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Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders
Malouf R, Ashraf A, Hadjinicolaou A V, Doree C, Hopewell S, Estcourt L J
The Cochrane Database of Systematic Reviews. 2018;5:CD012342.
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Abstract
BACKGROUND Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Clinical Commentary
Xiangrong He, MD, PhD & Claudia S. Cohn, MD, PhD, both of University of Minnesota, Department of Laboratory Medicine and Pathology.
What is known?
Thrombocytopenia represents a common problem for patients withchronic bone marrow failure disorders, the most common of which are myelodysplastic syndrome (MDS) and anaplastic anemia (AA). In addition to thrombocytopenia, both morphologic and functional platelet abnormalities may be seen in these patients as well. Platelet transfusion support is the primary management option for thrombocytopenia and active bleeding in these patients. Platelets are usually transfused prophylactically at counts less than 10 x 109/L and with higher counts in patients with hemorrhage. As compared with no prophylaxis, prophylactic platelet transfusions have been shown to be superior in reducing moderate to severe bleeding, primarily in people with leukemia. However, the evidence of prophylactic use for platelet transfusions in people with chronic bone marrow failure is lacking. Meanwhile, platelets are a precious resource and platelet transfusion carries many risks. Thus, avoiding unnecessary prophylactic platelet transfusions will have significant financial and safety implications for health services.
What did this paper set out to examine?
The authors set out to to review in thrombocytopenic patients with chronic bone marrow failure, whether prophylactic transfusions are really necessary or whether these patients can be effectively supported with only therapeutic platelet transfusions given with the onset of bleeding. In particular, they wanted to show that a therapeutic-only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant bleeding in thrombocytopenic patients with primary bone marrow failure disorders.
What did they show?
The review included all patients with MDS, acquired AA, or congenital bone marrow failure disorders that were not being actively treated with a stem cell transplant or intensive chemotherapy. To maximize the number of studies eligible for inclusion, not only randomized controlled trials (RCTs), but good quality non-RCTs, and controlled before-after studies were included. Only one trial met the inclusion criteria for this review. Unfortunately, the trial was incomplete due to an unexpected slow recruiting rate. Therefore, no results were provided by the trial authors. Although the review was unable to make any recommendations on prophylactic platelet transfusion policies for this patient population, it did identify an urgent need for good quality studies in this area.
What are the implications for practice and for future work?
Thrombocytopenia (platelet counts < 10 x 109/L) is one of the most common complications in patients with chronic bone marrow failure. For example, 40% to 65% of MDS patients have thrombocytopenia. Meanwhile, in some Western countries, bone marrow failure is one of the most common underlying reasons for receiving a prophylactic platelet transfusion. However, guidelines on a therapeutic platelet transfusion strategy versus a prophylactic platelet transfusion strategy in this population are still lacking. Due to the absence of relevant data, the current review was not able to reach any conclusions on the safety and efficacy of prophylactic platelet transfusion compared with therapeutic platelet transfusion for patients with chronic bone marrow failure. Nontheless, this review identified a major gap in the literature and underscored the urgency of prioritizing research in this area. In the meantime, platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.
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Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
Ker K, Shakur H, Roberts I
Bjog : an International Journal of Obstetrics and Gynaecology. 2016;123((11):):1745-52.
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BACKGROUND Postpartum haemorrhage is the leading cause of maternal mortality. Tranexamic acid (TXA) reduces surgical haemorrhage and the risk of death in bleeding trauma patients. OBJECTIVES To assess the effects of TXA on risk of postpartum haemorrhage and other clinically relevant outcomes. SEARCH STRATEGY We searched the MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and WHO ICTRP electronic databases to May 2015. SELECTION CRITERIA Randomised controlled trials comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section. DATA COLLECTION AND ANALYSIS Two authors extracted data and assessed the risk of bias for each trial. Because of data concerns we did not conduct a meta-analysis. MAIN RESULTS We found 26 trials including a total of 4191 women. Examination of the trial reports raised concerns about the quality of the data. Eight trial reports contained identical or similar text and there were important data inconsistencies in several trials. Two trials did not have ethics committee approval. Meta-analysis of baseline variables suggested that randomisation was inadequate in many trials. CONCLUSIONS There is no reliable evidence that TXA prevents postpartum haemorrhage during childbirth. Many of the trials conducted to date are small, low quality and contain serious flaws. TWEETABLE ABSTRACT No evidence that TXA prevents postpartum haemorrhage. Existing trials are unreliable, with serious flaws.
