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Effects of albumin and crystalloid priming strategies on red blood cell transfusions in on-pump cardiac surgery: a network meta-analysis
Wang, T., Wang, J., Zhang, M., Zhang, H., Zhang, Q., Liu, G., Dong, W., Wang, Y., Ji, B.
BMC anesthesiology. 2024;24(1):26
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Editor's Choice
Abstract
BACKGROUND In on-pump cardiac surgery, the albumin priming strategy could maintain colloid osmotic pressure better than crystalloid solutions and reduce excessive perioperative fluid balance. However, a high-quality meta-analysis is required to compare the safety of these approaches in perioperative red blood cell (RBC) transfusions. Owing to limited direct evidence, we conducted a network meta-analysis (NMA) to increase the pool of studies and provide indirect evidence. METHODS The pre-defined primary outcomes were intraoperative and the first 24 h postoperative RBC transfusion volume in units. The pre-defined secondary outcome was postoperative blood loss (the first 24 h). We reviewed all randomized controlled trials comparing albumin, crystalloid, and artificial colloid priming strategies. Studies that only displayed pre-defined outcomes could be included. A pairwise meta-analysis was performed on studies that directly compared the pre-defined outcomes between albumin and crystalloids. Additionally, a random-effects network meta-analysis (NMA) model was employed to generate indirect evidence for the pre-defined outcomes between albumin and crystalloids. RESULTS The literature search identified 830 studies,10 of which were included in the final analysis. Direct meta-analysis indicated that crystalloid priming significantly decreased total perioperative RBC transfusions (MD: -0.68U; 95%CI: -1.26, -0.09U; P = 0.02) and intraoperative RBC transfusions (MD: -0.20U; 95%CI: -0.39, -0.01U; P = 0.03) compared to albumin. Postoperative RBC transfusions showed a decreasing trend in the crystalloid group; however, the difference was not statistically significant. (MD: -0.16U; 95%CI: -0.45, 0.14U; P = 0.30). After including indirect evidence, the NMA results continued to demonstrate a higher RBC receiving with the albumin priming strategy compared to crystalloids, although the differences did not reach statistical significance. For postoperative blood loss, direct evidence showed no significant differences between albumin and crystalloid priming strategies. However, NMA evidence displayed that albumin exist higher probability of reducing postoperative blood loss than crystalloid. CONCLUSION Both direct and NMA evidence indicated that the albumin priming strategy resulted in more perioperative RBC transfusions than crystalloids. Considering the additional blood management burden, the application of an albumin-priming strategy in on-pump cardiac surgery still needs more consideration.
PICO Summary
Population
Adult patients undergoing cardiovascular surgery with cardiopulmonary bypass (10 randomised controlled trials).
Intervention
Network meta-analysis (NMA) to perform direct comparisons, including albumin vs. artificial colloid and artificial colloid vs. crystalloid, and to obtain indirect evidence for the comparisons between albumin and crystalloid priming strategies.
Comparison
Outcome
Direct meta-analysis indicated that crystalloid priming significantly decreased total perioperative red blood cell (RBC) transfusions (MD -0.68U; 95% CI [-1.26, -0.09U]) and intraoperative RBC transfusions (MD -0.20U; 95% CI [-0.39, -0.01U]) compared to albumin. Postoperative RBC transfusions showed a decreasing trend in the crystalloid group; however, the difference was not statistically significant (MD -0.16U; 95% CI: [-0.45, 0.14U]). After including indirect evidence, the NMA results continued to demonstrate a higher RBC receiving with the albumin priming strategy compared to crystalloids, although the differences did not reach statistical significance.
