Evidence-based practice guidelines for plasma transfusion_ 2632 1227..1239

BACKGROUND: There is little systematically derived evidence-based guidance to inform plasma transfusion decisions. To address this issue, the AABB commissioned the development of clinical practice guidelines to help direct appropriate transfusion of plasma. STUDY DESIGN AND METHODS: A systematic review (SR) and meta-analysis of randomized and observational studies was performed to quantify known benefits and harms of plasma transfusion in common clinical scenarios (see accompanying article). A multidisciplinary guidelines panel then used the SR and the GRADE methodology to develop evidence-based plasma transfusion guidelines as well as identify areas for future investigation. RESULTS: Based on evidence ranging primarily from moderate to very low in quality, the panel developed the following guidelines: 1) The panel suggested that plasma be transfused to patients requiring massive transfusion. However, 2) the panel could not recommend for or against transfusion of plasma at a plasma : red blood cell ratio of 1:3 or more during massive transfusion, 3) nor could the panel recommend for or against transfusion of plasma to patients undergoing surgery in the absence of massive transfusion. 4) The panel suggested that plasma be transfused in patients with warfarin therapy-related intracranial hemorrhage, 5) but could not recommend for or against transfusion of plasma to reverse warfarin anticoagulation in patients without intracranial hemorrhage. 6) The panel suggested against plasma transfusion for other selected groups of patients. CONCLUSION: We have systematically developed evidence-based guidance to inform plasma transfusion decisions in common clinical scenarios. Data from additional randomized studies will be required to establish more comprehensive and definitive guidelines for plasma transfusion. Volume 50, June 2010 TRANSFUSION 1227 P lasma transfusion is commonly prescribed for a variety of indications, including to replace volume and coagulation factors during massive transfusion, to prevent further or future bleeding in patients undergoing invasive procedures, to reverse warfarin therapy in patients with or without bleeding, and to address isolated coagulation factor abnormalities. Plasma for transfusion is usually termed fresh-frozen plasma (FFP, plasma frozen within 8 hours after phlebotomy) in everyday use as well as in the literature, although many plasma units transfused in the United States are actually frozen within 24 hours after phlebotomy (FP24). The primary difference between these products is that cryoprecipitate can be manufactured from FFP but not FP24, although FFP and FP24 can be transfused interchangeably. Thawed plasma (either FFP of FP24) stored for up to 5 days before administration is also commonly used for transfusion. (For simplicity, the term "plasma" is used throughout the text to refer to FFP, FP24, or thawed plasma.) The scientific evidence supporting many plasma transfusion practices is limited and weak. The lack of data, and the absence of authoritative interpretation of the available data, have led to inconsistencies in plasma transfusion practice and raise questions of optimal plasma transfusion strategies to improve patient care and maximize resource utilization. Practice guidelines (PGs) are systematically developed statements produced to assist practitioners and patients in their decisions about health care for specific clinical circumstances. 1 Attributes of high-quality PGs include validity, reliability, reproducibility, clinical applicability, multidisciplinary process, review of evidence, and documentation. PGs should be developed using evidencebased medicine (EBM) methods and principles which hold that systematic and explicit approaches in developing guidelines can help protect against errors, resolve disagreements, improve communication of medical information, and thus fulfill needs of all stakeholders (physicians, patients, policy-makers). EBM holds that recommendations for practice should, to the greatest extent possible, be consistent with evidence for or against a given intervention. The first EBM principle is that PG should be informed by systematic reviews (SRs; systematic review refers to the set of techniques and methods that limit bias in the assembly, critical appraisal, and synthesis of all relevant studies on a specific topic). Since evidence is necessary but not sufficient for decision-making, the second EBM principle is to separate assessment of evidence from formulating recommendations when developing PGs. To improve and standardize plasma transfusion practice, the AABB Board of Directors commissioned the development of evidence-based guidelines according to accepted EBM principles. The GRADE methodology (Grading of Recommendations, Assessment, Development, and Evaluation) was chosen for this process since it is becoming the worldwide standard for formulating evidence-based clinical PGs. MATERIALS AND METHODS Panel composition A committee composed of 17 members was formed to develop plasma transfusion PGs. Eleven members were representatives of the AABB CTMC (JR, JC, RD, MJD, AE, MF, MH, JRH, BSS, TS, and JW). Six members were chosen as subject matter experts to represent other professional organizations: