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Objective: To assess the impact of post-protamine neutralisation activated clotting time (ACT) values on postoperative outcomes including chest drain output, transfusion requirements, and CICU stay, in patients undergoing cardiac surgery., Study Design: Observational comparative study. Place and Duration of the Study: Department of Anaesthesiology, The Aga Khan University Hospital, Karachi, Pakistan, from February to August 2023., Methodology: Ethical approval was obtained to collect data from elective cardiac surgery patients' charts. A sequential sampling approach analysed the baseline and post-protamine neutralisation ACT values, categorising patients into two groups. Group A maintained ACT within 10% of baseline, while Group B deviated. The outcomes measured included transfusion needs, chest drain output, additional protamine, cardiac intensive care unit (CICU) stay, and postoperative reopening. Statistical analysis included mean, median, frequency, t-test / Mann-Whitney U test, and Chi-square test., Results: The study comprised 101 patients (39 in Group A, 62 in Group B), with similar baseline health. No significant differences were found in tranexamic acid use, CICU stay, chest drain output, or transfusion rates between the groups (p >0.05)., Conclusion: Maintaining ACT within 10% of baseline post-protamine neutralisation results in similar intraoperative and postoperative outcomes, suggesting potential benefits in avoiding the aggressive protamine therapy and ensuring haemostasis in cardiac surgery., Key Words: Coronary Artery bypass grafting, Cardiopulmonary bypass, Activated clotting time (ACT), Heparin, Postoperative bleeding, Blood transfusions.

Severe pulmonary vasoconstriction induced by protamine is a rare complication. We report a case of a 77-year-old male patient with a history of mitral valve plasty (MVP). He underwent redo MVP via right thoracotomy under the totally endoscopic procedure (MICS redo-MVP). Immediately after weaning cardiopulmonary bypass (CPB), protamine was administrated. 10 min later peak systolic pulmonary arterial pressure (sys PAP) rose to 62 mmHg, and 30 min later to 80 mmHg. Due to the negative impact of protamine administration, nitric oxide inhalation (iNO) therapy was started with a concentration of 20 ppm. 10 min after iNO therapy started, sys PAP decreased to 63 mmHg. After entering the intensive care unit (ICU), sys PAP decreased to 35 mmHg. Here, we present an effective iNO therapy case for pulmonary hypertension due to protamine and the patient had a good postoperative recovery. This study was approved by the Institutional Review Board at Kitaharima Medical Center (IRB-0602) with the waiver of informed consent., (© The Author(s), published by EDP Sciences, 2024.)

Competing Interests: Competing interests: Mark Crowther reports receiving consulting fees from Servier Canada, Asahi Kasei, Precision Biologics and Hemostasis Reference Laboratories; payments or honoraria for educational material or presentations from Bayer, Pfizer, CSL Behring and Diagnostica Stago; and payment for expert testimony for various cases in Canada and the United States. Dr. Crowther also reports holding positions as Treasurer of the American Society of Hematology and The Anticoagulation Forum, and as Vice Chair of the Senior Research Committee, Heart and Stroke Foundation. Dr. Crowther has past and current relationships with a number of not-for-profit and for-profit entities that are not pharmaceutical manufacturers, and holds the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr. Siraj Mithoowani reports receiving support from Leo Pharma for attending a meeting. No other competing interests were declared.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FF has received speaking fees and research support from Abbott Laboratories and LivaNova. He is a member of the Scientific Advisory Committees for Abbott Point-of-Care, Werfen and LivaNova. The other authors have declared that no competing interests exist.

Background: Rapid growth of cardiac wall hematoma is a rare but potentially fatal complication of cardiac surgery. However, its pathophysiology and optimal management remain undefined., Case Presentation: Here we present a rare case of a large cardiac wall hematoma in the right ventricle during a thoracic aortic and valvular surgery. The hematoma expanded rapidly with epicardial rupture during cardiopulmonary bypass. We could establish non-surgical hemostasis and prevent further expansion of hematoma by early weaning of the cardiopulmonary bypass, followed by the administration of protamine and manual compression by hemostatic agent application. His postoperative recovery was uneventful and upon computed tomography analysis, the hematoma was observed to have absorbed completely at 1 week postoperatively. The patient is doing well 1 year after the surgery without evidence of recurrent cardiac wall hematoma on follow-up computed tomography., Conclusions: Cardiovascular surgeons should bear in mind this potentially catastrophic complication during cardiac surgery. Because of the vulnerability of the cardiac wall at the area of the hematoma, we believe that a hemostatic approach without sutures may be effective for this lethal complication.

