units PRBCs) versus less.
We performed the following sensitivity analysis for the primary outcome:
To assess the robustness of estimates, we used both fixed-effect and random-effects models for all outcomes and compared results.
We conducted a sensitivity analysis comparing trials with low risk of bias, with those at unclear or high risk of bias, according to attrition bias (Higgins 2011).
We also conducted a sensitivity analysis based on transfused patients to explore the high heterogeneity.
Trial sequential analysis
We carried out a trial sequential analysis (TSA) for every dichotomous outcome evaluated in this systematic review: TRALI, death from any cause, infection from any cause, and adverse events/fever.
TSA is a type of statistical power analysis that can be used to further investigate the relevance of results ("strength of evidence") yielded by a meta-analysis (Wetterslev 2008). It is the counterpart of a sample size calculation as part of a conventional study design. TSA allows researchers to differentiate between "spurious" significant findings caused by random error in a data-set with only small numbers of participants and trials and a "truly" significant result with sufficient statistical power. Thereby, TSA also accounts for repeated significance testing. The optimal information size and O'Brien-Fleming alpha-spending boundaries indicating the "real" significance threshold are constructed by providing the numbers for alpha level, power, control group risk and inter-study heterogeneity (Thorlund 2011). TSA can be performed only if the information size (number of participants) is large enough as compared with the optimal information size, and only if the outcome is dichotomous. Further details can be found in the "User Manual for Trial Sequential Analysis (TSA)", provided by the Centre for Clinical Intervention Research of the Copenhagen Trial Unit (Thorlund 2011).
'Summary of findings' tables
We used the GRADE approach (Guyatt 2011b) to assess the overall quality of evidence. The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality of a body of evidence considers within-study risk of bias (methodological quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias (Balshem 2011; Brozek 2011; Guyatt 2011a; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h). We created a ‘Summary of Findings’ table using GRADEpro GDT Guideline Development Tool (www.gradepro.org). We have presented the body of evidence in Summary of findings for the main comparison.
Summary of main results
In this systematic review we included 13 trials involving cardiovascular surgical, gastro-oncology surgery, trauma and HIV patients who were randomised to receive leukoreduced compared with non-leukoreduced PRBC transfusion. After analysis of the study data, we are unable to conclude whether or not leukoreduction of PRBC has an effect on preventing TRALI (one trial), death (nine trials), infection (10 trials) and other adverse events (fever, reported in two trials). The quality of evidence was low (TRALI and adverse events) to very low (death and infection) due to high heterogeneity, imprecision and high risk of bias. None of the included trials reported on other non-infectious complications. The sensitivity analyses of trials at low risk of bias showed neither a beneficial or harmful effect of leukoreduction of PRBC on the pooled data regarding death, infection and adverse events.
Overall completeness and applicability of evidence
Overall completeness of evidence
We analysed 13 controlled clinical trials that met our predefined inclusion criteria. Two trials reported only physiological results and we excluded them from the meta-analyses. Only one RCT evaluated the primary outcome (TRALI). However, we obtained data from 11 trials which contributed to the effect estimates of the secondary outcomes (death from any cause, infection from any cause and adverse events/fever). We found no trials evaluating non-infectious complications other than TRALI (e.g. FNHTR). Therefore, the pre-specified objectives and outcomes of our Cochrane review were partially addressed and the results are inconclusive. Consequently, the findings of this review should be interpreted with caution until more data are available.
Applicability of evidence
This Cochrane review is complex for a variety of reasons:
Firstly, regarding the population: the identified studies enrolled patients with different health problems, including trauma, cancer, cardiac disease and HIV-infected patients. Some important patient populations were not studied at all (e.g. paediatric or obstetric patients) or were insufficiently assessed (e.g. one RCT of trauma patients). In this context, external validity may be limited due to a lack of studies analysing these populations. Furthermore, the effect of leukoreduction on some types of patients without a strong indication for leukoreduced PRBC has not been sufficiently evaluated: single-transfused patients, patients without history of FNHTR, patients who are not receiving long-term platelet transfusions and those who are not at risk of developing CMV disease.
Secondly, regarding the intervention, the included studies did not adequately report several aspects related to the transfusion of RBC that need to be considered when interpreting the results, namely: the use of leukoreduced or non-leukoreduced platelets as a co-intervention, the timing of leukoreduction (i.e. pre-storage or post-storage), the type of filter used (e.g. Cell select Optima, BPF4, RC 100, Sepacell RZ-200B1), leucocyte reduction definition (e.g. 0.1 to 0.3 × 106 WBC/unit, 5 × 106, 2 × 105 per unit, etc.) and the type of transfusion (i.e. allogeneic or autologous).
Thirdly, regarding the outcomes: not all the included trials assessed relevant clinical outcomes. Relevant infections (e.g. CMV), non-infectious complications (e.g. TRALI, FNHTR) and any other adverse events were not sufficiently assessed or reported (Schulz 2010). The various follow-up intervals (28 days to 15 months) may represent another limitation for the assessment of outcomes.
Fourthly, regarding the costs: leukoreduction is widely implemented in clinical practice in many countries and some countries have established universal leukoreduction for blood transfusions (Laupacis 2001). However, the high costs related to this procedure deserve special attention. Even though the reintroduction of non-leukoreduced products probably provides no clinical impact, it does entail economic consequences. Changing the strategy from performing universal to selective leukoreduction would result in an important decrease in the costs (e.g. almost EUR 30 million per year in Spain (AETSA 2007)). Tsantes 2014 reported an incremental cost-effectiveness ratio (ICER) of EUR 6916 to prevent one case of FNHTR. Additionally, it is reasonable to consider other costs associated with maintaining dual inventories of leukoreduced PRBC and non-leukoreduced PRBC.