Clinical Commentary
What is known?
Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide with about 50,000 deaths each year. In those women who survive PPH, hysterectomy is sometimes necessary to stop the haemorrhage, depriving many women of their ability to bear additional children. Tranexamic acid (TXA) reduces bleeding by inhibiting fibrinolysis. TXA is an inexpensive, widely available drug that has been proven to reduce bleeding in surgery and reduce the risk of death in bleeding trauma patients. TXA given at delivery could potentially prevent severe postpartum bleeding.
What did this paper set out to examine?
The authors conducted a systematic review of randomised controlled trials (RCTs) to assess the effects of TXA on the risk of PPH as well as other clinically relevant outcomes. They searched MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform electronic databases for reviews published as of May 2015. Selection criteria included RCTs comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section (CS).
What did they show?
The authors found 31 reports describing 26 trials involving 4191 women published between 2001 and 2015. Eight reports contained identical or similar data and there were important clinical inconsistencies in several trials. Two trials did not have ethics committee approval and meta-analysis showed that randomization was inadequate in many trials. The median sample size was 120 patients (74-740). All but one were single centre trials. Trials were conducted in China (3), Egypt (2), India (9), Iran (5), Malaysia (1), Pakistan (2), Turkey (3) and Ukraine (1). Twenty-two trials focused on the effects of TXA on women giving birth by CS and four in women delivering vaginally.
TXA was given within 30 minutes prior to incision in all of the CS trials except one (given at delivery of anterior shoulder). TXA was given at delivery of anterior shoulder in 3 and at delivery of placenta in the remaining vaginal births. The TXA dose ranged from 0.5 g to 1 g. Women receiving TXA were compared to those given placebo in 13 reports and with those in a no-TXA group in the remaining 13 trials.
The number of patients assigned to each group was not reported in one trial, rendering the data unusable. Frequency of PPH was reported in 13 of the trials (50%), blood loss in 24 (92%), thromboembolic events in 16 (62%), death in six (23%), surgical intervention in five (19%) and transfusion of blood products in 10 (38%). No trial reported on maternal well-being or quality of life. A major problem when comparing these studies is that even the definition of what constitutes PPH varied; four trials classified PPH as blood loss = 1000 mL after CS and = 500 mL after vaginal delivery. The remaining trials used other, lower thresholds such as = 500 mL after CS and = 400 mL after vaginal delivery.
Because of the authors’ concerns about the quality of the trials and data reliability, they chose not to perform a meta-analysis. They instead calculated effect estimates and 95% CI’s were presented as Forest plots. They concluded that, in all trials, fewer women in the TXA group developed PPH than in the control group. Additionally, from the data of the trials where blood loss was evaluated, the effect estimates were consistent with less blood loss in the TXA group; the difference was statistically significant in all but one trial. In the trials detailing blood product transfusion data, where products were transfused (7), fewer women in the TXA group received a blood transfusion than in the control group. In studies reporting adverse outcomes, there were no deaths, surgical interventions, myocardial infarctions, strokes or pulmonary embolisms.
What are the implications for practice and for future work?
This publication provided valuable data in its description of the scale and nature of deficiencies in the studies evaluating the effect of TXA in preventing PPH. Unless the problems with these studies are brought to the attention of the maternal fetal medicine and transfusion medicine leaders, treatment decisions may be based on unsound evidence putting women at risk. The information provided by the authors should serve to guide future trial developers such that conclusions are based on the highest quality research possible.
Based on the studies reviewed by the authors, it is clear that large, multicentre randomized control trials with clinically relevant endpoints must be developed before widespread clinical guidelines endorsing TXA in preventing PPH are implemented. It should be noted that the data from the WOMAN trial was not available at the time of this study.