Objectives: The aim of this study was to evaluate whether protamine administration for heparin reversal after transcatheter aortic valve replacement (TAVR) reduces bleeding complications and affects patient outcomes., Background: Occurrence of major bleeding complications in patients undergoing TAVR is associated with increased morbidity and mortality., Methods: This study included 873 patients undergoing TAVR, of whom 677 received protamine for heparin reversal. Standard access management included the use of pre-closure devices, manual compression, and percutaneous transluminal angioplasty or implantation of a covered stent graft, if necessary. The study complied with Good Clinical Practice guidelines and was approved by the local ethics committee. Written informed consent was obtained from all patients., Results: The primary endpoint, a composite of 30-day all-cause mortality and life-threatening and major bleeding, occurred less frequently in the protamine administration group (3.2%) compared with the control group (8.7%) (p = 0.003). This was driven mainly by lower rates of life-threatening and major bleeding in the protamine group (0.1% vs. 2.6% [p < 0.001] and 1.0% vs. 4.1% [p = 0.008], respectively). Furthermore, protamine administration resulted in a significantly shorter hospital stay (11.1 ± 5.8 days vs. 12.7 ± 7.8 days; p = 0.05). In the overall cohort, stroke was observed in 1.9% and myocardial infarction in 0.2% of patients, with no significant difference between the groups (p > 0.05). Multivariate analysis revealed that only protamine administration (odds ratio: 0.24; 95% confidence interval: 0.10 to 0.58; p = 0.001) and acute kidney injury (odds ratio: 5.82; 95% confidence interval: 2.02 to 16.77; p = 0.001) were independently associated with the primary endpoint., Conclusions: Protamine administration resulted in significantly lower rates of life-threatening and major bleeding complications compared with patients without heparin reversal. Occurrence of stroke and myocardial infarction was not increased by protamine administration., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.

Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin-initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB., Summary: Background Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population., (© 2018 International Society on Thrombosis and Haemostasis.)

Since there were a few articles to report the treatment of severe pulmonary vasoconstriction induced by protamine in cardiac surgery, we described the use of epoprostenol to reverse this condition.A total of 5 cases of severe pulmonary vasoconstriction induced by protamine in cardiac surgery were reviewed. The demographic, clinical data and treatment process were obtained. All the patients were followed up.Severe pulmonary vasoconstriction was occurred 4 to 10 minutes after protamine infusion. The primary sign was sudden hypotension, the pulmonary artery pressure was increased gradually, the arterial oxygen partial pressure was decreased in all the patients. Epoprostenol was infused via pulmonary artery catheter at dosage of 20 to 40 ng/kg·min in all the patients, 2 patients were underwent re-cardiac pulmonary bypass assistance. The hemodynamic instability status lasted 40 to 65 minutes respectively. All the patients were recovered uneventfully.All physicians should alert to the incidence of severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Use epoprostenol through pulmonary artery catheter could treat pulmonary artery vasoconstriction effectively and safely.

