Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass

Delavenne, Xavier; Ollier, Édouard; Chollet, S.; Sandri, Fabricio; Lanoiselée, Julien; Hodin, Sophie; Montmartin, Aurélie; Fuzellier, Jean‐François; Mismetti, Patrick; Gergelé, Laurent

doi:10.1093/bja/aex044

Cited by 21 publications

(25 citation statements)

References 23 publications

(19 reference statements)

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“…Prolonged ER stress induced by pressure overload was accompanied by the increased expression of GRP78 and CHOP [26, 27]. Moreover, GRP78 was up-regulated under stressful conditions of low oxygen and low calcium.…”

Section: Discussionmentioning

confidence: 99%

Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Zhang¹,

Wei²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background/Aims: An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB), extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro. Methods: Mice received aortic banding (AB) operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH), sham+NOB (NOB/SH), AB+vehicle (VEH/AB), and AB+ NOB (NOB/AB). Animals (n = 15 per group) were treated with vehicle or NOB (50 mg/kg) for 4 weeks after disease onset. Results: NOB prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX) 2 and NOX4 and mitigated endoplasmic reticulum (ER) stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM) hypertrophic response stimulated by phenylephrine (PE) and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE. Conclusions: Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE.

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Section: Discussionmentioning

confidence: 99%

Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Zhang¹,

Wei²,

Zheng³

et al. 2017

Cell Physiol Biochem

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“…Delavenne and colleagues 89 showed that a PK/pharmacodynamic model can be used for monitoring of the anticoagulation effect and calculation of an adequate protamine dose after CPB using the inhibitory effects of heparin on FXa as validation method. 89 Jia and colleagues 90 developed a two-compartment PK model based on antithrombin (FIIa) concentrations to predict heparin concentrations during hypothermic cardiac surgery. In particular, the level of thrombin inhibition by the heparin/anti-thrombin complex was used as an index to estimate plasma heparin concentrations.…”

Section: Model-based Titration Of Protaminementioning

confidence: 99%

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

Boer

Meesters

Veerhoek

et al. 2018

British Journal of Anaesthesia

162

146

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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.

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“…However, the effect of bolus administration of unfractionated heparin is variable, and it can be influenced by body mass and concurrent thrombolytic drug administration (26,27). UFH was used intra-operatively in this case for thromboprophylaxis to achieve a target ACT of 250-350 s (28,29). The prolonged duration of inhibition of coagulation in this case, apparent in the time it took the ACT to normalize, was unexpected, even when the variable effect of heparin on coagulation is considered.…”

Section: Discussionmentioning

confidence: 85%

Fatal Ovarian Hemorrhage Associated With Anticoagulation Therapy in a Yucatan Mini-Pig Following Venous Stent Implantation

et al. 2020

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Swine models are commonly utilized in endovascular research for development of intravascular interventions and medical device development. As part of a pilot study for a venous vascular stent device, a 5-year-old female Yucatan mini-pig underwent bilateral external iliac vein stent placement under general anesthesia. To reduce thrombotic complications by reduction of thrombus formation on wires, sheaths, and catheters, the pig was heparinized with a total of 300 IU/kg of heparin, establishing an activated clotting time (ACT) of 436 s. The ACT had returned to below 200 s by the end of the procedure. To prevent postoperative thrombosis, the pig received an anticoagulation therapy protocol consisting of enoxaparin, clopidogrel, and aspirin. There were no complications during the immediate postoperative period. However, the pig died 4 days after surgery. Necropsy established the cause of death as abdominal exsanguination due to severe, acute, intra-ovarian hemorrhage, most likely related to ovulation. Life-threatening ovarian hemorrhage is occasionally seen in women with congenital or acquired bleeding disorders; to our knowledge this is the first report of fatal ovarian hemorrhage in an animal enrolled in a pre-clinical research trial.

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Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass

Abstract: A population PK/PD analysis of heparin during CPB, using a routine haemostatic test, shows that Bayesian estimation might help to predict ACT on the basis of only one or two blood samples.

Cited by 21 publications

References 23 publications

Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

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

Fatal Ovarian Hemorrhage Associated With Anticoagulation Therapy in a Yucatan Mini-Pig Following Venous Stent Implantation

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