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

BackgroundThe 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 findingsWe 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 120 kg, and patients requiring therapeutic hypothermia to ConclusionsUsing 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 registrationClinicalTrials.gov Unique identifier NCT03532594

Major Pulmonary Resection for Non-Small Cell Lung Carcinoma during the COVID-19 Pandemic—Single Israeli Center Cross-Sectional Study

Background: The highly contagious COVID-19 has created unprecedented challenges in providing care to patients with resectable non-small cell lung carcinoma (NSCLC). Surgical management now needs to consider the risks of malignant disease progression by delaying surgery, and those of COVID-19 transmission to patients and operating room staff. The goal of our study was to describe our experience in providing both emergent and elective surgical procedures for patients with NSCLC during the COVID-19 pandemic in Israel, and to present our point of view regarding the safety of performing lung cancer surgery. Methods: This observational cross-sectional study included all consecutive patients with NSCLC who operated at Tel Aviv Medical Center, a large university-affiliated hospital, from February 2020 through December 2020, during the COVID-19 pandemic in Israel. The patients’ demographics, COVID-19 preoperative screening results, type and side of surgery, pathology results, morbidity and mortality rates, postoperative complications, including pulmonary complications management, and hospital stay were evaluated. Results: Included in the study were 113 patients, 68 males (60.2%) and 45 females (39.8%), with a median age of 68.2 years (range, 41–89). Of these 113 patients, 83 (73.5%) underwent video-assisted thoracic surgeries (VATS), and 30 (26.5%) underwent thoracotomies. Fifty-five patients (48.7%) were preoperatively screened for COVID-19 and received negative results. Fifty-six postoperative complications were reported in 35 patients (30.9%). A prolonged air leak was detected in 11 patients (9.7%), atrial fibrillation in 11 patients (9.7%), empyema in 5 patients (4.4%), pneumonia in 9 patients (7.9%) and lobar atelectasis in 7 patients (6.2%). Three patients (2.7%) with postoperative pulmonary complications required mechanical ventilation, and two of them (1.6%) underwent tracheostomy. Two patients (1.6%) were postoperatively diagnosed as positive for COVID-19. Conclusions: Our data demonstrate the feasibility and efficacy of implementing precautionary strategies to ensure the safety of lung cancer patients undergoing pulmonary resection during the COVID-19 pandemic. The strategy was equally effective in protecting the surgical staff and healthcare providers, and we recommend performing lung cancer surgery during the pandemic era

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

Funder: Jon Moulton Charity TrustBackground: 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 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