References
Adult Antifibrinolytic Agents/*administration & dosage Delivery, Obstetric/*adverse effects Female Humans Parturition/*drug effects Postpartum Hemorrhage/etiology/*prevention & control Pregnancy Randomized Controlled Trials as Topic Tranexamic Acid/*administration & dosage Treatment Outcome Postpartum haemorrhage systematic review tranexamic acid
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Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia
Estcourt LJ, Ingram C, Doree C, Trivella M, Stanworth SJ
The Cochrane Database of Systematic Reviews. 2016;((5)):CD011980.
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BACKGROUND People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, epidural haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians of the correct management of these patients. The risk of bleeding appears to be low but if bleeding occurs it can be very serious (spinal haematoma). Therefore, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit. OBJECTIVES To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS We searched for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2016, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 3 March 2016. SELECTION CRITERIA We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter. We only included RCTs published in English. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We identified no completed or ongoing RCTs in English. We did not exclude any completed or ongoing RCTs because they were published in another language. AUTHORS' CONCLUSIONS There is no evidence from RCTs to determine what is the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future RCT would need to be very large to detect a difference in the risk of bleeding. We would need to design a study with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000.
Clinical Commentary
Richard Kaufman MD, Brigham and Women’s Hospital, Boston
What is known?
In rare cases, bleeding complicates lumbar punctures and epidural anesthesia. The clinical consequences of bleeding in this setting range from trivial (traumatic tap detectable by cerebrospinal fluid cell count only) to devastating (spinal hematoma/paralysis). Most cases of spinal hematoma following lumbar puncture have been reported in patients with platelet counts below 50 X 109 cells/Lalthough other risk factors for bleeding were present in nearly all of these cases.1 Platelet transfusions are often administered prophylactically to thrombocytopenic patients having a lumbar puncture or epidural anesthesia. But what constitutes a safe minimum platelet count to perform these procedures is unclear, and clinical practices and published practice guidelines vary widely. This is an important topic because: (1) lumbar punctures and epidural anesthesia are performed commonly; (2) these procedures have rare but serious risks; (3) platelet transfusions carry a range of infectious and noninfectious risks; and (4) platelet units are expensive and limited in availability.
What did this paper set out to examine?
The authors conducted a systematic review of the literature aimed at evaluating the risks and benefits of different platelet transfusion thresholds before a lumbar puncture or epidural anesthesia in thrombocytopenic patients. This was an update of a 2016 Cochrane Review.
What did they show?
The authors found that the published literature on this topic remains extremely limited. They identified no high-quality studies. After rigorously screening 999 published reports, the authors included in their analysis only three retrospective cohort studies describing participants who received or did not receive lumbar puncture. One study was in adults; the other two were in children. No study compared different platelet count thresholds before a procedure. No major bleeding complications occurred in the two studies reporting this outcome (150 participants). There was no difference in minor bleeding (traumatic taps) among pediatric or adult patients who received or did not receive platelet transfusion pre-procedure. The authors concluded that no clinical study evidence exists on which to base a correct platelet transfusion threshold before lumbar puncture or epidural anesthesia.
At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
What are the implications for practice and for future work?
What are the implications for future research?Because bleeding complication rates are so low in the setting of lumbar puncture and epidural anesthesia, the authors estimate that performing a randomized trial would require more than 47,000 participants. Utilizing large electronic patient registries/databases thus appears to be the only realistic way that our understanding in this area could be improved moving forward.
Predicting bleeding in the setting of any invasive procedure has proven to be remarkably difficult. Hemostasis is complex; bleeding from most procedures is rare; and the tools that we have to assess bleeding risk are crude. Platelet counts tell us nothing about platelet hemostatic function. Other variables, including medications, coagulation factor activity, tissue integrity, and disease state may predominate in determining a patient’s bleeding risk. Platelet counts are easy to measure, but hopefully in the future we will discover better ways to determine whether a platelet transfusion should be given.
What are the implications for future practice? At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
References
1. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol. 148(1):15-25.
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Blood transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: a systematic review and meta-analysis
Kwok CS, Sherwood MW, Watson SM, Nasir SB, Sperrin M, NolanJ, Kinnaird T, Kiatchoosakun S, Ludman PF, de Belder MA, et al
JACC: Cardiovascular Interventions. 2015;8((3):):436-46.
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OBJECTIVES This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices.Copyright 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Clinical Commentary
What is known?
Allogenic red cell transfusion is associated with adverse clinical outcomes in many clinical settings.
