Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial.

While experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p<0.001), while post-protamine activated clotting times were similar among groups. The high dosing group revealed increased intrinsic clotting times (236 ± 74 vs 196 ± 64 s; p=0.006) and the maximum post-protamine thrombin generation was less suppressed in the low dosing group (38 ± 40 % vs 6 ± 9 %; p=0.001). Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95 % CI 500-830 ml vs 470 ml; 95 % CI 420-530 ml; p=0.021) when compared to the low dosing group, respectively. More patients in the high dosing group received fresh frozen plasma (11 % vs 0 %; p=0.02) and platelet concentrate (21 % vs 6 %; p=0.04) compared to the low dosing group. Our study confirms in vitro data that abundant protamine dosing is associated with increased postoperative blood loss and higher transfusion rates in cardiac surgery.

Ten-year patterns in blood product utilization during cardiothoracic surgery with cardiopulmonary bypass in a tertiary hospital.

BACKGROUND: This retrospective analysis describes blood conservation strategies and overall consumption of red blood cells (RBCs), fresh-frozen plasma (FFP), and platelet (PLT) concentrates during nonaortic cardiac surgery with cardiopulmonary bypass (CPB) in a tertiary hospital over a 10-year period. STUDY DESIGN AND METHODS: Study variables of 6026 patients that underwent cardiac surgery between 2002 and 2011 were incorporated in the database and included hemoglobin (Hb), lowest temperature, CPB duration, 24-hour blood loss, fluid balance, and overall transfusion requirements. RESULTS: Between 2002 and 2011, the lowest intraoperative Hb levels and temperature increased from 8.5 ± 1.2 to 10.4 ± 1.4 g/dL and from 32 ± 2 to 34 ± 1°C, respectively. In addition to the steep decrease in the postoperative fluid balance over time, a reduction in 24-hour blood loss from 815 ± 588 mL (2002) to 590 ± 438 mL (2011) was observed. These changes were paralleled by a 28% reduction in overall RBC transfusion from 1443 units in 2002 to 1038 in 2011. While RBC transfusion decreased over time, there was no significant change in the use of FFP or PLT concentrate transfusion. The probability to receive RBC transfusion increased after cessation of aprotinin, but reduced after routine cell salvage in all operations. CONCLUSION: This institutional report shows a large reduction in blood loss and transfusion requirements in cardiac surgery over a 10-year period. This reduction is most probably attributed to structural cell salvage, reduced intraoperative fluid volumes, and the increase in the lowest intraoperative body temperature.

Intraoperative cell salvage is associated with reduced postoperative blood loss and transfusion requirements in cardiac surgery: a cohort study.

BACKGROUND: This study investigated whether implementation of cell salvage of shed mediastinal and residual blood in all patients undergoing low-to-moderate-risk cardiac surgery reduces the need for allogeneic red blood cell (RBC) transfusion compared to patients not subjected to cell salvage. STUDY DESIGN AND METHODS: This retrospective cohort study included patients undergoing low-to-moderate-risk cardiac surgery with cardiopulmonary bypass without (control; n = 531) or with cell salvage (n = 433; Autolog, Medtronic). Study endpoints, including 24-hour blood loss and RBC requirements, were evaluated using adjusted logistic regression. RESULTS: Baseline characteristics were similar between groups. The cell saver group received 568 ± 267 mL of autologous blood. Median number of allogeneic RBC transfusions was higher in the control group (2 [1-5]) compared with the cell salvage group (1 [0-3]; p < 0.001). There were no clinically relevant differences in postoperative coagulation test results between groups. The relative risk (RR) for postoperative RBC transfusion was reduced to 0.76 (95% confidence interval [CI], 0.70-0.83; p < 0.0001) in the cell salvage group. Moreover, patients in the cell salvage group had a lower chance for myocardial infarction (RR, 0.26; 95% CI, 0.08-0.91; p = 0.035), whereas the cell salvage group was associated with a higher probability for intensive care discharge within 24 hours after surgery (RR, 1.08; 95% CI, 1.02-1.14; p = 0.009). CONCLUSION: The use of cell salvage throughout the entire procedure reduces postoperative blood loss and allogeneic RBC transfusion. These findings advocate implementation of cell salvage in all patients undergoing on-pump cardiac surgery, irrespective of anticipated surgery-related blood loss.

Residual blood processing by centrifugation, cell salvage or ultrafiltration in cardiac surgery: effects on clinical hemostatic and ex-vivo rheological parameters.

The study compared the effects of three blood concentration techniques after cardiopulmonary bypass on clinical hemostatic and ex-vivo rheological parameters. Residual blood of patients undergoing elective cardiac surgery was processed by centrifugation, cell salvage or ultrafiltration, and retransfused (n = 17 per group). Study parameters included blood loss, (free) hemoglobin, hematocrit, fibrinogen and erythrocyte aggregation, deformability and 2,3-diphosphoglycerate content. Patient characteristics were similar between groups. Ultrafiltration was associated with the highest weight of the transfusion bag [649 ± 261 vs. 320 ± 134 g (centrifugation) and 391 ± 158 g (cell salvage); P < 0.01]. Cell salvage resulted in the lowest hemolysis levels in the transfusion bag. Retransfusion of cell saver blood induced the largest gain in postoperative patient hemoglobin levels when compared to centrifugation and ultrafiltration, and was associated with the largest increase in 2,3-diphosphoglycerate when compared to ultrafiltration (Δ2,3-diphosphoglycerate 1.34 ± 1.92 vs. -0.77 ± 1.56 mmol/l; P = 0.03). Cell salvage is superior with respect to postoperative hemoglobin gain and washout of free hemoglobin when compared to centrifugation or ultrafiltration.

