Mortality and Adverse Events After Protamine Administration in Patients Undergoing Cardiopulmonary Bypass

Kimmel, Stephen E.; Sekeres, Mikkael A.; Berlin, Jesse A.; Ellison, Norig

doi:10.1097/00000539-200206000-00005

Cited by 41 publications

(30 citation statements)

References 20 publications

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“…1 Hemodynamic instability after protamine administration to reverse UFH during CPB has been reported to be associated with a 13.2% same hospital admission mortality rate. 2 These untoward sequelae have compelled basic science and clinical investigators to search for alternate anticoagulation strategies. Bivalirudin, a direct thrombin inhibitor, has been evaluated recently in several cardiac surgery trials.…”

Section: Résumémentioning

confidence: 99%

“…76 Moreover, the transfusion rate at day 7 was 84%, with platelets (mean of 8.6 ± 7.2 concentrates/patient, range 1-23) being the blood component used most often. 76 Each transfused patient also received FFP and PRBC (mean of 6.0 ± 4.7 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 5.6 ± 3.8 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16], respectively). 76 The CHOOSE-OFF trial was a prospective, multicentre, open-label study with no comparator arm assessing bivalirudin anticoagulation in OPCAB patients with confirmed or prior HIT/thrombotic syndrome (HIT/TS) and/or anti-PF4/UFH antibodies.…”

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confidence: 99%

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Utilisation de la bivalirudine en chirurgie cardiaque – de l’inhibition indirecte à l’inhibition directe de la thrombine

Anand

Viles-González

Mahboobi

et al. 2010

Can J Anesth/J Can Anesth

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Purpose Bivalirudin use for anticoagulating patients undergoing cardiac surgery, particularly those with or at risk for heparin-induced thrombocytopenia, has expanded over the past several years. The purpose of this review is to provide a summary of the following: the differences between indirect and direct thrombin inhibition, unfractionated heparin's limitations (i.e., heparin-induced thrombocytopenia), bivalirudin's pharmacology, recent cardiac surgery trials comparing bivalirudin and unfractionated heparin as anticoagulants, the growing role of bivalirudin-mediated anticoagulation for various surgical procedures, and the potential of bivalirudin-mediated vascular graft patency.

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Section: Résumémentioning

confidence: 99%

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confidence: 99%

Utilisation de la bivalirudine en chirurgie cardiaque – de l’inhibition indirecte à l’inhibition directe de la thrombine

Anand

Viles-González

Mahboobi

et al. 2010

Can J Anesth/J Can Anesth

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“…However, protamine use in CPB is associated with the development of a number of adverse effects, ranging from minor hemodynamic instability to life-threatening anaphylactic complications and fatal cardiovascular collapse. [1][2][3][4] Major adverse reactions related to protamine exposure have been reported to occur in 2.6% of cardiac surgical procedures, 3 and these complications of protamine therapy are highly associated with adverse postoperative outcome. 5,6 Protamine, a highly basic protein, binds heparin through charge interactions and sequesters heparin from its catalytic effects on antithrombin.…”

