Dennis Veerhoek

Individualized Heparin and Protamine Management Improves Rotational Thromboelastometric Parameters and Postoperative Hemostasis in Valve Surgery

OBJECTIVES This study investigated whether a tailored approach to heparin and protamine management improved thromboelastometric parameters after cardiopulmonary bypass and reduced postoperative blood loss compared with activated coagulation time (ACT)-based fixed target heparin and protamine management. DESIGN Randomized controlled study. SETTING Tertiary university hospital. PARTICIPANTS Patients undergoing elective valve surgery (n = 38). INTERVENTIONS Heparin and protamine management were based either on the ACT (n = 19) or hemostasis management system (HMS) measurements (n = 19; HMS Plus; Medtronic, Minneapolis, MN). MEASUREMENTS AND MAIN RESULTS The target ACT for initiation of cardiopulmonary bypass was 480 seconds. Study variables included rotational thromboelastometry EXTEM (extrinsic coagulation), HEPTEM (intrinsic coagulation with heparinase), and FIBTEM (fibrin part of clot formation) tests and 24-hour blood loss. The use of HMS reduced the median protamine-to-heparin ratio from 1.00 (1.00-1.00) to 0.62 (0.56-0.66; p<0.001). The ACT group showed a prolonged postbypass clotting time for both EXTEM (86 ± 13 seconds v 78 ± 10 seconds; p = 0.05) and HEPTEM (217 ± 58 seconds v 183 ± 24 seconds; p = 0.03) tests. There was a moderate correlation between protamine dosing with the EXTEM and HEPTEM clotting time (r = 0.42; p = 0.009 and r = 0.38; p = 0.02, respectively). The number of patients with more than 450 mL/24 hours was higher in the ACT than in the HMS group (42% v 12%; p = 0.04). CONCLUSIONS Individualized heparin and protamine management decreased the protamine-to-heparin ratio, improved postbypass thromboelastometric hemostatic parameters, and reduced the incidence of severe blood loss compared with an ACT-based strategy, supporting the added value of this approach for hemostatic optimization during cardiac surgery.

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.

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.

A Pharmacokinetic Model for Protamine Dosing After Cardiopulmonary Bypass

OBJECTIVE This study investigated postoperative hemostasis of patients subjected to conventional protamine dosing compared with protamine dosing based on a pharmacokinetic (PK) model following cardiopulmonary bypass. DESIGN Retrospective case-control study. SETTING Tertiary university hospital. PARTICIPANTS Patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS In 56 patients, protamine was dosed in a fixed ratio (CD), while 62 patients received protamine based on the PK model. MEASUREMENTS AND MAIN RESULTS There was no difference in heparin administration (414±107 mg (CD) v 403±90 mg (PK); p = 0.54), whereas protamine dosing was considerably different with a protamine-to-heparin dosing ratio of 1.1±0.3 for the CD group and 0.5±0.1 for the PK group (p<0.001). The changes in activated coagulation time (ΔACT) values (ACT after protamine minus preoperative ACT;+17±77 s v+6±15 s; p = 0.31) were equal between groups. Yet, the thromboelastometric intrinsically activated coagulation test clotting time (CT; 250±76 s v 203±44 s; p<0.001) and intrinsically activated coagulation test without the heparin effect CT (275±105 v 198±32 s; p<0.001) were prolonged in the CD group. Median packed red blood cell transfusion (0 [0-2] v 0 [0-0]), fresh frozen plasma transfusion (1 [0-2] v 0 [0-0]), and platelet concentrate transfusion (0 [0-1] v 0 [0-0]) were different between the fixed ratio and PK group, respectively (all p<0.001). CONCLUSIONS This study showed that patient-tailored protamine dosing based on a PK model was associated with a reduction in protamine dosing, with better hemostatic test results when compared with fixed-ratio protamine dosing.

Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review

&NA; Neutralisation of systemic anticoagulation with heparin in cardiac surgery with cardiopulmonary bypass requires protamine administration. If adequately dosed, protamine neutralises heparin and reduces the risk of postoperative bleeding. However, as its anticoagulant properties are particularly exerted in the absence of heparin, overdosing of protamine may contribute to bleeding and increased transfusion requirements. This narrative review describes the mechanisms underlying the anticoagulant properties and side‐effects of protamine, and the impact of protamine dosing on the activated clotting time and point‐of‐care viscoelastic test results, and explains the distinct protamine dosing strategies in relation to haemostatic activation and postoperative bleeding. The available evidence suggests that protamine dosing should not exceed a protamine‐to‐heparin ratio of 1:1. In particular, protamine‐to‐heparin dosing ratios >1 are associated with more postoperative 12 h blood loss. The optimal protamine‐to‐heparin ratio in cardiac surgery has, however, not yet been elaborated, and may vary between 0.6 and 1.0 based on the initial heparin dose.

The cardiovascular effects of hyperoxia during and after cabg surgery

Hyperoxia is frequently encountered in the intensive care unit (ICU) and during surgical procedures such as coronary artery bypass surgery (CABG). Higher oxygen concentrations intuitively provide a salutary oxygen reserve, but hyperoxia can induce adverse effects such as systemic vasoconstriction, reduction of cardiac output, increased microcirculatory heterogeneity and increased reactive oxygen species production. Previous studies in patients undergoing CABG surgery suggest reduced myocardial damage when avoiding extreme perioperative hyperoxia (>400 mmHg). Here, we compare moderate hyperoxia to near-physiological values.

0595. Quantitating granulocyte reactive oxygen species production by flow cytometry in a clinical setting

Oxidative stress is an important part of a wide range of pathologies and therefore an interesting parameter to determine. However, the detection of reactive oxygen species (ROS), is not straightforward. Sample heterogeneity, delayed analysis and sample preparation, reduces specificity and sensitivity due to probe activation by light, air, probe leakage from cells or cellular activation by sample manipulation. Hence, samples should be processed minimally and analysed immediately if possible. Since clinical research can be subject to uncontrollable timetables and only few departments have access to a dedicated laboratory, the quantification of ROS is challenging.