What did this paper set out to examine?
The authors conducted a systematic review of the evidence that relates to the relationship between red cell transfusion and adverse clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The study is timely because the increasingly elderly population referred for PCI are at increased risk of anaemia and acute haemorrhage, the two key indications for red cell transfusion.
What did they show?
The authors conducted a robust and well described systematic review of relevant databases. They identified 19 observational analyses that included 2,258,711 patients met their eligibility criteria; reporting of transfusions, death and Major Adverse Cardiac Events (MACE). The included studies were of mixed quality and showed differences in their design, definitions of primary and secondary exposures, duration of follow up, and type of analyses. Pooled effect estimates demonstrated strong associations between transfusion, mortality and MACE, although these analyses also demonstrated significant heterogeneity. Sub group analyses that included only studies with longer follow-up, or that contained adjustment for confounders such as transfusion volume or anaemia showed consistent associations between transfusion and harm, with some reduction in heterogeneity.
What are the implications for practice and for future work?
Implications for future research: The authors conclude that their data cannot demonstrate a causal relationship between transfusion and adverse outcomes in these patients. However they do discuss the possible pathological effects of transfusion and conclude that their data should support more restrictive transfusion practice. Implications for future practice: This study generates the hypothesis that reduced exposure to red cells may have benefits in these high risk patients. This hypothesis should be tested in a randomised controlled clinical trial. It is premature to suggest that the evidence presented here makes a case for restrictive practice.
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Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials
Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P
European Journal of Orthopaedic Surgery & Traumatologie. 2015;25((3):):525-41.
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BACKGROUND Tranexamic acid (TXA) is well established as a versatile intraarticular and intravenous (IV) antifibrinolytic agent that has been successfully used to control bleeding after total knee arthroplasty (TKA). The present meta-analysis aimed at assessing the effectiveness and safety of TXA in reducing blood loss and transfusion in TKA. METHODS We searched the PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases from 1966 to December 2013. Only randomized controlled trials (RCTs) were included in the present study. Two independent reviewers identified the eligible studies, assessed their methodological quality, and extracted data. The data were using fixed-effects or random-effects models with standard mean differences and risk ratios for continuous and dichotomous variables, respectively. Subgroup analysis was performed according to the IV or intraarticular administration of TXA. RESULTS Thirty-four RCTs encompassing 2,594 patients met the inclusion criteria for our meta-analysis. Our meta-analysis indicated that when compared with the control group, the IV or intraarticular use of TXA significantly reduced total blood loss, postoperative blood loss, Hb loss, and transfusion rate as well as blood units transfused per patient after primary TKA, but did not reduce intraoperative blood loss. No significant difference in deep vein thrombosis (DVT), pulmonary embolism, or other adverse events among the study groups. CONCLUSIONS IV or intraarticular use of TXA for patients undergoing TKA is effective and safe for the reduction blood loss and blood transfusion requirements, yet does not increase the risk of postoperative DVT. LEVEL OF EVIDENCE Level II.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
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One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration
Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F
Archives of Orthopaedic & Trauma Surgery. 2015;135((4):):573-88.
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BACKGROUND Tranexamic acid (TXA) in orthopedics has recently been gaining favor due to its efficacy and ease of use, both in intravenous (IV) and intraarticular (IA) usage. However, because of safety concerns with IV administration, there has been a growing interest in the IA use of TXA to prevent bleeding. MATERIALS AND METHODS This study conducted a systematic review and meta-analysis that included 31 randomized, controlled trials in which the effect of systemic and topical TXA on total blood loss (TBL), rates of transfusion, and thromboembolic events was investigated. RESULTS Compared to the control, the IA administration of TXA led to the significant reduction of mean TBL (p < 0.001), rate of transfusion (p < 0.001), and reduction of rate of thromboembolic events (p = 0.29). Compared to the control group, the IV administration of TXA resulted in significant reduction of mean TBL (p < 0.001), rate of transfusion (p < 0.001), and rate of thromboembolic events (p = 0.66). Although no significant differences in efficacy and safety between the IA and IV administration of TXA were found, the IA method was safer than the IV method in that it reduced rate of transfusion and thromboembolic events. CONCLUSION This study showed that TXA leads to significant reductions in TBL and the rate of allogeneic transfusions. Generally, no significant difference was detected between IA and IV administration of TXA; however, more studies with focus on safety and efficacy are warranted.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
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Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy in adult trauma patients with bleeding
Hunt H, Stanworth S, Curry N, Woolley T, Cooper C, UkoumunneO, Zhelev Z, Hyde C
Cochrane Database of Systematic Reviews. 2015;((2):):CD010438.