Section: Introductionmentioning

confidence: 99%

High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass

Lee¹,

Welsby

Phillips-Bute

et al. 2013

Blood

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Key Points• A single exposure to protamine and heparin during CPB is highly sensitizing; 29% of patients develop Abs to PRT/H complexes by day 30 after CPB.• PRT/H Abs share several features with platelet factor 4/ heparin Abs, including high titer formation after CPB, heparin dependence, antigen specificity, and platelet activation.Protamine is routinely used to reverse heparin anticoagulation during cardiopulmonary bypass (CPB). Heparin interacts with protamine to form ultralarge complexes that are immunogenic in mice. We hypothesized that patients exposed to protamine and heparin during CPB will develop antibodies (Abs) to protamine/heparin (PRT/H) complexes that are capable of platelet activation. Specimens from a recently completed prospective clinical trial (HIT [for heparin-induced thrombocytopenia] 5801 study; n 5 500) of CPB patients were examined for PRT/H Abs at baseline, at time of hospital discharge (between days 3 through 7), and 30 days after CPB. PRT/H antibody features were characterized and correlated with adverse cardiovascular outcomes. We found a high incidence of PRT/H antibody formation (29%) in patients undergoing cardiac surgery. PRT/H Abs were of high titer (mean titer 1:14 744), showed heparin-dependent binding, and activated platelets in the presence of protamine. PRT/H Abs showed no cross-reactivity to platelet factor 4/heparin complexes, but were cross-reactive with protamine-containing insulin preparations.In the absence of circulating antigen at day 30, there were no complications of thrombocytopenia, thrombotic events, or long-term cardiovascular events. These studies show that Abs to PRT/H occur commonly after cardiac bypass surgery, share a number of serologic features with HIT Abs, including platelet activation, and may pose health risks to patients requiring drug reexposure. (Blood. 2013;121(15):2828-2835 IntroductionProtamine sulfate is currently the only therapeutic agent approved by the US Food and Drug Administration for reversal of heparin anticoagulation. It is the mainstay of therapy in cardiopulmonary bypass (CPB), where rapid reversal of heparin anticoagulation is essential for achieving surgical hemostasis. However, protamine use in CPB is associated with the development of a number of adverse effects, ranging from minor hemodynamic instability to life-threatening anaphylactic complications and fatal cardiovascular collapse. [1][2][3][4] Major adverse reactions related to protamine exposure have been reported to occur in 2.6% of cardiac surgical procedures, 3 and these complications of protamine therapy are highly associated with adverse postoperative outcome. 5,6 Protamine, a highly basic protein, binds heparin through charge interactions and sequesters heparin from its catalytic effects on antithrombin. Recently, we have shown that heparinbinding proteins such as protamine and lysozyme interact with heparin in a charge-dependent manner to form protamine/heparin (PRT/H) or lysozyme/H ultralarge complexes that are immunogenic in mice. 7 In this preliminary clinical...

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“…Additionally, hemodynamic instability after protamine administration to reverse UFH during cardiopulmonary bypass (CPB) has been reported to be associated with a 13.2% posthospital admission mortality rate [1] . These untoward sequelae have compelled both basic science and clinical investigators to search for alternate anticoagulation strategies.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

et al. 2012

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Aim:To investigate the population pharmacokinetics (PK) and pharmacodynamics (PD) of bivalirudin, a synthetic bivalent direct thrombin inhibitor, in young healthy Chinese subjects. Methods: Thirty-six young healthy volunteers were randomly assigned into 4 groups received bivalirudin 0.5 mg/kg, 0.75 mg/kg, and 1.05 mg/kg intravenous bolus, 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg intravenous infusion per hour for 4 h. Blood samples were collected to measure bivalirudin plasma concentration and activated clotting time (ACT). Population PK-PD analysis was performed using the nonlinear mixed-effects model software NONMEM. The final models were validated with bootstrap and predictioncorrected visual predictive check (pcVPC) approaches. Results: The final PK model was a two-compartment model without covariates. The typical PK population values of clearance (CL), apparent distribution volume of the central-compartment (V 1 ), inter-compartmental clearance (Q) and apparent distribution volume of the peripheral compartment (V 2 ) were 0.323 L·h -1 ·kg -1 , 0.086 L/kg, 0.0957 L·h -1 ·kg -1 , and 0.0554 L/kg, respectively. The inter-individual variabilities of these parameters were 14.8%, 24.2%, fixed to 0% and 15.6%, respectively. The final PK-PD model was a sigmoid E max model without the Hill coefficient. In this model, a covariate, red blood cell count (RBC*), had a significant effect on the EC 50 value. The typical PD population values of maximum effect (E max ), EC 50 , baseline ACT value (E 0 ) and the coefficient of RBC* on EC 50 were 318 s, 2.44 mg/L, 134 s and 1.70, respectively. The inter-individual variabilities of E max , EC 50 , and E 0 were 6.80%, 46.4%, and 4.10%, respectively. Conclusion: Population PK-PD models of bivalirudin in healthy young Chinese subjects have been developed, which may provide a reference for future use of bivalirudin in China.

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Mortality and Adverse Events After Protamine Administration in Patients Undergoing Cardiopulmonary Bypass

Abstract: A retrospective cohort study demonstrated an association between adverse events after a protamine administration and increased in-hospital mortality.

Cited by 41 publications

References 20 publications

Utilisation de la bivalirudine en chirurgie cardiaque – de l’inhibition indirecte à l’inhibition directe de la thrombine

Utilisation de la bivalirudine en chirurgie cardiaque – de l’inhibition indirecte à l’inhibition directe de la thrombine

High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass

Population pharmacokinetics and pharmacodynamics of bivalirudin in young healthy Chinese volunteers

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