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1.
Tranexamic Acid in Patients Undergoing Noncardiac Surgery
Devereaux PJ, Marcucci M, Painter TW, Conen D, Lomivorotov V, Sessler DI, Chan MTV, Borges FK, Martínez-Zapata MJ, Wang CY, et al
The New England journal of medicine. 2022
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Editor's Choice
Abstract
BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).
PICO Summary
Population
Patients undergoing non-cardiac surgery (n= 9,535).
Intervention
Tranexamic acid at the start and end of surgery (n= 4,757).
Comparison
Placebo (n= 4,778).
Outcome
The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, non-haemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. A composite bleeding outcome event occurred in 433 patients (9.1%) in the tranexamic acid group and in 561 patients (11.7%) in the placebo group. A composite cardiovascular outcome event occurred in 649 patients (14.2%) in the tranexamic acid group and in 639 patients (13.9%) in the placebo group.
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2.
Effect of 6% hydroxyethyl starch 130/0.4 on kidney and haemostatic function in cardiac surgical patients: a randomised controlled trial
Duncan AE, Jia Y, Soltesz E, Leung S, Yilmaz HO, Mao G, Timur AA, Kottke-Marchant K, Rogers HJ, Ma C, et al
Anaesthesia. 2020
Abstract
Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40-85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1-68 [0-996]) ng.ml(-1) ) vs. albumin (5 (2-74 [0-1604]) ng.ml(-1) ), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.
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Tranexamic acid and rosuvastatin in patients at risk of cardiovascular events after noncardiac surgery: a pilot of the POISE-3 randomized controlled trial
Marcucci M, Duceppe E, Le Manach Y, Kearon C, Eikelboom JW, Pohl K, Vincent J, Darvish-Kazem S, Srinathan SK, Neary JDD, et al
Pilot Feasibility Stud. 2020;6:104
Abstract
BACKGROUND Surgical bleeding is associated with postoperative cardiovascular complications. The efficacy and safety of tranexamic acid (TXA) in noncardiac surgery are still uncertain. Statins may prevent perioperative cardiovascular complications. We conducted a pilot to assess the feasibility of a perioperative trial of TXA and rosuvastatin. METHODS Using a factorial design, we randomized patients at cardiovascular risk undergoing noncardiac surgery to intravenous TXA (1 g at the start and end of surgery) or placebo, and oral rosuvastatin (40 mg before and 20 mg daily for 30 days after surgery) or placebo. Feasibility outcomes included recruitment rates, follow-up, and compliance to interventions. Clinical outcomes were secondarily explored. RESULTS After 3 months, we changed the design to a partial factorial due to the difficult recruitment of statin-naive patients. Over 6 months, 100 patients were randomized in the TXA trial (49 TXA, 51 placebo), 34 in the rosuvastatin trial (18 rosuvastatin, 16 placebo). Ninety-two percent (95% CI 80-98) of TXA and 86% (95% CI 74-94) of TXA-placebo patients received the 2 study doses. Thirty-three percent (95% CI 13-59) of rosuvastatin patients and 37% (95% CI 15-65) of rosuvastatin-placebo patients discontinued the study drug. A major cardiovascular complication occurred at 30 days in 1 TXA and 6 TXA-placebo patients, and 1 rosuvastatin and no rosuvastatin-placebo patients. CONCLUSIONS Our pilot study supports the feasibility of a perioperative TXA trial in noncardiac surgery. Feasibility of a perioperative rosuvastatin trial is uncertain because of a high prevalence of statin use in the target population and concerns about compliance. TRIAL REGISTRATION ClinicalTrials.govNCT02546648.
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4.