American Association for the Study of Liver Diseases (SC), American Academy of Pediatrics (NL), the United States Army (JGP), American Society of Anesthesiology (AS), and American Society of Hematology (ES, CT; shared one vote). Nine of the members were pathologists and/or hematologists, two were anesthesiologists, three were internists, two were pediatricians, and one was a hepatologist. The panel was aided by three consultants who were methodologists: two who performed the SR and one who moderated and assisted the panel in their deliberations to develop these PGs (BD). None of the three consultants voted on the resulting PGs. Development of six questions to be addressed with guidelines The 11 panel members from the CTMC formulated questions that were believed to encompass many of the current pertinent and contentious issues in plasma transfusion. The panelists considered a number of approaches to formulate these questions (e.g., common plasma transfusion practices, practices that use the highest volume of plasma, or plasma transfusion in patient groups with specific diseases [such as liver disease]). Many of the approaches had validity, and it was clear that dozens of different questions could have been constructed to address distinct aspects of plasma transfusion practice. However, after extensive deliberations, the panel unanimously agreed to limit the scope of the present guidelines to six questions that represented the majority of plasma transfusion issues most often discussed between transfusion medicine practitioners and clinicians. The panel believed that addressing these six questions (through guidelines and further ROBACK ET AL. TRANSFUSION Volume 50, June 2010 clinical studies) would significantly improve plasma transfusion practice. Given the limitations of the data in the literature, as described in the SR, it was not possible to address the efficacy of plasma transfusion as a function of underlying coagulation variables in the recipient or to issue evidence-based guidelines addressing plasma dosage. Of note, the use of plasma during plasma exchange was not addressed here since it has recently been subject to detailed examination. 5 All questions were formulated in the terms of patient groups, intervention (plasma transfusion), and comparator/control treatment (defined in most cases as "no plasma transfusion" for these guidelines). The primary outcome of interest in all cases was mortality. While studies with other comparators were available (e.g., prothrombin complex concentrate), 6,7 these were considered to be outside the scope of this work. These and other questions remain important areas for future work. SR An SR of the relevant literature, including both randomized controlled and observational studies, was performed (see companion article 4 ). This SR process utilized a comprehensive literature search, evidence review by a blinded pair of reviewers, exploration of heterogeneity by subgroup, and sensitivity and metaregression methods. The SR also included preparation of the GRADE evidence profiles 8 summarizing the effect of plasma in various clinical scenarios. The evidence profiles displayed information on the effect of plasma in terms of benefits and harms for the most important clinical outcomes (including death and acute lung injuries). It should be noted that the SR focused on short-term outcomes (up to 30 days) and not longterm outcomes such as viral transmission that may occur after plasma transfusion. The effects were presented in terms of both absolute and relative effect measures. For each question, the evidence profiles were given tentative GRADE-quality criteria for each outcome of importance by the systematic reviewers. The GRADE methodology for clinical guidelines development (see Appendix) The panel's work was directed by the process for guideline development established by the GRADE group. 8 GRADE is an emerging system for developing PGs, which has been adopted by many professional organizations around the world and increasingly considered as the worldwide standard for formulating evidence-based PGs. 9 At its core, the GRADE system adheres to the following principles: The following factors affect the quality of evidence: 1) study design (randomized clinical trial vs. observational vs. any other types of evidence); 2) methodologic factors that may decrease quality of evidence (inadequate allocation concealment, lack of blinding, large drop-outs, failure to perform intention-to-treat analysis, failure to report outcomes, and stopping early for benefits); 3) factors that may increase quality of evidence (large magnitude of treatment effect, adequate accounting for confounders, and presence of a dose response); 12 4) consistency or inconsistency between the results of published evidence; 5) directness or indirectness of the evidence; 6) precision or imprecision; and 7) reporting bias. 11 Thus, the quality of evidence represents an estimate of the "correctness" or "truth" of the results obtained in clinical research based on the types of studies performed (e.g., randomized controlled trials or observational studies) as well as the assessment of characteristics of the studies for protection against bias and random error. Unlike in other guidelines systems, in which quality of evidence is equated with the