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1.
Evaluating the Impact of Cardiopulmonary Bypass Priming Fluids on Bleeding After Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis
Siemens K, Donnelly P, Hunt BJ, Carter MJ, Murdoch IA, Tibby SM
Journal of cardiothoracic and vascular anesthesia. 2021
Abstract
OBJECTIVES Cardiopulmonary bypass (CPB) predisposes young children to coagulopathy. The authors evaluated possible effects of CPB priming fluids on perioperative bleeding in pediatric cardiac surgery. DESIGN Meta-analysis and systematic review of previously published studies. SETTING Each study was conducted in a surgical center or intensive care unit. PARTICIPANTS Studies investigating patients <18 years without underlying hematologic disorders were included. INTERVENTIONS The authors evaluated randomized controlled trials (RCTs) published between 1980 and 2020 on MEDLINE, EMBASE, PubMed, and CENTRAL databases. The primary outcome was postoperative bleeding; secondary endpoints included blood product transfusion, mortality, and safety. MEASUREMENTS AND MAIN RESULTS Twenty eligible RCTs were analyzed, with a total of 1,550 patients and a median of 66 patients per study (range 20-200). The most frequently assessed intervention was adding fresh frozen plasma (FFP) to the prime (8/20), followed by albumin (5/20), artificial colloids (5/20), and blood-based priming solutions (3/20). Ten studies with 771 patients evaluated blood loss at 24 hours in mL/kg and were included in a meta-analysis. Most of them investigated the addition of FFP to the priming fluid (7/10). No significant difference was found between intervention and control groups, with a mean difference of -0.13 (-2.61 to 2.34), p = 0.92, I(2) = 69%. Further study endpoints were described but their reporting was too heterogeneous to be quantitatively analyzed. CONCLUSIONS This systematic review of current evidence did not show an effect of different CPB priming solutions on 24-hour blood loss. The analysis was limited by heterogeneity within the dataset regarding population, type of intervention, dosing, and the chosen comparator, compromising any conclusions.
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2.
Tranexamic Acid in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis
Dionne JC, Oczkowski SJW, Hunt BJ, Antonelli M, Wijnberge M, Raasveld SJ, Vlaar APJ
Critical care medicine. 2021
Abstract
OBJECTIVES Tranexamic acid is proposed as a treatment for gastrointestinal bleeding. The Haemorrhage Alleviation with Tranexamic Acid-Intestinal System trial evaluated extended-use (24 hr) high-dose tranexamic acid, prompting a reappraisal for tranexamic acid in gastrointestinal bleeding. DATA SOURCES We conducted a systematic review and meta-analysis of randomized controlled trials comparing tranexamic acid with usual care or placebo in adults with gastrointestinal bleeding. We searched MEDLINE, EMBASE, and CENTRAL (inception to September 2019). DATA SELECTION Two reviewers independently screened citations, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool in duplicate. The main outcomes were mortality, bleeding, and adverse events. DATA EXTRACTION Studies were analyzed as high-dose IV tranexamic acid versus all other dosing strategies for tranexamic acid using fixed-effects models. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS Five randomized controlled trials evaluated extended-use high-dose IV tranexamic acid, seven evaluating low-dose IV or enteral tranexamic acid. Extended-use high-dose IV tranexamic acid did not reduce mortality (relative risk, 0.98%; 95% CI, 0.88-1.09; I2 = 63%; high certainty) or bleeding (relative risk, 0.92; 95% CI, 0.82-1.04; p = 0.17 and absolute risk differences, -0.7%; 95% CI, -1.5 to 0.3; high certainty) but resulted in a small increase in deep venous thrombosis (relative risk, 2.01; 95% CI, 1.08-3.72; I2 = 0%), pulmonary embolism (relative risk, 1.78; 95% CI, 1.06-3.0; I2 = 0%), and seizure (relative risk, 1.73; 95% CI, 1.03-2.93) with high certainty. Low-dose IV/enteral tranexamic acid did not reduce mortality (relative risk, 0.62; 95% CI, 0.36-1.09; I2 = 0%) but did reduce risk of rebleeding (relative risk, 0.5; 95% CI, 0.33-0.75; I2 = 9%) and need for surgery (relative risk, 0.58; 95% CI, 0.38-0.88; I2 = 11%), with moderate certainty. CONCLUSIONS Extended-use high-dose IV tranexamic acid does not improve mortality or bleeding outcomes and increases adverse events. Low-dose/enteral tranexamic acid may be effective in reducing hemorrhage; more evidence is required to demonstrate its safety.
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3.
Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis
Siemens K, Sangaran DP, Hunt BJ, Murdoch IA, Tibby SM
Anesthesia and analgesia. 2021
Abstract
BACKGROUND Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P = <.00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.
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4.