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Cost-effectiveness of Fibrinogen Concentrate vs Cryoprecipitate for Treating Acquired Hypofibrinogenemia in Bleeding Adult Cardiac Surgical Patients
Abrahamyan L, Tomlinson G, Callum J, Carcone S, Grewal D, Bartoszko J, Krahn M, Karkouti K
JAMA surgery. 2023
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Abstract
IMPORTANCE Excessive bleeding requiring fibrinogen replacement is a serious complication of cardiac surgery. However, the relative cost-effectiveness of the 2 available therapies-fibrinogen concentrate and cryoprecipitate-is unknown. OBJECTIVE To determine cost-effectiveness of fibrinogen concentrate vs cryoprecipitate for managing active bleeding in adult patients who underwent cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS A within-trial economic evaluation of the Fibrinogen Replenishment in Surgery (FIBERS) randomized clinical trial (February 2017 to November 2018) that took place at 4 hospitals based in Ontario, Canada, hospitals examined all in-hospital resource utilization costs and allogeneic blood product (ABP) transfusion costs incurred within 28 days of surgery. Participants included a subset of 495 adult patients from the FIBERS trial who underwent cardiac surgery and developed active bleeding and acquired hypofibrinogenemia requiring fibrinogen replacement. INTERVENTIONS Fibrinogen concentrate (4 g per dose) or cryoprecipitate (10 units per dose) randomized (1:1) up to 24 hours postcardiopulmonary bypass. MAIN OUTCOMES AND MEASURES Effectiveness outcomes included number of ABPs administered within 24 hours and 7 days of cardiopulmonary bypass. ABP transfusion (7-day) and in-hospital resource utilization (28-day) costs were evaluated and a multivariable net benefit regression model built for the full sample and predefined subgroups. RESULTS Patient level costs for 495 patients were evaluated (mean [SD] age 59.2 [15.4] years and 69.3% male.) Consistent with FIBERS, ABP transfusions and adverse events were similar in both treatment groups. Median (IQR) total 7-day ABP cost was CAD $2280 (US dollars [USD] $1697) (CAD $930 [USD $692]-CAD $4970 [USD $3701]) in the fibrinogen concentrate group and CAD $2770 (USD $1690) (IQR, CAD $1140 [USD $849]-CAD $5000 [USD $3723]) in the cryoprecipitate group. Median (interquartile range) total 28-day cost was CAD $38 180 (USD $28 431) $(IQR, CAD $26 350 [USD $19 622]-CAD $65 080 [USD $48 463]) in the fibrinogen concentrate group and CAD $38 790 (USD $28 886) (IQR, CAD $26 180 [USD $19 495]-CAD $70 380 [USD $52 409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2000 (USD $1489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness. CONCLUSIONS AND RELEVANCE Fibrinogen concentrate is cost-effective when compared with cryoprecipitate in most bleeding adult patients who underwent cardiac surgery with acquired hypofibrinogenemia requiring fibrinogen replacement. The generalizability of these findings outside the Canadian health system needs to be verified.
PICO Summary
Population
A subset of patients enrolled in the FIBERS trial who underwent cardiac surgery and experienced bleeding resulting in acquired hyperfibrinogenemia (n= 495).
Intervention
Fibrinogen concentrate (n= 251).
Comparison
Cryoprecipitate (n= 244).
Outcome
Patient level costs were evaluated. Median (interquartile range (IQR)) total 7-day allogeneic blood product (ABP) cost was CAD $2,280 (US dollars [USD] $1,697) (CAD $930 [USD $692]-CAD $4,970 [USD $3,701]) in the fibrinogen concentrate group and CAD $2,770 (USD $1,690) (IQR, CAD $1,140 [USD $849]-CAD $5,000 [USD $3,723]) in the cryoprecipitate group. Median (IQR) total 28-day cost was CAD $38,180 (USD $28 431) (IQR, CAD $26,350 [USD $19,622]-CAD $65,080 [USD $48,463]) in the fibrinogen concentrate group and CAD $38,790 (USD $28,886) (IQR, CAD $26,180 [USD $19,495]-CAD $70,380 [USD $52,409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs. cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2,000 (USD $1,489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness.
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Intravenous albumin in cardiac and vascular surgery: a systematic review and meta-analysis
Skubas, N. J., Callum, J., Bathla, A., Keshavarz, H., Fergusson, D., Wu, B., Stanworth, S., Shehata, N.