Objectives: Pulmonary endarterectomy (PEA) is the only curative treatment option for patients with chronic thromboembolic pulmonary hypertension. Massive endobronchial bleeding that precludes weaning from cardiopulmonary bypass is an often-fatal complication of PEA. The aim of this study was to determine whether short-term extracorporeal membrane oxygenation (ECMO) is a safe and feasible procedure in patients with severe endobronchial bleeding., Methods: From January 2014 to December 2016, 396 patients (mean age 60 ± 18 years, 54.5% male) underwent PEA in our department. Patients with severe endobronchial hemorrhage at the time of weaning from cardiopulmonary bypass (CPB) were switched to a heparin-coated venoarterial ECMO circuit. After full-dose protamine administration to restore normal coagulation, weaning from ECMO was attempted in the operating room., Results: In-hospital mortality was 2.3% (9/396 patients). Eight patients (2.0%) developed severe endobronchial bleeding classified as diffuse (n = 6) or localized (n = 2) by bronchoscopy. After reinstitution of CPB and subsequent switch to ECMO, the mean duration of ECMO support was 49 ± 13 minutes, and all 8 patients were weaned successfully from ECMO in the operating theater without further signs of endobronchial bleeding. One patient needed venovenous ECMO support for poor oxygenation 6 hours after surgery. Seven patients were discharged after a prolonged postoperative stay of 17.6 ± 4.1 days. One patient died. This new concept significantly reduced mortality compared with previous (2009-2013) ECMO support (P = .0406)., Conclusions: For patients with massive endobronchial bleeding after PEA, the intraoperative switch from CPB to venoarterial ECMO support with full-dose protamine administration is a new and potentially life-saving treatment concept., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To examine if methylene blue (MB) can counteract or prevent protamine (P) cardiovascular effects., Methods: The protocol included five heparinized pig groups: Group Sham -without any drug; Group MB - MB 3 mg/kg infusion; Group P - protamine; Group P/MB - MB after protamine; Group MB/P - MB before protamine. Nitric oxide levels were obtained by the nitric oxide/ozone chemiluminescence method, performed using the Nitric Oxide Analizer 280i (Sievers, Boulder, CO, USA). Malondialdehyde plasma levels were estimated using the thiobarbiturate technique., Results: 1) Groups Sham and MB presented unchanged parameters; 2) Group P - a) Intravenous protamine infusion caused mean arterial pressure decrease and recovery trend after 25-30 minutes, b) Cardiac output decreased and remained stable until the end of protamine injection, and c) Sustained systemic vascular resistance increased until the end of protamine injection; 3) Methylene blue infusion after protamine (Group P/MB) - a) Marked mean arterial pressure decreased after protamine, but recovery after methylene blue injection, b) Cardiac output decreased after protamine infusion, recovering after methylene blue infusion, and c) Sustained systemic vascular resistance increased after protamine infusion and methylene blue injections; 4) Methylene blue infusion before protamine (Group MB/P) - a) Mean arterial pressure decrease was less severe with rapid recovery, b) After methylene blue, there was a progressive cardiac output increase up to protamine injection, when cardiac output decreased, and c) Sustained systemic vascular resistance decreased after protamine, followed by immediate Sustained systemic vascular resistance increase; 5) Plasma nitrite/nitrate and malondialdehyde values did not differ among the experimental groups., Conclusion: Reviewing these experimental results and our clinical experience, we suggest methylene blue safely prevents and treats hemodynamic protamine complications, from the endothelium function point of view., Competing Interests: No conflict of interest.

Coronary artery perforation is a highly feared complication of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) and can lead to pericardial effusion, tamponade, and, rarely, emergent cardiac surgery. Perforation of epicardial collaterals during retrograde CTO-PCI may be particularly challenging to treat, as embolization from both sides of the perforation may be required to control the bleeding. However, conservative measures can occasionally be effective. We present a case of epicardial collateral vessel perforation that was managed conservatively with anticoagulation reversal.