Individualized, Intraoperative Dosing of Fibrinogen Concentrate for the Prevention of Bleeding in Neonatal and Infant Cardiac Surgery Using Cardiopulmonary Bypass (FIBCON): A Phase 1b/2a Randomized Controlled Trial
Siemens K, Hunt BJ, Harris J, Nyman AG, Parmar K, Tibby SM
Circulation. Cardiovascular interventions. 2020;:Circinterventions120009465
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Editor's Choice
Abstract
BACKGROUND Mediastinal bleeding is common following pediatric cardiopulmonary bypass surgery for congenital heart disease. Fibrinogen concentrate (FC) represents a potential therapy for preventing bleeding. METHODS We performed a single-center, phase 1b/2a, randomized controlled trial on infants 2.5 to 12 kg undergoing cardiopulmonary bypass surgery, aimed at (1) demonstrating the feasibility of an intraoperative point-of-care test, rotational thromboelastometry, to screen out patients at low risk of postoperative bleeding and then guide individualized FC dosing in high-risk patients and (2) determining the dose, safety, and efficacy of intraoperative FC supplementation. Screening occurred intraoperatively 1-hour before bypass separation using the rotational thromboelastometry variable fibrinogen thromboelastometry maximum clot firmness (FibTEM-MCF; fibrinogen contribution to clot firmness). If FibTEM-MCF ≥7 mm, patients entered the monitoring cohort. If FibTEM-MCF ≤6 mm, patients were randomized to receive FC/placebo (2:1 ratio). Individualized FC dose calculation included weight, bypass circuit volume, hematocrit, and intraoperative measured and desired FibTEM-MCF. The coprimary outcomes, measured 5 minutes post-FC administration were FibTEM-MCF (desired range, 8-13 mm) and fibrinogen levels (desired range, 1.5-2.5 g/L). Secondary outcomes were thrombosis and thrombosis-related major complications and postoperative 24-hour mediastinal blood loss. RESULTS We enrolled 111 patients (cohort, n=21; FC, n=60; placebo, n=30); mean (SD) age, 6.4 months (5.8); weight, 5.9 kg (2.0). Intraoperative rotational thromboelastometry screening effectively excluded low-risk patients, in that none in the cohort arm (FibTEM-MCF, ≥7 mm) demonstrated clinically significant early postoperative bleeding (>10 mL/kg per 4 hours). Among randomized patients, the median (range) FC administered dose was 114 mg/kg (51-218). Fibrinogen levels increased from a mean (SD) of 0.91 (0.22) to 1.7 g/L (0.41). The postdose fibrinogen range was 1.2 to 3.3 g/L (72% within the desired range). The corresponding FibTEM-MCF values were as follows: pre-dose, 5.3 mm (1.9); post-dose, 13 mm (3.2). Ten patients (8 FC and 2 placebo) exhibited 12 possible thromboses; none were clearly related to FC. There was an overall difference in mean (SD) 24-hour mediastinal drain loss: cohort, 12.6 mL/kg (6.4); FC, 11.6 mL/kg (5.2); placebo, 17.1 mL/kg (14.3; ANOVA P=0.02). CONCLUSIONS Intraoperative, individualized dosing of FC appears feasible. The need for individualized dosing is supported by the finding that a 4-fold variation in FC dose is required to achieve therapeutic fibrinogen levels. Registration: URL: https://eudract.ema.europa.eu/; Unique identifier: 2013-003532-68. URL: https://www.isrctn.com/; Unique identifier: 50553029.
PICO Summary
Population
Infants undergoing cardiopulmonary bypass surgery (n= 111).
Intervention
Fibrinogen concentrate (FC), (n= 60).
Comparison
Placebo (n= 30).
Outcome
Among randomized patients, the median (range) FC administered dose was 114 mg/kg (51-218). Fibrinogen levels increased from a mean (SD) of 0.91 (0.22) to 1.7 g/L (0.41). The postdose fibrinogen range was 1.2 to 3.3 g/L (72% within the desired range). The corresponding FibTEM-MCF values were as follows: pre-dose, 5.3 mm (1.9); post-dose, 13 mm (3.2). Ten patients (8 FC and 2 placebo) exhibited 12 possible thromboses; none were clearly related to FC. There was an overall difference in mean (SD) 24-hour mediastinal drain loss: cohort, 12.6 mL/kg (6.4); FC, 11.6 mL/kg (5.2); placebo, 17.1 mL/kg (14.3).
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5.
A comparison of haemostatic biomarkers during low-risk patients undergoing cardiopulmonary bypass using either conventional centrifugal cell salvage or the HemoSep device
Boyle G, Kuffel A, Parmar K, Gibson K, Smith M, Grehan A, Hunt BJ, Chambers DJ
Perfusion. 2018;:267659118789051.