British journal of anaesthesia. 2023
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Editor's Choice
Abstract
BACKGROUND Intravenous albumin is commonly utilised in cardiovascular surgery for priming of the cardiopulmonary bypass circuit, volume replacement, or both, although the evidence to support this practice is uncertain. The aim was to compare i.v. albumin with synthetic colloids and crystalloids for paediatric and adult patients undergoing cardiovascular surgery for all-cause mortality and other perioperative outcomes. METHODS A systematic review and meta-analysis of randomised controlled trials (RCTs) of i.v. albumin compared with synthetic colloids and crystalloids on the primary outcome of all-cause mortality was conducted. Secondary outcomes included renal failure, blood loss, duration of hospital or intensive care unit stay, cardiac index, and blood component use; subgroups were analysed by age, comparator fluid, and intended use (priming, volume, or both). We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CCRT) from 1946 to November 23, 2022. RESULTS Of 42 RCTs, mortality was assessed in 15 trials (2711 cardiac surgery patients) and the risk difference was 0.00, 95% confidence interval (CI) -0.01 to 0.01, I(2)=0%. Among secondary outcomes, i.v. albumin resulted in smaller fluid balance, mean difference -0.55 L, 95% CI -1.06 to -0.4, I(2)=90% (nine studies, 1975 patients) and higher albumin concentrations, mean difference 7.77 g L(-1), 95% CI 3.73-11.8, I(2)=95% (six studies, 325 patients). CONCLUSIONS Intravenous albumin use was not associated with a difference in morbidity and mortality in patients undergoing cardiovascular surgery, when compared with comparator fluids. The lack of improvement in patient-important outcomes with albumin and its higher cost suggests it should be used restrictively. SYSTEMATIC REVIEW PROTOCOL PROSPERO; CRD42020171876.
PICO Summary
Population
Paediatric and adult patients undergoing cardiovascular surgery (42 randomised controlled trials).
Intervention
Intravenous albumin.
Comparison
Synthetic colloids and crystalloids.
Outcome
Primary outcome of all-cause mortality. Secondary outcomes included renal failure, blood loss, duration of hospital or intensive care unit stay, cardiac index, and blood component use. Mortality was assessed in 15 trials (n= 2,711) and the risk difference was 0.00; 95% confidence interval (CI) [-0.01, 0.01] I(2)= 0%. Among secondary outcomes, intravenous albumin resulted in smaller fluid balance, mean difference -0.55 L; 95% CI [-1.06, -0.4], I(2)= 90% (nine studies, n= 1,975) and higher albumin concentrations, mean difference 7.77 gL(-1); 95% CI [3.73, 11.8], I(2)= 95% (six studies, n= 325). Intravenous albumin use was not associated with a difference in morbidity and mortality in patients undergoing cardiovascular surgery, when compared with comparator fluids.
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Prothrombin Complex Concentrate vs Plasma for Post-Cardiopulmonary Bypass Coagulopathy and Bleeding: A Randomized Clinical Trial
Smith MM, Schroeder DR, Nelson JA, Mauermann WJ, Welsby IJ, Pochettino A, Montonye BL, Assawakawintip C, Nuttall GA
JAMA surgery. 2022
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Editor's Choice
Abstract
IMPORTANCE Post-cardiopulmonary bypass (CPB) coagulopathy and bleeding are among the most common reasons for blood product transfusion in surgical practices. Current retrospective data suggest lower transfusion rates and blood loss in patients receiving prothrombin complex concentrate (PCC) compared with plasma after cardiac surgery. OBJECTIVE To analyze perioperative bleeding and transfusion outcomes in patients undergoing cardiac surgery who develop microvascular bleeding and receive treatment with either PCC or plasma. DESIGN, SETTING, AND PARTICIPANTS A single-institution, prospective, randomized clinical trial performed at a high-volume cardiac surgical center. Patients were aged 18 years or older and undergoing cardiac surgery with CPB. Patients undergoing complex cardiac surgical procedures (eg, aortic replacement surgery, multiple procedures, or repeated sternotomy) were preferentially targeted for enrollment. During the study period, 756 patients were approached for enrollment, and 553 patients were randomized. Of the 553 randomized patients, 100 patients met criteria for study intervention. INTERVENTIONS Patients with excessive microvascular bleeding, a prothombin time (PT) greater than 16.6 seconds, and an international normalized ratio (INR) greater than 1.6 were randomized to receive treatment with either PCC or plasma. The PCC dose was 15 IU/kg or