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.govIdentifier: 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 identifierNCT03532594.

Without anticoagulation, cardiopulmonary bypass would not have developed over the last nearly 60 years into one of the most influential innovations in medicine; without the ability to reverse anticoagulation, cardiac surgery might not have become the common intervention, which is now practiced globally. Despite the recent breathtaking developments in extracorporeal technology, heparin and protamine remain the pillars of anticoagulation and its reversal until this day. However, there is still much controversy in particular about protamine dosing regimens. A number of recent publications investigating various approaches to dosing protamine have rekindled this debate. This review is seeking to capture the current thinking about protamine dosing after cessation of cardiopulmonary bypass.

Unfractionated heparin is the mainstay of anticoagulation during cardiac surgery on cardiopulmonary bypass (CPB) due to its low cost, quick onset, and ease of reversal. Since over 30 years, the activated clotting time (ACT) has been used to assess the level of heparin activity both before and after CPB. We compared two different methods of measuring the ACT: i-STAT, which uses amperometric detection of thrombin cleavage, and Hemochron Jr, which is based on detecting viscoelastic changes in blood. We included 402 patients from three institutions (Papworth Hospital, Cambridge, UK; Groote Schuur, Cape Town, South Africa; University Hospital Basel, Basel, Switzerland) undergoing elective cardiac surgery on CPB in our study. We analyzed duplicate samples on both devices at all standard measuring points during the procedure. The correlation coefficient between two Hemochron and two i-STAT devices was .9165 and .9857, respectively. The within-subject coefficient of variation (WSCV) ranged from 8.2 to 13.6% for the Hemochron and from 4.1 to 9.1% for the i-STAT. We found that the number of occasions where one of the duplicate readings was >1,000 seconds while the other was below or close to the clinically significant threshold of 400 seconds were higher for the Hemochron. We found the i-STAT to systematically return higher measurements. We conclude that the i-STAT provides a more reliable test for heparin activity and assesses safe anticoagulation during cardiac surgery on pump. The fact the that the i-STAT reads higher than the Hemochron leads to the recommendation to validate the methods against each other before changing devices.

Without anticoagulation, cardiopulmonary bypass would not have developed over the last nearly 60 years into one of the most influential innovations in medicine; without the ability to reverse anticoagulation, cardiac surgery might not have become the common intervention, which is now practiced globally. Despite the recent breathtaking developments in extracorporeal technology, heparin and protamine remain the pillars of anticoagulation and its reversal until this day. However, there is still much controversy in particular about protamine dosing regimens. A number of recent publications investigating various approaches to dosing protamine have rekindled this debate. This review is seeking to capture the current thinking about protamine dosing after cessation of cardiopulmonary bypass.

Pulsatile flow has been used during cardiopulmonary bypass (CPB) for decades and its use is increasing with advancing extracorporeal technology. Pulsatile flow generates higher circuit pressures and shear forces than nonpulsatile flow at comparable pump flow and patient mean arterial pressure. Very little is known about the effect this has on erythrocytes. We included 62 adult patients (32 in the pulsatile group and 30 in the nonpulsatile group) undergoing elective coronary artery bypass grafting in this prospective observational study. Blood samples were collected at routine sampling times throughout surgery and were analyzed for the presence of free heme and globin using mass spectroscopy. Patient characteristics, CPB, and aortic cross-clamp times, pump flow as well as patient mean arterial pressure were similar in both groups. Maximum circuit pressure in the pulsatile flow group was statistically significantly higher than that in the nonpulsatile flow group (257.12 vs. 190.64 mmHg, p < 0.0001). Both heme and globin levels were higher in the pulsatile flow group. This reached statistical significance with globin at 30 minutes of CPB and with heme after aortic unclamping. We conclude that pulsatile CPB using roller pumps results in a greater extent of hemolysis. The clinical significance, however, is not yet known.