Background: Viscoelastic point-of-care tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are increasingly used to guide hemostatic therapy after cardiac surgery. The aim of this study was to assess their clinical utility during cardiopulmonary bypass to predict postbypass coagulation status and to guide therapy., Methods: In this prospective study, TEG and ROTEM tests were performed in 52 adult patients undergoing elective cardiac surgery at two time points: near the end of cardiopulmonary bypass and after heparin reversal with protamine. The 95% confidence intervals of the mean difference were compared with a prespecified clinically relevant limit of ± 20% of the value after protamine., Results: Both viscoelastic fibrinogen assays were well within the prespecified clinically relevant limit (≥ 79% of patients). The laboratory Clauss fibrinogen was much lower during cardiopulmonary bypass than after protamine (mean difference 1.2 g L(-1) , 95% CI 1.03-1.4, which was outside a clinically acceptable difference. For intrinsically activated tests, clotting times (CT) were different and outside the prespecified limit on TEG (mean difference -1.2 min, 95% CI -1.8 to -0.6) but not on ROTEM (mean difference 2.3 sec, 95% CI -8.6 to 13.2), while clot strength was well within the clinical limit on both devices (≥ 94% of patients). For extrinsically activated tests, clot strength on both TEG and ROTEM was within the pre-specified limit in 98% of patients., Conclusions: Results from TEG and ROTEM tests performed toward the end of cardiopulmonary bypass are similar to results after reversal of heparin. Amplitudes indicating clot strength were the most stable parameters across all tests, whereas CT showed more variability. In contrast, laboratory testing of fibrinogen using the Clauss assay was essentially invalid during cardiopulmonary bypass., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Individualized heparin management (IHM) uses heparin dose-response curves to improve hemostasis management during cardiac surgery as compared with activated clotting time-based methods., Objectives: IHM was compared with conventional hemostasis management (CHM) in a randomized, prospective study (ID DRKS00007580)., Methods: One-hundred and twenty patients undergoing multivessel coronary artery bypass grafting (CABG) were enrolled. Heparin and protamine consumption, blood losses, blood transfusions and administration of hemostatic agents were recorded. Time courses of platelet counts and of coagulation parameters were determined. Coagulation was analyzed at intensive care unit (ICU) arrival by thromboelastometry., Results: IHM patients received significantly lower initial heparin doses (289.3IU kg(-1) [interquartile range (IQR) 221.5-376.2 IU kg(-1) ] versus 350.5 IU kg(-1) [IQR 346.8-353.7 IU kg(-1) ], P < 0.0001) but similar total heparin doses (418.5 IU kg(-1) [IQR 346.9-590.5 IU kg(-1) ] versus 435.8 IU kg(-1) [IQR 411.7-505.1 IU kg(-1) ]). IHM patients received significantly less protamine, resulting in protamine/total heparin ratios of 0.546 [IQR 0.469-0.597] versus 0.854 [IQR 0.760-0.911] in CHM patients (P < 0.0001). Activated partial thromboplastin time (50.5 s [IQR 40.0-60.0 s] versus 37.0 s [IQR 33.0-40.0 s], P < 0.0001), activated clotting time (136 s [IQR 129.0-150.5 s] versus 126.5 s [IQR 120.3-134.0 s], P = 0.0002) and INTEM clotting times (215 s [IQR 192-237] versus 201 s [IQR 191-216 s], P = 0.0397) were significantly longer in IHM patients than in CHM patients at ICU arrival, with no difference in prothrombin time (P = 0.538). IHM patients lost significantly more blood within 12 h postoperatively (420 mL [IQR 337.5-605.0 mL] versus 345 mL [IQR 230.0-482.5 mL], P = 0.0041), and required significantly more hemostatic agents to control bleeding. Red blood cell transfusion requirements and time courses of platelet counts did not differ between groups., Conclusions: Multivessel CABG patients did not benefit from IHM in comparison with our established protocol based on activated clotting time., (© 2015 International Society on Thrombosis and Haemostasis.)