closest standardized dose; the plasma dose was a suggested volume of 10 to 15 mL/kg rounded to the nearest unit. MAIN OUTCOMES AND MEASURES The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. Secondary outcomes were PT/INR, rates of intraoperative red blood cell (RBC) transfusion after treatment, avoidance of allogeneic transfusion from the intraoperative period to the end of postoperative day 1, postoperative bleeding, and adverse events. RESULTS One hundred patients (mean [SD] age, 66.8 [13.7] years; 61 [61.0%] male; and 1 [1.0%] Black, 1 [1.0%] Hispanic, and 98 [98.0%] White) received the study intervention (49 plasma and 51 PCC). There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799-1575] mL vs 937 [708-1443] mL). After treatment, patients in the PCC arm had a greater improvement in PT (effect estimate, -1.37 seconds [95% CI, -1.91 to -0.84]; P < .001) and INR (effect estimate, -0.12 [95% CI, -0.16 to -0.07]; P < .001). Fewer patients in the PCC group required intraoperative RBC transfusion after treatment (7 of 51 patients [13.7%] vs 15 of 49 patients [30.6%]; P = .04); total intraoperative transfusion rates were not significantly different between groups. Seven (13.7%) of 51 patients receiving PCCs avoided allogeneic transfusion from the intraoperative period to the end of postoperative day 1 vs none of those receiving plasma. There were no significant differences in postoperative bleeding, transfusions, or adverse events. CONCLUSIONS AND RELEVANCE The results of this study suggest a similar overall safety and efficacy profile for PCCs compared with plasma in this clinical context, with fewer posttreatment intraoperative RBC transfusions, improved PT/INR correction, and higher likelihood of allogeneic transfusion avoidance in patients receiving PCCs. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02557672.
PICO Summary
Population
Patients undergoing cardiac surgery who developed microvascular bleeding (n= 100).
Intervention
Prothrombin complex concentrate (PCC), (n= 51).
Comparison
Plasma (n= 49).
Outcome
The primary outcome was postoperative bleeding (chest tube output) from the initial postsurgical intensive care unit admission through midnight on postoperative day 1. There was no significant difference in chest tube output between the plasma and PCC groups (median [IQR], 1022 [799, 1575] mL vs. 937 [708, 1443] mL). After treatment, patients in the PCC group had a greater improvement in prothombin time, (effect estimate, -1.37 seconds, 95% CI [-1.91, -0.84]) and international normalized ratio (effect estimate, -0.12, 95% CI [-0.16, -0.07]). Fewer patients in the PCC group required intraoperative red blood cell transfusion after treatment (7 of 51 patients [13.7%] vs. 15 of 49 patients [30.6%]); total intraoperative transfusion rates were not significantly different between groups. Seven (13.7%) of 51 patients receiving PCCs avoided allogeneic transfusion from the intraoperative period to the end of postoperative day 1 vs. none of those receiving plasma. There were no significant differences in postoperative bleeding, transfusions, or adverse events.
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Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding
Hayes, K., Fernando, M. C., Jordan, V.
The Cochrane Database of Systematic Reviews. 2022;11(11):Cd013551
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Abstract
BACKGROUND Coagulopathy following cardiac surgery is associated with considerable blood product transfusion and high morbidity and mortality. The treatment of coagulopathy following cardiac surgery is challenging, with the replacement of clotting factors being based on transfusion of fresh frozen plasma (FFP). Prothrombin complex concentrate (PCCs) is an alternative method to replace clotting factors and warrants evaluation. PCCs are also an alternative method to treat refractory ongoing bleeding post-cardiac surgery compared to recombinant factor VIIa (rFVIIa) and also warrants evaluation. OBJECTIVES Assess the benefits and harms of PCCs in people undergoing cardiac surgery who have coagulopathic non-surgical bleeding. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase and Conference Proceedings Citation Index-Science (CPCI-S) on the Web of Science on 20 April 2021. We searched Clinicaltrials.gov (www. CLINICALTRIALS gov), and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/), for ongoing or unpublished trials. We checked the reference lists for additional references. We did not limit the searches by language or publication status. SELECTION CRITERIA We included randomised controlled trials (RCTs) and non-randomised trials (NRSs). DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS Eighteen studies were included (4993 participants). Two were RCTs (151 participants) and 16 were NRSs. Both RCTs had low risk of bias (RoB) in almost all domains. Of the 16 NRSs, 14 were retrospective cohort analyses with one prospective study and one case report. The nine studies used in quantitative analysis were judged to have critical RoB, three serious and three moderate. 