Abstract
BACKGROUND Cardiac surgery using cardiopulmonary bypass (CPB) is associated with a coagulopathy due to haemodilution, thrombocytopenia and platelet dysfunction and the activation of coagulation and fibrinolysis, despite the use of large doses of unfractionated heparin. Conventional red cell salvage may exacerbate post-operative bleeding as plasma containing haemostatic factors is discarded. We hypothesized that a novel cell salvage device (HemoSep) may attenuate haemostatic changes associated with red cell salvage. We studied haemostatic markers following autologous transfusion from conventional cell salvage or the HemoSep device. METHODS This randomised, controlled trial compared haemostatic markers in patients undergoing coronary artery bypass grafting or aortic valve replacement who received autologous blood returned from cell salvage (control) or HemoSep (study). Blood samples were taken pre-operatively, end of CPB, post-transfusion of salvaged blood and 3 hours post-operatively and analysed for full blood count (FBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer and endogenous thrombin potential (ETP). RESULTS Fifty-four patients were recruited (n=28 control, n=26 study). Processed blood volume for transfusion was significantly (p<0.001) higher in the HemoSep group. In the HemoSep group, the PT was shorter (18.7+/-0.3 vs 19.9+/-0.3 sec; p<0.05) post-operatively and the aPTT was longer (48.6+/-3.8 vs 37.3+/-1.0 sec; p<0.01) following autologous transfusion. In the control group, D-dimer and ETP levels were higher (1903+/-424 vs.1088+/-151; p<0.05 and 739+/-46 vs. 394+/-60; p<0.001, respectively) following autologous transfusion. CONCLUSIONS Although centrifuged cell salvage is known to adequately haemoconcentrate and remove unwanted substrates and bacteriological contamination, the process can exacerbate coagulopathy. The HemoSep device demonstrated some increase in haemostatic markers when used in low-risk cardiac surgery patients.
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Strategies for prevention and management of bleeding following pediatric cardiac surgery on cardiopulmonary bypass: a scoping review
Siemens K, Sangaran DP, Hunt BJ, Murdoch IA, Tibby SM
Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2017;19((1):):40-47
Abstract
OBJECTIVE We aimed to systematically describe, via a scoping review, the literature reporting strategies for prevention and management of mediastinal bleeding post pediatric cardiopulmonary bypass surgery. DATA SOURCES MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL Register. STUDY SELECTION Two authors independently screened publications from 1980 to 2016 reporting the effect of therapeutic interventions on bleeding-related postoperative outcomes, including mediastinal drain loss, transfusion, chest re-exploration rate, and coagulation variables. Inclusions: less than 18 years, cardiac surgery on cardiopulmonary bypass. DATA EXTRACTION Data from eligible studies were extracted using a standard data collection sheet. DATA SYNTHESIS Overall, 299 of 7,434 screened articles were included, with observational studies being almost twice as common (n = 187, 63%) than controlled trials (n = 112, 38%). The most frequently evaluated interventions were antifibrinolytic drugs (75 studies, 25%), blood products (59 studies, 20%), point-of-care testing (47 studies, 16%), and cardiopulmonary bypass circuit modifications (46 studies, 15%). The publication rate for controlled trials remained constant over time (4-6/yr); however, trials were small (median participants, 51; interquartile range, 57) and overwhelmingly single center (98%). Controlled trials originated from 22 countries, with the United States, India, and Germany accounting for 50%. The commonest outcomes were mediastinal blood loss and transfusion requirements; however, these were defined inconsistently (blood loss being reported over nine different time periods). The majority of trials were aimed at bleeding prevention (98%) rather than treatment (10%), nine studies assessed both. CONCLUSIONS Overall, this review demonstrates small trial sizes, low level of evidence, and marked heterogeneity of reported endpoints in the included studies. The need for more, higher quality studies reporting clinically relevant, comparable outcomes is highlighted. Emerging fields such as the use of coagulation factor concentrates, goal-directed guidelines, and anti-inflammatory therapies appear to be of particular interest. This scoping review can potentially guide future trial design and form the basis for therapy-specific systematic reviews.
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Fibrinogen in paediatric cardiac surgery: the FIB-CON trial breaking RCT news
Siemens K, Hunt BJ, Harris J, Nyman A, Perkins J, Murdoch IA, Tibby SM
Transfusion Medicine. 2017;27((S1)):19.. s25.
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8.
Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery
Avidan MS, Alcock EL, Da Fonseca J, Ponte J, Desai JB, Despotis GJ, Hunt BJ
British Journal of Anaesthesia. 2004;92((2):):178-86.