Objective: To determine whether graft patency after on-pump and off-pump coronary artery bypass surgery is similar when performed using the same heparinization protocol., Methods: In a randomized, controlled, multicenter trial, 900 patients more than 70 years of age received either on-pump or off-pump coronary artery bypass surgery. Heparin was given to achieve an activated clotting time of 400 seconds before arteriotomy in both groups. After the procedure, protamine sulfate was given to revert the activated clotting time to less than 120 seconds. Coronary angiography was performed 6 months after the operation and graft patency was assessed by independent blinded observers., Results: A total of 481 patients underwent angiography. In the off-pump group, 561 (79%) of 710 grafts were open, 65 (9%) were stenotic, and 84 (12%) were occluded. In the on-pump group, 549 (86%) of 650 grafts were open, 38 (5%) were stenotic, and 63 (9%) were occluded. The difference between the proportion of open grafts was statistically significant in favor of on-pump surgery (P=.01). The proportion of open left internal thoracic artery grafts was 95% in both groups. Perioperative use of intracoronary shunts did not increase the risk of stenosis of the coronary artery distal to the anastomosis., Conclusions: Despite comparable heparinization, graft patency after off-pump surgery was inferior to that after on-pump surgery., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The goal of this study was to evaluate whether protamine usage after carotid endarterectomy (CEA) increased within the Vascular Study Group of New England (VSGNE) in response to studies indicating that protamine reduces bleeding complications associated with CEA without increasing the risk of stroke., Methods: We reviewed 10,059 CEAs, excluding concomitant coronary bypass, performed within the VSGNE from January 2003 to July 2012. Protamine use and reoperation for bleeding were evaluated monthly using statistical process control. Twelve centers and 77 surgeons entering the VSGNE between 2003 and 2008 were classified as original participants, and 14 centers and 60 surgeons joining after May 2009 were considered new. Protamine use for surgeons was categorized as rare (<10%), selective (10%-80%), or routine (>80%). Outcome measures were in-hospital reoperation for bleeding, postoperative myocardial infarction (POMI), and stroke or death., Results: Two significant increases occurred in protamine use for all VSGNE centers over time. From 2003 to 2007, the protamine rate remained stable at 43%. In 2008, protamine usage increased to 52% (P < .01), coincident with new centers joining the VSGNE. Protamine usage then increased to 62% in 2010 (P < .01), shortly after the presentations of the data showing a benefit of protamine. This effect was due to 10 surgeons in the original VSGNE centers who increased their usage of protamine: six surgeons from rare use to selective use and four surgeons to routine use. Reoperation for bleeding was reduced by 0.84% (relative risk reduction, 57.2%) in patients who received protamine (0.6% vs 1.44%; P < .001). There were no differences in POMI (1.1% vs 1.09%) or stroke or death (1.1% vs 1.03%) between protamine treated and untreated patients, respectively. Reoperation for bleeding was decreased for surgeons who used protamine routinely (0.5%; P < .001) compared with selective (1.4%) and rare users (1.5%) of protamine. There were no differences in POMI (0.9%, 1.2%, 1.1%; P = .720) and stroke or death rates (1.0%, 1.2%, 1.0%; P = .656) for rare, selective, and routine users of protamine., Conclusions: Protamine use increased over time by VSGNE surgeons, most significantly after the presentations of VSGNE-derived data showing the benefit of protamine, and was associated with a decrease in reoperation for bleeding. Improvements in processes of care and outcomes can be achieved in regional quality groups by sharing safety and efficacy data., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Protamine, which is routinely used after cardiac surgery to reverse the anticoagulant effects of heparin, is known to be immunogenic. Observing patients with an otherwise unexplained rapid decrease in platelet count directly after protamine administration, we determined the incidence and clinical relevance of protamine-reactive antibodies in patients undergoing cardiac-surgery. In vitro, these antibodies activated washed platelets in a FcγRIIa-dependent fashion. Using a nonobese diabetic/severe combined immunodeficiency mouse model, those antibodies induced thrombocytopenia only when protamine and heparin were present but not with protamine alone. Of 591 patients undergoing cardiopulmonary bypass surgery, 57 (9.6%) tested positive for anti-protamine-heparin antibodies at baseline and 154 (26.6%) tested positive at day 10. Diabetes was identified as a risk factor for the development of anti-protamine-heparin antibodies. In the majority of the patients, these antibodies were transient and titers decreased substantially after 4 months (P < .001). Seven patients had platelet-activating, anti-protamine-heparin antibodies at baseline and showed a greater and more prolonged decline in platelet counts compared with antibody-negative patients (P = .003). In addition, 2 of those patients experienced early arterial thromboembolic complications vs 9 of 584 control patients (multivariate analysis: odds ratio, 21.58; 95% confidence interval, 2.90-160.89; P = .003). Platelet-activating anti-protamine-heparin antibodies show several similarities with anti-platelet factor 4-heparin antibodies and are a potential risk factor for early postoperative thrombosis.

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 = 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.