1. PCC versus standard treatment Evidence from RCTs showed PCCs are likely to reduce the number of units transfused compared to standard care (MD -0.89, 95% CI -1.78 to 0.00; participants = 151; studies = 2; moderate-quality evidence). Evidence from NRSs agreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (MD -1.87 units, 95% CI -2.53 to -1.20; participants = 551; studies = 2; very low-quality evidence). There was no evidence from RCTs showing a difference in the incidence of red blood cell (RBC) transfusion compared to standard care (OR 0.53, 95% CI 0.20 to 1.40; participants = 101; studies = 1; low-quality evidence). Evidence from NRSs disagreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (OR 0.54, 95% CI 0.30 to 0.98; participants = 1046; studies = 4; low-quality evidence). There was no evidence from RCTs showing a difference in the number of thrombotic events with PCC compared to standard care (OR 0.68 95% CI 0.20 to 2.31; participants = 152; studies = 2; moderate-quality evidence). This is supported by NRSs, showing that PCCs may have no effect on the number of thrombotic events compared to standard care but the evidence is very uncertain (OR 1.32, 95% CI 0.87 to 1.99; participants = 1359; studies = 7; very low-quality evidence). There was no evidence from RCTs showing a difference in mortality with PCC compared to standard care (OR 0.53, 95% CI 0.12 to 2.35; participants = 149; studies = 2; moderate-quality evidence). This is supported by evidence from NRSs, showing that PCCs may have little to no effect on mortality compared to standard care but the evidence is very uncertain (OR 1.02, 95% CI 0.69 to 1.51; participants = 1334; studies = 6; very low-quality evidence). Evidence from RCTs indicated that there was little to no difference in postoperative bleeding (MD -107.05 mLs, 95% CI -278.92 to 64.83; participants = 151, studies = 2; low-quality evidence). PCCs may have little to no effect on intensive care length of stay (RCT evidence: MD -0.35 hours, 95% CI -19.26 to 18.57; participants = 151; studies = 2; moderate-quality evidence) (NRS evidence: MD -18.00, 95% CI -43.14 to 7.14; participants = 225; studies = 1; very low-quality evidence) or incidence of renal replacement therapy (RCT evidence: OR 0.72, 95% CI 0.14 to 3.59; participants = 50; studies = 1; low-quality evidence) (NRS evidence: OR 1.46, 95% CI 0.71 to 2.98; participants = 684; studies = 2; very low-quality evidence). No studies reported on additional adverse outcomes. 2. PCC versus rFVIIa For this comparison, all evidence was provided from NRSs. PCC likely results in a large reduction of RBCs transfused intra-operatively in comparison to rFVIIa (MD-4.98 units, 95% CI -6.37 to -3.59; participants = 256; studies = 2; moderate-quality evidence). PCC may have little to no effect on the incidence of RBC units transfused comparative to rFVIIa; evidence is very uncertain (OR 0.16, 95% CI 0.02 to 1.56; participants = 150; studies = 1; very low-quality evidence). PCC may have little to no effect on the number of thrombotic events comparative to rFVIIa; evidence is very uncertain (OR 0.51, 95% CI 0.23 to 1.16; participants = 407; studies = 4; very low-quality evidence). PCC may have little to no effect on the incidence of mortality (OR 1.07, 95% CI 0.38 to 3.03; participants = 278; studies = 3; very low-quality evidence) or intensive care length of stay comparative to rFVIIa (MD -40 hours, 95% CI -110.41 to 30.41; participants = 106; studies = 1; very low-quality evidence); evidence is very uncertain . PCC may reduce bleeding (MD -674.34 mLs, 95% CI -906.04 to -442.64; participants = 150; studies = 1; very low-quality evidence) and incidence of renal replacement therapy (OR 0.29, 95% CI 0.12 to 0.71; participants = 106; studies = 1; very low-quality evidence) comparative to rFVIIa; evidence is very uncertain. No studies reported on other adverse events. AUTHORS' CONCLUSIONS PCCs could potentially be used as an alternative to standard therapy for coagulopathic bleeding post-cardiac surgery compared to FFP as shown by moderate-quality evidence and it may be an alternative to rFVIIa in refractory non-surgical bleeding but this is based on moderate to very low quality of evidence.