Effect of red blood cell storage duration on major postoperative complications in cardiac surgery: A randomized trial
Koch CG, Sessler DI, Duncan AE, Mascha EJ, Li L, Yang D, Figueroa P, Sabik JF 3rd, Mihaljevic T, Svensson LG, et al
The Journal of thoracic and cardiovascular surgery. 2019
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Editor's Choice
Abstract
BACKGROUND Although observational studies suggest an association between transfusion of older red blood cell (RBC) units and increased postoperative risk, randomized trials have not supported this. The objective of this randomized trial was to test the effect of RBC storage age on outcomes after cardiac surgery. METHODS From July 2007 to May 2016, 3835 adults undergoing coronary artery bypass grafting, cardiac valve procedures, or ascending aorta repair, either alone or in combination, were randomized to transfusion of RBCs stored for ≤14 days (younger units) or for ≥20 days (older units) intraoperatively and throughout the postoperative hospitalization. According to protocol, 2448 patients were excluded because they did not receive RBC transfusions. Among the remaining 1387 modified intent-to-treat patients, 701 were randomized to receive younger RBC units (median age, 11 days) and the remaining 686 to receive older units (median age, 25 days). The primary endpoint was composite morbidity and mortality, analyzed using a generalized estimating equation (GEE) model. The trial was discontinued midway owing to enrollment constraints. RESULTS A total of 5470 RBC units were transfused, including 2783 in the younger RBC storage group and 2687 in the older RBC storage group. The GEE average relative-effect odds ratio was 0.77 (95% confidence interval [CI], 0.50-1.19; P = .083) for the composite morbidity and mortality endpoint. In-hospital mortality was lower for the younger RBC storage group (2.1% [n = 15] vs 3.4% [n = 23]), as was occurrence of other adverse events except for atrial fibrillation, although all CIs crossed 1.0. CONCLUSIONS This clinical trial, which was stopped at its midpoint owing to enrollment constraints, supports neither the efficacy nor the futility of transfusing either younger or older RBC units. The effects of transfusing RBCs after even more prolonged storage (35-42 days) remains untested.
PICO Summary
Population
Adults undergoing coronary artery bypass grafting, cardiac valve procedures, or ascending aorta repair, either alone or in combination (n=3835).
Intervention
Younger red blood cell (RBC) units (median age, 11 days), (n=701).
Comparison
Older units (median age, 25 days), (n=686).
Outcome
A total of 5470 RBC units were transfused, including 2783 in the younger RBC storage group and 2687 in the older RBC storage group. The generalized estimating equation (GEE) average relative-effect odds ratio was 0.77 for the composite morbidity and mortality endpoint. In-hospital mortality was lower for the younger RBC storage group (2.1% [n = 15] vs 3.4% [n = 23]), as was occurrence of other adverse events except for atrial fibrillation.
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A randomized clinical trial of red blood cell transfusion triggers in cardiac surgery
Koch CG, Sessler DI, Mascha EJ, Sabik JF 3rd, Li L, Duncan AI, Zimmerman NM, Blackstone EH
The Annals of Thoracic Surgery. 2017;104((4):):1243-1250
Abstract
BACKGROUND Class I evidence supporting a threshold for transfusion in the cardiac surgical setting is scarce. We randomly allocated patients to a transfusion hematocrit trigger of 24% versus 28% to compare morbidity, mortality, and resource use. METHODS From March 2007 to August 2014, two centers randomly assigned 722 adults undergoing coronary artery bypass graft surgery or valve procedures to a 24% hematocrit trigger (n = 363, low group) or 28% trigger (n = 354, high group). One unit of red blood cells was transfused if the hematocrit fell below the designated threshold. The primary endpoint was a composite of postoperative morbidities and mortality. Treatment effect was primarily assessed using an average relative effect generalized estimating equation model. RESULTS At the second planned interim analysis, the a priori futility boundary was crossed, and the study was stopped. There was no detected treatment effect on the composite outcome (average relative effect odds ratio, low versus high, 0.86, 95% confidence interval: 0.29 to 2.54, p = 0.71). However, the low group received fewer red blood cell transfusions than the high group (54% versus 75%, p < 0.001), mostly administered in the operating room (low group, 112 [31%]; high group, 208 [59%]), followed by intensive care unit (low, 105 [31%]; high, 115 [34%]) and floor (low, 41 [12%]; high, 42 [13%]). The low group was exposed to lower hematocrits: median before transfusion, 22% (Q1 = 21%, Q3 = 23%) versus 24% (Q1 = 22%, Q3 = 25%). CONCLUSIONS Negative exposures differed between treatment groups, with lower hematocrit in the 24% trigger group and more red blood cells used in the 28% group, but adverse outcomes did not differ. Because red blood cell use was less with a 24% trigger without adverse effects, our randomized trial results support aggressive blood conservation efforts in cardiac surgery.