strength of recommendations, Strong recommendations indicate that most (but perhaps not all) well-informed people would make the same choice. Weak recommendations, in contrast, indicate that while many well-informed people would make that choice, a substantial minority would not. In cases where neither a strong nor a weak recommendation can be agreed upon, no specific recommendation is made, or the use of intervention is endorsed in the context of research. Development of plasma transfusion guidelines Each member of the panel was sent a full copy of the SR along with the GRADE evidence profiles. Each member of the panel was asked to make his or her final judgments on the strength of recommendation and the overall quality of the body of evidence. Voting was anonymous and was based on the use of GRADE grids for formulation of the strength of recommendations. 14 The panel previously agreed to issue a strong recommendation (e.g., "We recommend . . .") if 70% or more of the panel members voted strongly for (or against) that intervention. A weak recom- EVIDENCE-BASED GUIDELINES FOR PLASMA USE Volume 50, June 2010 TRANSFUSION 1229 mendation (e.g., "We suggest . . .") was issued if there were insufficient votes for a strong recommendation, but the total votes strongly and weakly for (or against) the intervention comprised 70% or more of the panel. If at least 70% of the panel was neither for nor against an intervention, no recommendation was issued (e.g., "We cannot recommend . . ."). PLASMA TRANSFUSION GUIDELINES Below, each of the six questions is followed by the panel's recommendations for plasma transfusion in those settings. Supporting background for each of these questions is then presented, followed by a summary of the relevant evidence, potential benefits and harms, and rationale for the panel's recommendations. Detailed descriptions of the studies can be found in the accompanying SR. 4 Question 1 Should plasma transfusion (vs. no plasma) be used in trauma patients requiring massive transfusion? Recommendation: We suggest that plasma be transfused to trauma patients requiring massive transfusion (quality of evidence = moderate). Question 2 Should a plasma : red blood cell (RBC) transfusion ratio of 1:3 or more (vs. <1:3) be used in trauma patients requiring massive transfusion? Recommendation: We cannot recommend for or against transfusion of plasma at a plasma : RBC ratio of 1:3 or more in trauma patients during massive transfusion (quality of evidence = low). The panel strongly endorsed further testing of plasma : RBC transfusion ratio of 1:3 or more (vs. <1:3) in the context of well-designed randomized controlled trials. Background Recent observational studies in trauma patients have suggested that increasing the volume of plasma infused during massive transfusion (based on the plasma : RBC ratio) improves patient outcome. These findings have led to changes in clinical practice in some settings. If these results are accurate and generalizable, they would have important benefits for trauma care. However, broad implementation of these changes would also increase plasma usage, raising concerns of resource utilization, and may increase the occurrence of transfusion-related acute lung injury (TRALI) and other adverse effects of plasma transfusion. To our knowledge, these observational studies have not previously been subjected to detailed meta-analysis, and the benefits and risks of this approach have not been carefully weighed by subject matter experts. The committee separately considered two aspects of the practice of plasma infusion during massive transfusion: should plasma be used during massive transfusion and should plasma be transfused at a ratio of 1:3 or more in these settings? Evidence summary We found 10 observational studies (reported in 12 publications) that assessed the effects of plasma : RBC transfusion ratios on mortality in trauma patients experiencing massive transfusion (defined as transfusion of Ն10 units of RBCs). In these studies, transfusion of plasma at plasma : RBC ratios greater than 1:3 (in the range of 1:2.5-1:1) was associated with significant reductions in mortality (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.24-0.60; I 2 = 85%) and a reduced risk of multiorgan failure (OR, 0.40; 95% CI, 0.26-0.60). Potential benefits In trauma patients who require massive transfusion, plasma infusion reduced the death rate by approximately 60% (OR, 0.38) and also reduced the risk of multiorgan failure by approximately 60% (OR, 0.40) in comparison with control. Potential harms In nontrauma studies evaluated as part of the SR, plasma transfusion was associated with an almost threefold increased risk of acute lung injury (OR, 2.92; 95% CI, 1.99-4.29). 4 Increased use of plasma in massive transfusion patients may also reduce plasma inventories, raising questions of optimal resource utilization. Although increased plasma transfusion may slightly increase the risks of viral transmission, this potential harm was consid-ROBACK ET AL. TRANSFUSION Volume 50, June 2010 ered to be much less significant given that the current risk of transmitting human immunodeficiency virus and hepatitis C virus, for example, by transfusion is approximately 1 in 2,000,000. 