PICO Summary
Population
Patients of all age groups undergoing cardiac surgery who had coagulopathic bleeding (18 studies, n= 4,993).
Intervention
Prothrombin complex concentrates (PCCs).
Comparison
Standard therapy (current institutional protocol for bleeding diathesis), fresh frozen plasma (FFP) and recombinant factor VIIa (rFVIIa).
Outcome
Of the 18 studies included, two were randomised controlled trials (RCTs), and 16 were non‐randomised trials (NRSs). PCCs compared to standard therapy: PCCs had an overall reduction in red blood cell (RBC) transfusion (both units of RBC transfusion and incidence of RBC transfusion) when compared to FFP. There was potentially no reduction in chest drain output (bleeding) in the RCTs. There was no difference in the reported outcomes of blood clots, death, intensive care stay and the requirement of dialysis in both RCTs and NRSs. The RCTs had moderate to low quality of evidence and the NRS had very low to low quality of evidence. PCCs compared to rFVIIa: PCCs had a large reduction in red blood cell transfusion when compared to rFVIIa. The quality of this evidence was moderate. For the remaining outcomes, two studies found that there was no difference in blood clots, death, bleeding into drains, intensive care stay and the requirement for dialysis. The quality of the evidence for these outcomes was very low.
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Impact of cardiopulmonary bypass duration on efficacy of fibrinogen replacement with cryoprecipitate compared with fibrinogen concentrate: a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) randomised controlled trial
Bartoszko J, Martinez-Perez S, Callum J, Karkouti K
British journal of anaesthesia. 2022
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Editor's Choice
Abstract
BACKGROUND Coagulopathy in cardiac surgery is frequently associated with acquired hypofibrinogenaemia, which can be treated with either purified fibrinogen concentrate (FC) or cryoprecipitate. Because the latter is not purified and therefore contains additional coagulation factors, it is thought to be more effective for treatment of coagulopathy that occurs after prolonged cardiopulmonary bypass (CPB). We examined the impact of CPB duration on the efficacy of the two therapies in cardiac surgery. METHODS This was a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) RCT comparing FC (4 g) to cryoprecipitate (10 U) in adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia (n=735). The primary outcome was allogeneic blood products transfused within 24 h after CPB. Subjects were stratified by CPB duration (≤120, 121-180, and >180 min). The interaction of treatment assignment with CPB duration was tested. RESULTS Subjects with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n=134; cryoprecipitate, n=146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 h was 0.90 (one-sided 97.5% confidence interval [CI]: 0.00-1.12); P=0.004. For subjects with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI: 0.00-1.22]; P=0.03], and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI: 0.00-1.12]; P=0.005). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes. CONCLUSIONS The haemostatic efficacy of FC was non-inferior to cryoprecipitate irrespective of CPB duration in cardiac surgery. CLINICAL TRIAL REGISTRATION NCT03037424.
PICO Summary
Population
Adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia, enrolled in the FIBRES trial, across 11 centres in Canada (n= 735).
Intervention
Fibrinogen concentrate (FC), (n= 372).
Comparison
Cryoprecipitate (n= 363).
Outcome
The primary outcome was allogeneic blood products transfused within 24 hours after cardiopulmonary bypass (CPB). Patients with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n= 134; cryoprecipitate, n= 146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 hours was 0.90 (one-sided 97.5% confidence interval (CI), [0.00, 1.12]). For patients with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI [0.00, 1.22]), and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI [0.00, 1.12]). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes.
