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.

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.

Cardiac response is greater for colloid than saline fluid loading after cardiac or vascular surgery.

OBJECTIVE: To study the effects on volume expansion and myocardial function of colloids or crystalloids in the treatment of hypovolaemic hypotension after cardiac and major vascular surgery. DESIGN AND SETTING: A single-centre, single-blinded, randomized clinical trial at the intensive care unit of a university hospital. PATIENTS AND METHODS: Patients (n=67) were subjected to a 90-min filling pressure-guided fluid challenge with saline 0.9% or the colloids gelatin 4%, hydroxyethyl starch 6% or albumin 5%. Biochemical variables and haemodynamics (transpulmonary thermodilution) were measured. RESULTS: An amount of 1800 (1300-1800) ml of saline or 1600 (750-1800) ml of colloid solution (P< 0.005) was infused. Colloid osmotic pressure (COP) decreased in the saline group and increased in the colloid groups (P< 0.001). Plasma volume increased by 3.0% (-18 to 24) in the saline versus 19% (-11 to 50) in the colloid groups (P< 0.001). Cardiac index increased by median 13% (ns) in the saline group and by 22% in the colloid groups (P<0.005). The rise in left ventricular stroke work index was greater in the colloid than in the saline groups. The different colloids were equally effective. The rise in cardiac index related to the rise in plasma volume and global end-diastolic volume, confirming plasma volume and preload augmentation by the fluid loading. CONCLUSION: After cardiac or major vascular surgery, the pressure- and time-guided fluid response is dependent on the type of fluid used. Colloid fluid loading leads to a greater increase in preload-recruitable cardiac and left ventricular stroke work indices than that with saline, because of greater plasma volume expansion following an increase in plasma COP.