Abstract
BACKGROUND Using algorithms based on point of care coagulation tests can decrease blood loss and blood component transfusion after cardiac surgery. We wished to test the hypothesis that a management algorithm based on near-patient tests would reduce blood loss and blood component use after routine coronary artery surgery with cardiopulmonary bypass when compared with an algorithm based on routine laboratory assays or with clinical judgement. METHODS Patients (n=102) undergoing elective coronary artery surgery with cardiac bypass were randomized into two groups. In the point of care group, the management algorithm was based on information provided by three devices, the Hepcon, thromboelastography and the PFA-100 platelet function analyser. Management in the laboratory test group depended on rapidly available laboratory clotting tests and transfusion of haemostatic blood components only if specific criteria were met. Blood loss and transfusion was compared between these two groups and with a retrospective case-control group (n=108), in which management of bleeding had been according to the clinician's discretion. RESULTS All three groups had similar median blood losses. The transfusion of packed red blood cells (PRBCs) and blood components was greater in the clinician discretion group (P<0. 05) but there was no difference in the transfusion of PRBCs and blood components between the two algorithm-guided groups. CONCLUSION Following algorithms based on point of care tests or on structured clinical practice with standard laboratory tests does not decrease blood loss, but reduces the transfusion of PRBCs and blood components after routine cardiac surgery, when compared with clinician discretion. Cardiac surgery services should use transfusion guidelines based on laboratory-guided algorithms, and the possible benefits of point of care testing should be tested against this standard.
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9.
Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting
Bidstrup BP, Hunt BJ, Sheikh S, Parratt RN, Bidstrup JM, Sapsford RN
Annals of Thoracic Surgery. 2000;69((2):):541-7.
Abstract
BACKGROUND Aspirin therapy is widely used in the treatment of cardiac disease. It has been recognized as a causative factor for increased bleeding and blood loss after open heart operations. METHODS To determine whether high-dose aprotinin maintained its efficacy in reducing blood loss in the presence of aspirin pretreatment in patients undergoing aortocoronary bypass, we performed a double blind study on 60 adult patients. Half received high-dose aprotinin (Trasylol) and half placebo. RESULTS Total hemoglobin loss, the primary efficacy variable was reduced from 36.1 +/- 31.4 g (mean +/- SD) to 14.1 +/- 16.0 g (p = 0.002). Blood loss was reduced intraoperatively and total loss was reduced from 837.3 mL +/- 404.9 mL to 368.7 mL +/- 164.3 mL (p < 0.001). The number of patients who did not receive any donor blood products was significantly higher in the aprotinin-treated patients (56.7% versus 23.3%, p = 0.008). Activation of the clotting cascade was significantly less in the treated patients toward the end of cardiopulmonary bypass both by measurement of thrombin-antithrombin III complex (p < 0.0001) and prothrombin fragment 1 + 2 (p < 0.0001). D-Dimer generation was significantly less from the onset of bypass and after reversal of heparin in the aprotinin-treated patients (p < 0.0001). CONCLUSIONS High-dose aprotinin was highly effective in reducing bleeding in this high-risk group of patients. Biochemical analyses suggest the mechanism by which aspirin increases blood loss after cardiopulmonary bypass is different from the blood-preserving effects of aprotinin, which is acting as an antifibrinolytic agent.
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10.
Complement activation during major surgery: the effect of extracorporeal circuits and high-dose aprotinin
Segal H, Sheikh S, Kallis P, Cottam S, Beard C, Potter D, Townsend E, Bidstrup BP, Yacoub M, Hunt BJ
Journal of Cardiothoracic & Vascular Anesthesia. 1998;12((5):):542-7.
Abstract
OBJECTIVE To assess the in vivo contribution to complement activation of an extracorporeal circuit and the use of high-dose aprotinin during major surgery. DESIGN Sequential samples were obtained from 8 patients undergoing thoracic surgery, 20 patients undergoing orthotopic liver transplantation (OLT) using venovenous bypass, and 19 patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). INTERVENTION The latter two groups were part of a randomized controlled trial of high-dose aprotinin. MEASUREMENTS Total complement activation was measured with the hemolytic complement activity and the C3 activation-specific marker, C3d antigen. MAIN RESULTS Complement activation did not occur during thoracic surgery. During OLT, C3d antigen levels, expressed as mean +/- standard deviation (SD), were elevated from baseline at skin closure (8.6 +/- 2.5 v 13.0 +/- 5.2 mg/L; p = 0.0082). During cardiac surgery, C3d antigen levels increased 10 minutes after the start of CPB (pre-CPB, 8.0 +/- 1.9 v 14.2 +/- 3.1 mg/L; p = 0.0001) and remained at greater than baseline values postoperatively (8.0 +/- 1.9 v 11.8 +/- 2.3 mg/L; p = 0.002). There was no difference in complement activation in those receiving high-dose aprotinin during OLT or cardiac surgery. Complement activation during cardiac surgery using extracorporeal circulation occurred to a greater extent than during OLT and thoracic surgery. Complement activation during cardiac surgery or OLT was not attenuated by the use of high-dose aprotinin.