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Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial
Karkouti K, Bartoszko J, Grewal D, Bingley C, Armali C, Carroll J, Hucke HP, Kron A, McCluskey SA, Rao V, et al
JAMA network open. 2021;4(4):e213936
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Abstract
IMPORTANCE Approximately 15% of patients undergoing cardiac surgery receive frozen plasma (FP) for bleeding. Four-factor prothrombin complex concentrates (PCCs) have logistical and safety advantages over FP and may be a suitable alternative. OBJECTIVES To determine the proportion of patients who received PCC and then required FP, explore hemostatic effects and safety, and assess the feasibility of study procedures. DESIGN, SETTING, AND PARTICIPANTS Parallel-group randomized pilot study conducted at 2 Canadian hospitals. Adult patients requiring coagulation factor replacement for bleeding during cardiac surgery (from September 23, 2019, to June 19, 2020; final 28-day follow-up visit, July 17, 2020). Data analysis was initiated on September 15, 2020. INTERVENTIONS Prothrombin complex concentrate (1500 IU for patients weighing ≤60 kg and 2000 IU for patients weighing >60 kg) or FP (3 U for patients weighing ≤60 kg and 4 U for patients weighing >60 kg), repeated once as needed within 24 hours (FP used for any subsequent doses in both groups). Patients and outcome assessors were blinded to treatment allocation. MAIN OUTCOMES AND MEASURES Hemostatic effectiveness (whether patients received any hemostatic therapies from 60 minutes to 4 and 24 hours after initiation of the intervention, amount of allogeneic blood components administered within 24 hours after start of surgery, and avoidance of red cell transfusions within 24 hours after start of surgery), protocol adherence, and adverse events. The analysis set comprised all randomized patients who had undergone cardiac surgery, received at least 1 dose of either treatment, and provided informed consent after surgery. RESULTS Of 169 screened patients, 131 were randomized, and 101 were treated (54 with PCC and 47 with FP), provided consent, and were included in the analysis (median age, 64 years; interquartile range [IQR], 54-73 years; 28 [28%] were female; 82 [81%] underwent complex operations). The PCC group received a median 24.9 IU/kg (IQR, 21.8-27.0 IU/kg) of PCC (2 patients [3.7%; 95% CI, 0.4%-12.7%] required FP). The FP group received a median 12.5 mL/kg (IQR, 10.0-15.0 mL/kg) of FP (4 patients [8.5%; 95% CI, 2.4%-20.4%] required >2 doses of FP). Hemostatic therapy was not required at the 4-hour time point for 43 patients (80%) in the PCC group and for 32 patients (68%) in the FP group (P = .25) nor at the 24-hour time point for 41 patients (76%) in the PCC group and for 31 patients (66%) patients in the FP group (P = .28). The median numbers of units for 24-hour cumulative allogeneic transfusions (red blood cells, platelets, and FP) were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 14.0 U (IQR, 8.0-20.0 U) in the FP group (ratio, 0.58; 95% CI, 0.45-0.77; P < .001). After exclusion of FP administered as part of the investigational medicinal product, the median numbers of units were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 10.0 U (IQR, 6.0-16.0 U) in the FP group (ratio, 0.80; 95% CI, 0.59-1.08; P = .15). For red blood cells alone, the median numbers were 1.5 U (IQR, 0.0-4.0 U) in the PCC group and 3.0 U (IQR, 1.0-5.0 U) in the FP group (ratio, 0.69; 95% CI, 0.47-0.99; P = .05). During the first 24 hours after start of surgery, 15 patients in the PCC group (28%) and 8 patients in the FP group (17%) received no red blood cells (P = .24). Adverse event profiles were similar. CONCLUSIONS AND RELEVANCE This randomized clinical trial found that the study protocols were feasible. Adequately powered randomized clinical trials are warranted to determine whether PCC is a suitable substitute for FP for mitigation of bleeding in cardiac surgery. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04114643.
PICO Summary
Population
Cardiac surgery patients (n= 101).
Intervention
Prothrombin complex concentrate (PCC group, n= 54).
Comparison
Frozen plasma (FP group, n= 47).
Outcome
Haemostatic therapy was not required at the 4-hour time point for 43 patients (80%) in the PCC group and for 32 patients (68%) in the FP group, nor at the 24-hour time point for 41 patients (76%) in the PCC group and for 31 patients (66%) patients in the FP group. The median numbers of units for 24-hour cumulative allogeneic transfusions (red blood cells, platelets, and FP) were 6.0 U in the PCC group and 14.0 U in the FP group. After exclusion of FP administered as part of the investigational medicinal product, the median numbers of units were 6.0 U in the PCC group and 10.0 U in the FP group. For red blood cells alone, the median numbers were 1.5 U in the PCC group and 3.0 U in the FP group. During the first 24 hours after start of surgery, 15 patients in the PCC group (28%) and 8 patients in the FP group (17%) received no red blood cells. Adverse event profiles were similar.