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Abstract
BACKGROUND Trauma-induced coagulopathy (TIC) is a disorder of the blood clotting process that occurs soon after trauma injury. A diagnosis of TIC on admission is associated with increased mortality rates, increased burdens of transfusion, greater risks of complications and longer stays in critical care. Current diagnostic testing follows local hospital processes and normally involves conventional coagulation tests including prothrombin time ratio/international normalized ratio (PTr/INR), activated partial prothrombin time and full blood count. In some centres, thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are standard tests, but in the UK they are more commonly used in research settings. OBJECTIVES The objective was to determine the diagnostic accuracy of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for TIC in adult trauma patients with bleeding, using a reference standard of prothrombin time ratio and/or the international normalized ratio. SEARCH METHODS We ran the search on 4 March 2013. Searches ran from 1970 to current. We searched The Cochrane Library, MEDLINE (OvidSP), EMBASE Classic and EMBASE, eleven other databases, the web, and clinical trials registers. The Cochrane Injuries Group's specialised register was not searched for this review as it does not contain diagnostic test accuracy studies. We also screened reference lists, conducted forward citation searches and contacted authors. SELECTION CRITERIA We included all cross-sectional studies investigating the diagnostic test accuracy of TEG and ROTEM in patients with clinically suspected TIC, as well as case-control studies. Participants were adult trauma patients in both military and civilian settings. TIC was defined as a PTr/INR reading of 1.2 or greater, or 1.5 or greater. DATA COLLECTION AND ANALYSIS We piloted and performed all review stages in duplicate, including quality assessment using the QUADAS-2 tool, adhering to guidance in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. We analysed sensitivity and specificity of included studies narratively as there were insufficient studies to perform a meta-analysis. MAIN RESULTS Three studies were included in the final analysis. All three studies used ROTEM as the test of global haemostatic function, and none of the studies used TEG. Tissue factor-activated assay EXTEM clot amplitude (CA) was the focus of the accuracy measurements in blood samples taken near to the point of admission. These CAs were not taken at a uniform time after the start of the coagulopathic trace; the time varied from five minutes, to ten minutes and fifteen minutes. The three included studies were conducted in the UK, France and Afghanistan in both civilian and military trauma settings. In two studies, median Injury Severity Scores were 12, inter-quartile range (IQR) 4 to 24; and 22, IQR 12 to 34; and in one study the median New Injury Severity Score was 34, IQR 17 to 43.There were insufficient included studies examining each of the three ROTEM CAs at 5, 10 and 15 minutes to make meta-analysis and investigation of heterogeneity valid. The results of the included studies are thus reported narratively and illustrated by a forest plot and results plotted on the receiver operating characteristic (ROC) plane.For CA5 the accuracy results were sensitivity 70% (95% CI 47% to 87%) and specificity 86% (95% CI 82% to 90%) for one study, and sensitivity 96% (95% CI 88% to 100%) and specificity 58% (95% CI 44% to 72%) for the other.For CA10 the accuracy results were sensitivity 100% (95% CI 94% to 100%) and specificity 70% (95% CI 56% to 82%).For CA15 the accuracy results were sensitivity 88% (95% CI 69% to 97%) and specificity 100% (95% CI 94% to 100%).No uninterpretable ROTEM study results were mentioned in any of the included studies.Risk of bias and concerns around applicability of findings was low across all studies for the patient and flow and timing domains. However, risk of bias and concerns around applicability of findings for the index test domain was either high or unclear
Clinical Commentary
What is known?