Removal of aprotinin from low-dose aprotinin/tranexamic acid antifibrinolytic therapy increases transfusion requirements in cardiothoracic surgery.

This retrospective study investigated whether withdrawal of aprotinin from combined low-dose aprotinin/tranexamic acid (TXA) antifibrinolytic therapy altered postoperative blood loss and transfusion requirements in patients undergoing cardiothoracic surgery employing cardiopulmonary bypass (CPB). The study included data from patients receiving a combination of low-dose aprotinin (2×10(6) KIU in CPB prime; n=615) and 2000 mg TXA or patients receiving TXA only (n=587). In both groups, TXA was given after protamine administration. Study endpoints were blood loss, transfusion requirements and reoperation. There were no differences in EuroSCORE, CPB time, antiangial medication and baseline coagulation parameters between groups. There were more males in the TXA group (85%) as compared to the TXA+aprotinin group (77%; P=0.02). Postoperative blood loss (0.80±0.69 vs. 0.66±0.52 l; P=0.001) and transfusion of fresh frozen plasma (0.6±0.7 vs. 0.4±0.6 U; P<0.001), packed cells (3.9±5.5 vs. 2.7±3.3 U; P<0.001) and platelets (0.7±0.6 vs. 0.5±0.6 U; P<0.001) was higher in the TXA group than in patients receiving combined therapy, respectively. There were more reoperations for bleeding in the TXA group (53 vs. 34, respectively; P=0.03) with similar mortality and deterioration in glomerular filtration rate. In conclusion, withdrawal of aprotinin from combined antifibrinolytic therapy is associated with increased blood loss, transfusion requirements and reoperations.

The impact of balanced hydroxylethyl starch cardiopulmonary bypass priming solution on the fibrin part of clot formation: ex vivo rotation thromboelastometry.

INTRODUCTION: Balanced colloidal priming solutions are supposed to further minimize the effects of cardiopulmonary bypass (CPB) on haemostasis as compared to gelatin-based preparations. This exploratory study investigated whether clot formation, in particular the fibrin part of the clot, is less altered by a modern balanced HES solution as compared to a gelatin-based priming solution. METHODS: CPB priming solutions containing 60% gelatin (Gelofusin®) or balanced HES starch (100% or 60% Tetraspan®) were mixed with blood samples from healthy volunteers and compared with respect to their impact on clotting time (CT), alpha angle, maximum clot firmness (MCF), and fibrinogen, using thromboelastometry. RESULTS: The 100% and 60% HES priming solutions significantly increased the EXTEM CT from 66 ± 9 s to 82 ± 19 and 83 ± 13, respectively (both P<0.05 vs. baseline). The speed of solid clot formation decreased significantly for all priming solutions compared with baseline values. The INTEM MCF decreased from 59 ± 4 mm to 47 ± 4, 44 ± 4 and 43 ± 3 mm, whereas the EXTEM MCF decreased from 57 ± 4 mm to 51 ± 4, 51 ± 4 and 50 ± 4 mm after dilution with 60% gelatin, 100% HES or 60% HES priming solution, respectively (all P<0.01 vs. baseline). The priming solutions containing HES induced the largest decrease in MCF attributed to fibrinogen from 12 ± 3 mm to 4 ± 4 mm and 3 ± 2 mm (both P<0.05) for the 100% and mixed priming solution, respectively. CONCLUSIONS: Ex vivo rotation thromboelastometry did not reveal the expected preservation of coagulation parameters, in particular the fibrin part of clot formation, by a balanced HES priming solution.

Profound effects of cardiopulmonary bypass priming solutions on the fibrin part of clot formation: an ex vivo evaluation using rotation thromboelastometry.

OBJECTIVES: Dilutional coagulopathy as a consequence of cardiopulmonary bypass (CPB) system priming may also be affected by the composition of the priming solution. The direct effects of distinct priming solutions on fibrinogen, one of the foremost limiting factors during dilutional coagulopathy, have been minimally evaluated. Therefore, the authors investigated whether hemodilution with different priming solutions distinctly affects the fibrinogen-mediated step in whole blood clot formation. DESIGN: Prospective observational laboratory study. SETTING: University hospital laboratory. PARTICIPANTS: Eight male healthy volunteers. INTERVENTIONS: Blood samples diluted with gelatin-, albumin-, or hydroxyethyl starch (HES)-based priming solutions were ex-vivo evaluated for clot formation by rotational thromboelastometry. MEASUREMENTS AND MAIN RESULTS: The intrinsic pathway (INTEM) coagulation time increased from 186 +/- 19 seconds to 205 +/- 16, 220 +/- 17, and 223 +/- 18 seconds after dilution with gelatin-, albumin-, or HES-containing prime solutions (all p < 0.05 v baseline). The extrinsic pathway (EXTEM) coagulation time was only minimally affected by hemodilution. Moreover, all 3 priming solutions significantly reduced the INTEM and EXTEM maximum clot firmness. The HES-containing priming solution induced the largest decrease in the maximum clot firmness attributed to fibrinogen, from 13 +/- 1 mm (baseline) to 6 +/- 1 mm (p < 0.01 v baseline). CONCLUSIONS: All studied priming solutions prolonged coagulation time and decreased clot formation, but the fibrinogen-limiting effect was the most profound for the HES-containing priming solution. These results suggest that the composition of priming solutions may distinctly affect blood clot formation, in particular with respect to the fibrinogen component in hemostasis.