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Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery
Nakayama Y, Nakajima Y, Tanaka KA, Sessler DI, Maeda S, Iida J, Ogawa S, Mizobe T
British Journal of Anaesthesia. 2015;114((1):):91-102.
Abstract
BACKGROUND Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements. METHODS We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements. RESULTS CPB time, post-bypass rotational thromboelastometry (ROTEM()) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg(-1), P<0.001) and packed red cell transfusion requirement (11 vs 23 ml kg(-1), P=0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P=0.014). CONCLUSIONS Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients. CLINICAL TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011). The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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The effects of mild perioperative hypothermia on blood loss and transfusion requirement
Rajagopalan S, Mascha E, Na J, Sessler DI
Anesthesiology. 2008;108((1):):71-7.
Abstract
BACKGROUND Anesthetic-induced hypothermia is known to reduce platelet function and impair enzymes of the coagulation cascade. The objective of this meta-analysis and systematic review was to evaluate the hypothesis that mild perioperative hypothermia increases surgical blood loss and transfusion requirement. METHODS The authors conducted a systematic search of published randomized trials that compared blood loss and/or transfusion requirements in normothermic and mildly hypothermic (34-36 degrees C) surgical patients. Results are expressed as a ratio of the means or relative risks and 95% confidence intervals (CI); P < 0.05 was considered statistically significant. RESULTS Fourteen studies were included in analysis of blood loss, and 10 in the transfusion analysis. The median (quartiles) temperature difference between the normothermic and hypothermic patients among studies was 0.85 degrees C (0.60 degrees C versus 1.1 degrees C). The ratio of geometric means of total blood loss in the normothermic and hypothermic patients was 0.84 (0.74 versus 0.96), P = 0.009. Normothermia also reduced transfusion requirement, with an overall estimated relative risk of 0.78 (95% CI 0.63, 0.97), P = 0.027. CONCLUSION Even mild hypothermia (<1 degree C) significantly increases blood loss by approximately 16% (4-26%) and increases the relative risk for transfusion by approximately 22% (3-37%). Maintaining perioperative normothermia reduces blood loss and transfusion requirement by clinically important amounts.
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8.
Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty
Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A
Lancet. 1996;347((8997):):289-92.
Abstract
BACKGROUND In-vitro studies indicate that platelet function and the coagulation cascade are impaired by hypothermia. However, the extent to which perioperative hypothermia influences bleeding during surgery remains unknown. Accordingly, we tested the hypothesis that mild hypothermia increases blood loss and allogeneic transfusion requirements during hip arthroplasty. METHODS Blood loss and transfusion requirements were evaluated in 60 patients undergoing primary, unilateral total hip arthroplasties who were randomly assigned to normothermia (final intraoperative core temperature 36.6 [0.4] degrees C) or mild hypothermia (35.0 [0.5] degrees C). Crystalloid, colloid, scavenged red cells, and allogeneic blood were administered by strict protocol. FINDINGS Intra- and postoperative blood loss was significantly greater in the hypothermic patients: 2.2 (0.5) L vs 1.7 (0.3) L, p < 0.001). Eight units of allogeneic packed red cells were required in seven of the 30 hypothermic patients, whereas only one normothermic patient required a unit of allogeneic blood (p < 0.05 for administered volume). A typical decrease in core temperature in patients undergoing hip arthroplasty will thus augment blood loss by approximately 500 mL. INTERPRETATION The maintenance of intraoperative normothermia reduces blood loss and allogeneic blood requirements in patients undergoing total hip arthroplasty.