Trauma induced coagulopathy (TIC) is an impairment of blood clotting that occurs soon after injury and has been reported to confer a mortality rate as high as 50%. TIC is associated with increased rates of transfusion, organ failure, sepsis and longer critical care stays. Early recognition of TIC may allow trauma teams to treat coagulopathy more rapidly and may lead to improved clinical outcomes. Historically, TIC has been defined using standard laboratory coagulation tests, most commonly the prothrombin time (PT) and the PT ratio (PTr) or INR. More recently, viscoelastic tests (VHA tests) are being used with increasing frequency, favoured by clinical teams for being both point-of-care tests and for the speed with which useful results can be obtained. There is a great deal of interest in the role that VHA tests can play in the diagnosis of TIC as well as how they can be used optimally to guide transfusion therapy.
What did this paper set out to examine?
This Cochrane review set out to determine how good TEG and ROTEM assessments were at diagnosing TIC in adult trauma patients with bleeding. This was a diagnostic test accuracy review and the accuracy of the TEG and ROTEM was compared against the PTr/INR which was used as the reference standard.
What did they show?
This paper included 3 cross-sectional studies (including 430 patients in total), with civilian and military patients. No RCTs were identified. All three studies compared ROTEM to standard clotting tests and no study was specifically designed to evaluate test accuracy. The included studies focussed on a single ROTEM measure -EXTEM clot amplitude (CA) to assess TIC, but the time points that CA values were reported varied i.e. CA5, CA10 and CA15 (result at 5, 10 or 15 minutes). The reference standard that the studies used also varied with 2 studies using a PTr > 1.5 and 1 study using a PTr > 1.2.
The authors found that the 3 studies provided very little evidence on the accuracy of ROTEM and no evidence for TEG in the diagnosis of TIC. 4 domains were evaluated for risk of bias, and bias was thought to be high for two domains: (a) the choice of index test (ie ROTEM) and (b) the choice of reference standard (ie PTr/INR). The authors highlighted that this raised concerns around the interpretation of sensitivity and specificity results of the 3 studies.
What are the implications for practice and for future work?
The conclusion from this review was that there were no high quality data to confirm the accuracy of TEG or ROTEM in the diagnosis of TIC and the authors recommended that VHA tests should be limited to the research setting only.
Future research will need to focus on several areas. Interventional studies looking at the effect of ROTEM/TEG guided algorithms for diagnosis or even treatment of TIC, when compared to standard treatment without a VHA device, may be required to fully evaluate the use of these devices. However, without consensus about which VHA (or indeed standard clotting test) parameter(s) diagnose TIC the value of these interventions will be limited.
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Risks associated with red blood cell transfusion in the trauma population, a meta-analysis
Patel SV, Kidane B, Klingel M, Parry N
Injury. 2014;45((10):):1522-33.
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INTRODUCTION A previous meta-analysis has found an association between red blood cell (RBC) transfusions and mortality in critically ill patients, but no review has focused on the trauma population only. OBJECTIVES To determine the association between RBC transfusion and mortality in the trauma population, with secondary outcomes of multiorgan failure (MOF) and acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). DATA SOURCES EMBASE (1947-2012) and MEDLINE (1946-2012). STUDY ELIGIBILITY CRITERIA Randomized controlled trials and observational studies were to be included if they assessed the association between RBC transfusion and either the primary (mortality) or secondary outcomes (MOF, ARDS/ALI). PARTICIPANTS Trauma patients. EXPOSURE Red blood cell transfusion. METHODS A literature search was completed and reviewed in duplicate to identify eligible studies. Studies were included in the pooled analyses if an attempt was made to determine the association between RBC and the outcomes, after adjusting for important confounders. A random effects model was used for and heterogeneity was quantified using the I(2) statistic. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS 40 observational studies were included in the qualitative review. Including studies which adjusted for important confounders found the odds of mortality increased with each additional unit of RBC transfused (9 Studies, OR 1.07, 95%CI 1.04-1.10, I(2) 82.9%). The odds of MOF (3 studies, OR 1.08, 95%CI 1.02-1.14, I(2) 95.9%) and ARDS/ALI (2 studies, OR 1.06, 95%CI 1.03-1.10, I(2) 0%) also increased with each additional RBC unit transfused. CONCLUSIONS We have found an association between RBC transfusion and the primary and secondary outcomes, based on observational studies only. This represents the extent of the published literature. Further interventional studies are needed to clarify how limiting transfusion can affect mortality and other outcomes. Copyright 2014 Elsevier Ltd. All rights reserved.