Finally, as leukoreduction of PRBC was shown to have no effect on preventing TRALI, death, infection and other adverse events reported by RCTs, these results have to be adequately interpreted within the context of current clinical practice which differs internationally and among populations. Other strategies might be more cost-effective than leukoreduction in terms of avoiding adverse events related to transfusion PRBC, such as the use of restrictive transfusion triggers (Carson 2012; Rohde 2014), that have shown effectiveness regardless of whether blood products are leukoreduced or not.
Quality of the evidence
The body of evidence available to date does not allow a definitive conclusion to be drawn about the benefits and harms of leukoreduction. The included RCTs had important methodological limitations: 1. poor and incomplete reporting of inclusion and exclusion criteria; 2. important attrition bias due to the exclusion of many patients included, but not transfused; 3. incomplete information on allocation concealment; 4. inadequate reporting of other blood components as co-interventions; and 5. incomplete reporting of clinical outcomes of interest. Additionally, some of the included trials showed important inconsistency in the estimates of effect.
Potential biases in the review process
We applied Cochrane systematic review methodology to the search for and selection of studies for inclusion in the review. However, despite our effort to include all published studies evaluating leukoreduction for the prevention of adverse reactions from allogeneic blood transfusion, it is possible that not all relevant data were identified. The small number of trials identified in our review raises concerns about publication bias. In order to identify this potential bias we performed a funnel plot. However, this visual method was possible only for one outcome (infection of any cause), since fewer than 10 studies assessed the other outcomes.
We contacted trial authors during the identification of trials (see Appendix 3) to clarify some questions related to the eligibility criteria, but not while we completed data extraction and analysis. We took into account only published data during these processes, considering the missing information as reporting bias.
In the review protocol we defined the main analysis based on the ITT approach (Simancas-Racines 2012). However, during the data extraction we identified an important number of patients included but not transfused. This may affect the precision of the effect estimations. In order to explore this scenario, we carried out a per-protocol analysis (only transfused patients) which did not reflect relevant differences in relation to the primary outcome (TRALI) and secondary outcomes death and infection from any cause, but the secondary outcome adverse events (fever) showed differences.
A limitation of the review was not considering the effect of buffy coat depletion in the estimations through a sensitivity analysis, because we had not planned such analysis in advance. Another limitation was not considering the subgroup analysis of the potential effect of different types of filters used in the included studies for all outcomes. We planned this analysis in the review protocol only for the primary outcome.
Agreements and disagreements with other studies or reviews
Reviews and meta-analyses on postoperative infection and death related to the leukoreduction of blood products have been carried out previously. However, as far as we know, no systematic reviews focused on non-infectious complications, such as TRALI or FNHTR, have yet been published. In the overall analysis of death from any cause, the findings of other reviews are in accordance with our results. Nevertheless, one systematic review showed a 50% reduction in the probability of postoperative infection (Blumberg 2007) and another review analysing "only patients who received transfusion" found a statistically significant reduction of 40% in postoperative infection, but a non-significant reduction in mortality (Fergusson 2004).
These two reviews have several limitations. They included studies with other blood components apart from leukoreduced PRBC cells as interventions, as well as non-randomised studies. Moreover, heterogeneity between studies was not taken into account and the risk of bias of included studies was not appropriately assessed. Furthermore, some relevant studies were not included.
Daniel Simancas-Racines is a Ph.D. candidate at the Department of Pediatrics, Gynecology and Obstetrics, and Preventive Medicine, Universitat Autònoma de Barcelona, Spain.
We thank Ms. Marta Roqué i Figuls, Iberoamerican Cochrane Centre, for her advice on statistical analysis; Dr. Christian Gluud, Centre for Clinical Intervention Research, Denmark, for his advice on interpreting the trial sequential analyses; and Ms. Maria Victoria Leo Rosas for revising and improving the grammar and style of the review.
This project was supported by the UK National Institute for Health Research, through Cochrane Infrastructure funding to the Cochrane Injuries Group. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Contributions of authors
All review authors contributed to the conception and design of this Cochrane review. Doctors Simancas-Racines, Arevalo-Rodriguez and Osorio contributed to the analysis and interpretation of data, and drafted the manuscript. All review authors contributed by commenting on the review critically for intellectual content and gave final approval of the document to be published.
Differences between protocol and review
In order to improve the quality of this Cochrane review, we made the following changes from the original protocol (Simancas-Racines 2012):
Data synthesis included a second meta-analysis: 'only transfused patients' as a sensitivity analysis. We performed this analysis due to the important number of patients not transfused as reported in most of the included studies. This analysis complements the main analysis planned in the review protocol: events reported among the total number of randomised patients.
We carried out a sensitivity analysis "excluding post-storage leukoreduction studies" to explore the effect of this variable on the effect estimate.
We conducted a TSA to assess the risk of random errors in the cumulative meta-analyses.
We changed our criteria for assessing the statistical heterogeneity in the meta-analyses. In the protocol it was classified an I² statistic value of 40 to 60% as moderate, and 75% and above as high. In the review, we have now defined moderate heterogeneity as an I² statistic of 50 to 74%, and high as 75% or above.
In future versions of this review we will also include, for all outcomes:
a subgroup analysis by medical condition
a subgroup analysis by type of filter
a sensitivity analysis by buffy coat