27 Rationale for recommendations Based on the data from these studies and the analysis described, all panel members supported the practice of infusing plasma to trauma patients during massive transfusion; half of the panel strongly supported this practice while half were in weak support The panel's suggestion to infuse plasma to trauma patients requiring massive transfusion indicates that most practitioners would make the choice to infuse plasma in this setting, although a substantial minority may not. Some panelists who were weakly in favor of this therapy believed that patient-specific circumstances such as the amount of blood lost, the speed with which bleeding was controlled, and the likelihood of ongoing bleeding may influence clinical judgment regarding plasma use in trauma patients. Nonetheless, the committee's suggestion to transfuse plasma means that the benefits of this therapy likely outweigh the potential harms for most trauma patients. Half of the panel was weakly in favor of using a plasma : RBC ratio of 1:3 or more in this setting ( Question 3 Should plasma transfusion (vs. no plasma) be used in surgical and/or trauma patients in the absence of massive transfusion? Recommendation: We cannot recommend for or against transfusion of plasma for patients undergoing surgery in the absence of massive transfusion (quality of evidence = very low). Background Plasma transfusions are commonly ordered during surgery or other invasive procedures. Most of these transfusions do not occur during massive transfusion episodes B A EVIDENCE-BASED GUIDELINES FOR PLASMA USE Volume 50, June 2010 TRANSFUSION 1231 (i.e., transfusion of <10 RBC units), and many are ordered prophylactically in the absence of bleeding. Given the risks associated with plasma transfusion, the panel believed that it was important to define acceptable plasma transfusion practices in this patient population. Evidence summary Twelve studies reported mortality in patients undergoing surgery in settings other than trauma and massive transfusion, although six reported no deaths and did not contribute to the analysis. 22,38 Meta-analysis of these studies shows that plasma transfusion was associated with a trend toward increased risk of death (OR, 1.22; 95% CI, 0.73-2.03; I 2 = 61%) which, however, fell short of significance. Potential benefits In these studies, there were no obvious benefits of plasma transfusion, such as lower mortality, less bleeding, reduced blood loss and blood product usage, or reduced rates of myocardial infarction and stroke. Potential harms Plasma transfusions in these patients was associated with a trend toward increased mortality and as described above is also associated with an increased rate of lung injury. Additionally, transfusion of plasma to patients who do not require it raises issues of resource utilization. Rationale for recommendation Despite the widespread use of plasma in patients undergoing surgery or other invasive procedures in the absence of massive transfusion, 69% of the panel recommended against this practice based on the available evidence including the trend toward increased risk of death in this patient population and the known risks of TRALI with plasma transfusion Question 4 Should plasma transfusion (vs. no plasma) be used for patients with warfarin anticoagulation-related intracranial hemorrhage? Recommendation: We suggest that plasma be transfused in patients with warfarin anticoagulation-related intracranial hemorrhage (quality of evidence = low)

Recognition of c. 1780 Ma magmatism and metamorphism in the buried northeastern Gawler Craton: Correlations with events of the Aileron Province

The far northeastern Gawler Craton, South Australia, lies at the northern margin of one of the major building blocks of the Australian continent and is a region that is important in models for the Proterozoic tectonic evolution of Australia. However, this region is overlain by Phanerozoic sedimentary cover and consequently has had no previous geological study. We report the lithotypes, geochronology, geochemistry and isotopic composition of rocks recovered in a mineral exploration drill hole in the far northeastern Gawler Craton, the sole drill hole to sample crystalline basement in this region. Lithologies within the drill hole are garnet- and pyrite-bearing metasedimentary gneiss, pyroxenite and gabbroic intrusions, along with granitic bodies. Metasedimentary gneiss has a maximum depositional age of 1841 ± 4 Ma and a provenance pattern more similar to rocks of the Aileron Province of the Arunta Region, central Australia, in particular the Lander Rock Formation, than to other metasedimentary rocks of the Gawler Craton. Amphibolite facies metamorphism occurred at c. 1780 Ma and was synchronous with emplacement of high Mg, crustally contaminated mafic rocks, along with several types of felsic intrusion. This metamorphic event is very similar in age and style to the Yambah Event of the Aileron Province, and has not been documented previously in the Gawler Craton. The overall geological features of this portion of the northern Gawler Craton support models that link it with the Aileron Province of the Arunta Region. The rocks of drill hole TB02 underwent thermal resetting recorded by a biotite 40Ar/39Ar age of c. 480 Ma, likely as a result of the Cambro-Ordovician Delamerian Orogeny along the eastern margin of Gondwana