Clinical Commentary
Dr Annemarie Docherty, University of Edinburgh, Edinburgh, UK.
What is known?
Death from haemorrhage is the second most common cause of death in the trauma population and a high proportion of severely injured patients receive red blood cell transfusions. Evidence from randomised controlled trials in critically ill patients support a restrictive transfusion threshold, however the effect of transfusion on outcomes in trauma may differ due to the timing and amount of transfusion required. Trauma patients may be unstable or actively bleeding, as opposed to the slow decline in haemoglobin often seen in critical care. Evidence in the trauma population is based primarily on small observational studies.
What did this paper set out to examine?
This systematic review and meta-analysis set out to assess the association between red blood cell transfusion and mortality in the trauma population. Secondary outcomes included acute respiratory distress syndrome or acute lung injury (ARDS/ALI) and multiorgan failure. Comparative observational and interventional studies were eligible for inclusion.
What did they show?
The authors included 40 studies in the qualitative review. No randomised controlled trials addressed the study question. All studies were observational cohort studies, which increased the risk of selection bias and confounding. Particularly relevant confounders were injury severity and other measures of shock which were strongly associated with the study outcomes. The authors assessed the quality of the studies using the Newcastle-Ottawa Scale, and the quality of the meta-analysis using the GRADE guidelines.
There was significant heterogeneity. Study size varied from 29 to 25,299. Timing of red blood cell transfusion varied considerably from studies that included transfusion within 24-48 hours only, total in-hospital transfusion, to studies that excluded patients transfused within 48 hours of admission. There were also marked differences in the categorisation of red blood cell transfusion: continuous variable (per unit change), binary variable (transfused/not transfused) and a categorical variable. In addition to this, patient populations also varied: multiply injured patients, patients with only one system injured, massively transfused patients, patients only admitted to the intensive care unit, surgical patients only, intubated patients only, and various injury severity score cutoffs.
Seventeen studies attempted to determine the effect of transfusion on mortality after adjusting for important confounders, and nine of these had enough information to be pooled in the meta-analysis. Eight studies found that red blood cell transfusion was associated with increased odds of mortality, and the adjusted pooled analysis showed an increase in the odds of mortality with each additional unit transfused (OR 1.07, 95%CI 1.04-1.10, p<0.001, I^2=94.6%). The authors graded this evidence as low.
Six studies attempted to determine the adjusted association with multiorgan failure. The odds of multiorgan failure increased with each additional unit of blood (OR 1.08, 95%CI 1.02-1.14, p=0.012, I^2=95.9%). The grade of evidence was moderate.
Six studies assessed the adjusted association between transfusion and ARDS, but only two had enough information to be included in the meta-analysis (transfused vs not transfused: OR 2.04, 95%CI 1.47-2.83, p<0.001, I^2=0%). The authors graded this evidence as very low.
What are the implications for practice and for future work?
The observational studies all showed an association between transfusion and mortality and other negative outcomes. However, there was considerable heterogeneity between the studies, and as the authors acknowledge, it is likely that significant confounding persisted even after attempts to adjust for injury and illness severity. The authors have graded the evidence as very low to moderate, and it is not possible to refine red blood cell transfusion practice in trauma on the basis of these observational studies.
This systematic review highlights the lack of evidence for red blood cell transfusion in trauma, and the need for a robust randomised controlled trial in this population. This would minimise confounding and bias, and give a definitive answer regarding the effect of red blood cell transfusion on mortality.
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Association of red blood cell transfusion and in-hospital mortality in patients admitted to the intensive care unit: a systematic review and meta-analysis
Zheng Y, Lu C, Wei S, Li Y, Long L, Yin P
Critical Care (London, England). 2014;18((6):):515.