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8.
Prothrombin complex concentrate vs. fresh frozen plasma in adult patients undergoing heart surgery - a pilot randomised controlled trial (PROPHESY trial)
Green L, Roberts N, Cooper J, Agarwal S, Brunskill SJ, Chang I, Gill R, Johnston A, Klein AA, Platton S, et al
Anaesthesia. 2020
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Editor's Choice
Abstract
There is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post-intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg(-1) based on factor IX) or fresh frozen plasma (15 ml.kg(-1) ). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67-81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27-44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow-up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α(2) -antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.
PICO Summary
Population
Cardiac surgery patients who developed bleeding within 24 hours of surgery (n= 50).
Intervention
Prothrombin complex concentrate (n= 25).
Comparison
Fresh frozen plasma (n= 25).
Outcome
There were 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α(2) -antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels.
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9.
Fibrin and Thrombin Sealants in Vascular and Cardiac Surgery: A Systematic Review and Meta-analysis
Daud SA, Kaur B, McClure GR, Belley-Cote EP, Harlock J, Crowther M, Whitlock RP
Eur J Vasc Endovasc Surg. 2020
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Editor's Choice
Abstract
OBJECTIVE In vascular and cardiac surgery, the ability to maintain haemostasis and seal haemorrhagic tissues is key. Fibrin and thrombin based sealants were introduced as a means to prevent or halt bleeding during surgery. Whether fibrin and thrombin sealants affect surgical outcomes is poorly established. A systematic review and meta-analysis was performed to examine the impact of fibrin or thrombin sealants on patient outcomes in vascular and cardiac surgery. DATA SOURCES Cochrane CENTRAL, Embase, and MEDLINE, as well as trial registries, conference abstracts, and reference lists of included articles were searched from inception to December 2019. REVIEW METHODS Studies comparing the use of fibrin or thrombin sealant with either an active (other haemostatic methods) or standard surgical haemostatic control in vascular and cardiac surgery were searched for. The Cochrane risk of bias tool and the ROBINS-I tool (Risk Of Bias In Non-randomised Studies - of Interventions) were used to assess the risk of bias of the included randomised and non-randomised studies; quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Two reviewers screened studies, assessed risk of bias, and extracted data independently and in duplicate. Data from included trials were pooled using a random effects model. RESULTS Twenty-one studies (n = 7 622 patients) were included: 13 randomised controlled trials (RCTs), five retrospective, and three prospective cohort studies. Meta-analysis of the RCTs showed a statistically significant decrease in the volume of blood lost (mean difference 120.7 mL, in favour of sealant use [95% confidence interval {CI} -150.6 - -90.7; p < .001], moderate quality). Time to haemostasis was also shown to be reduced in patients receiving sealant (mean difference -2.5 minutes [95% CI -4.0 - -1.1; p < .001], low quality). Post-operative blood transfusions, re-operation due to bleeding, and 30 day mortality were not significantly different for either RCTs or observational data. CONCLUSION The use of fibrin and thrombin sealants confers a statistically significant but clinically small reduction in blood loss and time to haemostasis; it does not reduce blood transfusion. These Results may support selective rather than routine use of fibrin and thrombin sealants in vascular and cardiac surgery.
PICO Summary
Population
Adult patients undergoing major open vascular and cardiac surgical procedures (21 studies, n= 7622).
Intervention
Fibrin or thrombin based sealant to control any source of operative bleeding.
Comparison
Any alternate form of operative haemostasis, including bone wax, other non-fibrin and non-thrombin surgical sealants, polytetrafluoroethylene patch, or manual compression.
Outcome
Meta-analysis of the randomised controlled trials (RCTs) showed a statistically significant decrease in the volume of blood lost (mean difference 120.7 mL) in favour of sealant use. Time to haemostasis was also shown to be reduced in patients receiving sealant (mean difference -2.5 minutes). Post-operative blood transfusions, re-operation due to bleeding, and 30 day mortality were not significantly different for either RCTs or observational data.
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10.
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).