Background: Safety of atrial fibrillation (AF) ablation in conditions of periprocedural therapeutic international normalized ratio (INR) in combination with heparin is still uncertain, and little is known about the pre-procedural therapeutic INR influence on bleeding complications (BC) in this method., Methods and Results: The subjects were 150 consecutive patients who underwent catheter ablation for AF with therapeutic INR. The patients were classified into 2 groups, BC (Group BC) and no BC (Group No BC), by whether they did or did not have BC, respectively. Differences in various parameters, including pre- and post-procedural prothrombin time-INR and activated partial thromboplastin time (APTT), were compared between the 2 groups. None of the patients experienced stroke or transient ischemic attack. In the 22 patients (15%) who had BC (Group BC), 3 patients had major and 19 patients had minor BC. There were no significant differences between the 2 groups in pre-procedural INR, APTT, and amount of heparin administered during the procedure. However, post-procedural INR and APTT were significantly prolonged in Group BC (2.5 ± 0.5 vs. 2.2 ± 0.5, P=0.016, 65 ± 45 vs. 44 ± 11, P<0.0001 respectively). Multivariable analysis showed that post-procedural APTT was the only independent bleeding risk factor (P=0.022)., Conclusions: AF ablation with peri-procedural therapeutic INR in combination with heparin seems to be safe. Presence or absence of BC are not related to the pre-procedural INR level, but to post-procedural APTT.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was what the optimal intraoperative anticoagulation strategy should be in patients undergoing off-pump coronary artery bypass graft (CABG) surgery. A total of 157 papers were identified using the reported search, of which 8 were judged to represent the best evidence. The authors, journal, date, country of publication, study type, patient group studied, relevant outcomes and results were tabulated. The quality of clinical trials was assessed. Off-pump CABG is currently considered as a safe and effective alternative to CABG with the use of cardiopulmonary bypass, especially in the presence of off-pump expertise and certain pathologies. Although most technical steps in off-pump revascularization are standardized, it appears that there is inconsistency in intraoperative anticoagulation practice. Surveys conducted in the USA and Europe confirm the lack of uniform policy, with heparin dose ranging between 70 and 500 U/kg and from full-dose protamine to no reversal of anticoagulation. Although the quality of evidence is low, there is a trend for utilization of heparin at 150 U/kg, followed by half-dose protamine reversal, which appears to provide adequate anticoagulation for the safe conduct of anastomoses and thromboprophylaxis without significantly increasing the risk of postoperative bleeding. However, more research is necessary before firm recommendations can be made.

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti-hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents., (© 2011 International Society on Thrombosis and Haemostasis.)

Three to 5 percent of the patients undergoing cardiac surgery are reoperated because of bleeding. When a surgical cause can be excluded, heparin/protamine mismatch may be considered. Insufficient reversal of heparin and overdosing of protamine may cause postoperative bleeding. The purpose of the study was to evaluate whether a heparin-protamine titration system, Hemochron RxDx, could reduce postoperative bleeding and blood transfusion. Fifty-three patients were included prospectively over a 6-month period. The test group (RxDx group; 28 patients) received heparin and protamine doses calculated using the Hemochron RxDx system, which performs a baseline activated clotting time (ACT) value together with a heparin response test. An accurate heparin dose was calculated based on the Bull dose/response curve. Protamine doses were calculated by the same method. In the control group (25 patients), heparin was administered based on weight (3.5 mg/kg) and monitored by ACT. Heparin was reversed with protamine (1 mg/l mg of total heparin). Postoperative bleeding was significantly lower in the RxDx group (375 mL; range, 125-700 mL) compared with the control group (600 mL; range, 250-1920 mL; p = .018). A reduced number of patients needed blood transfusions in the RxDx group, although this was not statistically significant (19% vs. 38%, respectively; p = .13). Initial heparin dose was significantly reduced in the RxDx group (250 mg; range, 100-375 mg) compared with the control group (300 mg; range, 200-350 mg; p = .04). The additional heparin during cardiopulmonary bypass (CPB) was significantly lower as well 62 (range, 0-185) vs. 100 mg (range, 0-350 mg); p = .04. Initial protamine dose was reduced in the RxDx group 200 (range, 75-340) vs. 350 mg (range, 200-500 mg); p = .0001. Satisfactory end ACT values were obtained in both groups. Using the Hemochron RxDx, we observed a significant reduction in postoperative blood loss, as well as the amount of heparin and initial doses of protamine used during CPB. Individual patient managed anticoagulation during cardiac surgery using dose/response curve techniques based on in vitro analysis of heparin and protamine seems to reduce bleeding.

