Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

Abstract

Background The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. Methods and findings We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78–1.14] vs. 0.75 [IQR 0.57–0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75–245] vs. 135 [IQR 94–222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160–210] vs. 280 [IQR 250–300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). Conclusions Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. Trial registration ClinicalTrials.gov Unique identifier NCT03532594.

Hemodynamic Effects of Protamine Infusion in Dogs with Myxomatous Mitral Valve Disease Undergoing Mitral Valvuloplasty

“…Additionally, there are also concerns regarding the dose of protamine. In the human medical setting, since refinement of protamine dosage is proposed [26], we also need to reconsider the protamine dosage in the veterinary medical setting. Lower doses of protamine may reduce the incidence of PIH, however further clinical research is needed.…”

Coagulation and Transfusion Updates From 2021

“…Miles et al attempted to determine the most optimal protamine dosing strategy in their publication appearing in Perfusion. 64 Current guidelines recognize the controversy among various reversal strategies and provide little guidance beyond limiting protamine doses to <2.6 mg protamine per 100 units of heparin. 62 These ratio strategies remain commonplace but notoriously have significant variation.…”

“…To continue investigating the issue, Miles et al compared fixed-ratio dosing to modeling-based dosing. 64 Models were derived from compartmental models in consideration of protamine pharmacology. Previous investigations into complex dosing calculations have had mixed results and lacked any formal support.…”

“…Investigations supporting ratios below 1:1 also have been published in the past. 64 More studies still are needed to elucidate optimal protamine dosing strategies to limit both under-and over-dosing. In consideration of the work of Miles et al and other studies, it seems likely lower ratios of protamine-to-heparin are more important than dose calculation methods.…”

Circulating small extracellular vesicle-encapsulated SEMA5A-IT1 attenuates myocardial ischemia–reperfusion injury after cardiac surgery with cardiopulmonary bypass

“…Cardiac valve replacement with CPB is a common method in the clinical treatment of cardiac valve diseases [ 1 , 2 ]. The success of cardiac valve replacement is closely related to the cardioprotection measures during the operation, while cardiomyocyte injury during the operation is mainly related to the stress response, hemodynamic instability, and cardiac oxygen imbalance [ 3 , 4 ].…”