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INTRODUCTION Previous research has debated whether red blood cell (RBC) transfusion is associated with decreased or increased mortality in patients admitted to the intensive care unit (ICU). We conducted a systematic review and meta-analysis to assess the relationship of RBC transfusion with in-hospital mortality in ICU patients. METHODS We carried out a literature search on Medline (1950 through May 2013), Web of Science (1986 through May 2013) and Embase (1980 through May 2013). We included all prospective and retrospective studies on the association between RBC transfusion and in-hospital mortality in ICU patients. The relative risk for the overall pooled effects was estimated by random effects model. Sensitivity analyses were conducted to assess potential bias. RESULTS The meta-analysis included 28,797 participants from 18 studies. The pooled relative risk for transfused versus nontransfused ICU patients was 1.431 (95% CI, 1.105 to 1.854). In sensitivity analyses, the pooled relative risk was 1.211 (95% CI, 0.975 to 1.505) if excluding studies without adjustment for confounders, 1.178 (95% CI, 0.937 to 1.481) if excluding studies with relative high risk of bias, and 0.901 (95% CI, 0.622 to 1.305) if excluding studies without reporting hazard ratio (HR) or relative risk (RR) as an effect size measure. Subgroup analyses revealed increased risks in studies enrolling patients from all ICU admissions (RR 1.513, 95%CI 1.123 to 2.039), studies without reporting information on leukoreduction (RR 1.851, 95%CI 1.229 to 2.786), studies reporting unadjusted effect estimates (RR 3.933, 95%CI 2.107 to 7.343), and studies using odds ratio as an effect measure (RR 1.465, 95%CI 1.049 to 2.045). Meta-regression analyses showed that RBC transfusion could decrease risk of mortality in older patients (slope coefficient -0.0417, 95%CI -0.0680 to -0.0154). CONCLUSIONS There is lack of strong evidence to support the notion that ICU patients who receive RBC transfusion have an increased risk of in-hospital death. In studies adjusted for confounders, we found that RBC transfusion does not increase the risk of in-hospital mortality in ICU patients. Type of patient, information on leukoreduction, statistical method, mean age of patient enrolled and publication year of the article may account for the disagreement between previous studies.
Clinical Commentary
Dr Annemarie Docherty, University of Edinburgh, Edinburgh, UK.
What is known?
Anaemia is prevalent in critically ill patients, and is associated with poor outcomes including acute myocardial infarction, heart failure, chronic kidney disease and risk of death. In critically ill patients, the standard method of reversing anaemia is with transfusion of red blood cells, with the aim of improving oxygen delivery to the tissues. However, blood transfusion is not without risks. These include immunosuppression, risk for infection, transfusion reactions and transfusion-related acute lung injury. There is conflicting evidence surrounding the association between red blood cell transfusion and mortality, with some studies suggesting a higher risk of death in transfused patients, and others finding a lower risk of death.
What did this paper set out to examine?
The authors have set out to examine whether there is an association between red blood cell transfusion and mortality in critically ill patients. The authors have performed a meta-analysis of all published retrospective and prospective observational studies comparing red blood cell transfused with non-transfused ICU patients, looking at all-cause in-hospital mortality, and risk factors of death in transfused patients.
What did they show?
The authors identified 18 observational studies which looked at mortality of transfused patients. Eight studies were prospective, and the other ten retrospective, six studies were very high overall quality, nine studies high overall quality and three studies median overall quality. The overall pooled risk ratio of in-hospital mortality of transfused patients compared to non-transfused patients was 1.431 (95%CI 1.105 to 1.854). However, in order to account for the impact of the observational design of the studies on the results, they performed several sensitivity analyses, including only studies that adjusted for confounders, only high quality studies, and only studies that included risk or hazard ratios. When only including studies that adjusted for confounding (of particular importance in observational studies), the RR was 1.211 (95%CI 0.795 to 1.505). The authors performed a subgroup analysis looking at different types of admission (sepsis and shock, surgical, trauma, and other). There was no association between RBC transfusion and mortality in each type of admission, however the pooled effect estimate suggested that type of admission was a significant predictor of in-hospital mortality. Other significant predictors were age of patient, and year of publication. Recent studies were more likely to report lower risk ratios, which the authors suggest means that blood transfusion may have got safer over time.
What are the implications for practice and for future work?
As a result of these observational limitations, although this systematic review suggests that RBC transfusion is not linked to in-hospital mortality, a randomised controlled trial designed and powered to answer this question would be required to determine causality. This review suggests that in the heterogenous ICU population, there is no association between RBC transfusion and in-hospital mortality after adjustment for confounders. Clinicians can perhaps be reassured that there does not appear to be an inherent risk with RBC transfusion, and that the decision to transfuse should be based on assessment of the patient’s physiological status and comorbidity.