Coronary perforation is an undesirable complication during percutaneous coronary intervention (PCI). We reviewed the cases of overt coronary perforation in our institute and analyzed their clinical backgrounds, the characteristics of the target lesion, management, and clinical outcomes. Between 1991 and 2005, we experienced 12 cases (0.35%) of coronary perforation in a total of 3415 PCI procedures. The perforation occurred during the use of debulking devices in 3 cases, immediately after stenting in 2, immediately after postdilatation of the stent in 2, and during wiring in 3 cases. Restoration was attempted by long inflation of a balloon in 7 cases, implantation of a covered stent graft in 1, and emergency surgical repair in 1 case. Subsequent cardiac tamponade occurred in 3 patients who required pericardiocentesis, and 1 patient died due to congestive heart failure. Administration of protamine was effective in stopping the bleeding in 6 patients, whereas continuation of antiplatelet therapy resulted in no overt rebleeding. Coronary perforation during PCI is a rare complication but is associated with significant morbidity and mortality. Intravenous administration of protamine is effective when it is used in conjunction with nonsurgical devices for initial management of perforation.

Background: Excessive protamine administration to neutralize heparin after cardiopulmonary bypass has been implicated as a cause of postoperative hemorrhage. Protamine directly inhibits thrombin and tissue factor (TF)-mediated activation of factor VII. However, the half-life of protamine is only 4.5 minutes; thus the purpose of this study was to determine if protamine could enhance fibrinolysis, explaining the delayed, protamine-associated hemorrhage observed in the postoperative period., Methods: Human plasma containing 0, 6.25, 12.5, or 25 microg/mL of protamine (n = 6 per condition) was exposed to 0.01% tissue factor and tissue-type plasminogen activator (tPA, 100 U/mL) for 30 minutes, with clot growth and disintegration measured by Thromboelastograph (Haemoscope Corp, Skokie, IL). The TF was increased to 0.1% in additional experiments with plasma containing protamine (25 microg/mL) and tPA., Results: Protamine significantly (p < 0.05) delayed the time to clot initiation, decreased the speed of clot propagation, and diminished clot strength in a concentration-dependent fashion. The onset of fibrinolysis was significantly (p < 0.05) increased only in samples with 25 microg/mL of protamine, and the rate of clot lysis was not different among the conditions. The clot duration time (from initiation to disintegration) was significantly (p < 0.05) decreased in a concentration-dependent manner by protamine. Increased TF concentration (0.1%) significantly improved clot growth kinetics and prolonged clot duration in samples with 25 microg/mL of protamine compared with samples activated with 0.01% TF., Conclusions: Protamine enhanced fibrinolysis by decreasing clot strength by diminishing TF-initiated thrombin generation. Additional, clinical investigation is warranted to mechanistically implicate protamine-mediated enhancement of fibrinolysis to delayed bleeding after cardiopulmonary bypass.

Objective: The complement cascade and granulocytes are activated in on-pump cardiac surgery. If activation of complement directly regulates granulocytes, granulocyte elastase (GEL) should increase significantly after protamine administration. We examined the effect of protamine on granulocytes by protamine administration and observation of the effect on GEL and C3a., Methods: Thirty patients who underwent coronary artery bypass grafting were randomly assigned to two groups. In 15 patients, protamine was administered 5 min after the termination of cardiopulmonary bypass, and was administered 35 min after cardiopulmonary bypass in the other 15 patients. All patients were perfused with heparin-coated circuits and received 300 IU/kg heparin and 3 mg/kg protamine. GEL and C3a concentrations were measured at 7 time points., Results: GEL concentrations increased significantly just before aortic declamping and did not increase significantly after protamine administration. C3a concentrations, however, did not increase during cardiopulmonary bypass and did increase significantly after protamine administration., Conclusions: This study indicates that GEL does not increase after protamine administration and that complement concentration does not directly affect GEL release.

Background: Bivalirudin is a short-acting direct thrombin inhibitor, with advantages over unfractionated heparin for anticoagulation in cardiac surgery. We hypothesized that bivalirudin is not associated with a clinically important increase in blood loss compared with heparin with protamine reversal in patients undergoing off pump coronary artery bypass (OPCAB) surgery. We also assessed flow with angiography at 3 months using a modified Thombolysis in Myocardial Infarction (TIMI) grade in the grafted coronary arteries., Methods: One hundred patients were randomly assigned to receive bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion) or heparin (150 to 300 U/kg bolus) with protamine reversal., Results: A median of 3 (range, 1 to 5) grafts were inserted per patient. Blood loss for the 12 hours after study drug initiation in the bivalirudin group (median, 793 mL; interquartile range, 532 to 1,214 mL; range, 320 to 4,909 mL; n = 50) was not significantly greater than in the heparin group (median, 805 mL; interquartile range, 517 to 1,117 mL; range, 201 to 2,567 mL; n = 50; p = 0.165). Median graft flow was 3.0 in the bivalirudin group (n = 40) and 2.67 in the heparin group (n = 39; p = 0.047). The bivalirudin group had more patients with grade 3 (ie, full) flow in at least 1 graft (100% versus 90%; p = 0.04), a trend toward more patients with grade 3 flow in all grafts (60% versus 38%; p = 0.06), and more grafts with grade 3 flow (82% versus 67%; p = 0.03)., Conclusions: Anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. Graft flow was better in the bivalirudin patients; the impact of this on clinical outcomes requires a larger study.

Unlabelled: The synthetic vasopressin analog desmopressin has hemostatic properties and may reduce postoperative bleeding after coronary artery bypass grafting (CABG). A study on the effects of recent aspirin ingestion on platelet function in cardiac surgery showed a greater impairment of platelet function in patients treated with aspirin <2 days before the operation. We evaluated the effects of desmopressin on postoperative bleeding in CABG patients who were treated with aspirin 75 or 160 mg until the day before surgery. The study was a prospective, randomized, double-blinded, placebo-controlled, parallel group trial. One-hundred patients were included and divided into two groups. One group received desmopressin 0.3 micro g/kg and the other received placebo (0.9% NaCl) after the neutralization of heparin with protamine sulfate. Postoperative blood loss was recorded for 16 h. The mean (SD) bleeding was 606 (237) mL in the desmopressin group and 601 (301) mL in the placebo group (P = 0.93), representing no significant difference (95% confidence interval, -107 to 117 mL). We conclude that desmopressin does not reduce postoperative bleeding in CABG patients treated with aspirin until the day before surgery., Implications: Continuation of aspirin until the day before coronary artery bypass grafting may increase postoperative bleeding. The administration of desmopressin to these patients after the neutralization of heparin with protamine sulfate does not reduce postoperative bleeding.

Unlabelled: Tranexamic acid reduces postoperative bleeding after coronary artery bypass grafting. We evaluated the effects of a single dose of tranexamic acid given immediately before cardiopulmonary bypass (CPB) in patients treated with aspirin until the day before surgery. The study was a prospective, randomized, double-blinded, placebo-controlled, parallel-group trial. Eighty patients were included and divided into two groups: one group received tranexamic acid 30 mg/kg, and one group received placebo (0.9% NaCl) as a bolus injection before CPB. Postoperative blood loss was recorded for 16 h. Transfusions of blood products were recorded for the whole hospital stay. Transfusions of packed red cells were given when the hematocrit value was less than 20% during CPB and less than 25% after surgery. The patients in the tranexamic acid group had significantly less postoperative bleeding compared with the patients in the placebo group (mean [SD]) (475 [274] mL versus 713 [243] mL; P < 0.001). An effective inhibition of fibrinolysis was found in patients receiving tranexamic acid. Tranexamic acid reduces postoperative bleeding in coronary artery bypass grafting patients treated with aspirin until the day before surgery., Implications: Continuation of aspirin medication until the day before coronary artery bypass grafting may increase postoperative bleeding. The administration of a single dose of tranexamic acid (30 mg/kg) immediately before cardiopulmonary bypass significantly reduced postoperative bleeding and inhibited fibrinolysis in these patients.

Unlabelled: Heparinase-I, a specific heparin-degrading enzyme, may represent an alternative to protamine. We explored the dose of heparinase-I for efficacy and safety in patients undergoing coronary artery surgery. At the conclusion of cardiopulmonary bypass, subjects received 5, 7, or 10 microg/kg of open-label heparinase-I instead of protamine. Activated clotting time (ACT) and its difference from a contemporaneous heparin-free sample (DeltaACT) at 3 min before and 3, 6, and 9 min after heparinase-I determined reversal efficacy. After surgery, we recorded hourly chest tube drainage. Systemic and pulmonary arterial blood pressure and cardiac output measurements before and immediately after heparinase-I were used to evaluate hemodynamic safety. Coagulation measurements included anti-factor Xa and anti-factor IIa activities. Forty-nine patients from seven institutions participated: 12 received 5 microg/kg, 21 received 7 microg/kg, 4 received two doses of 7 microg/kg, 8 received 10 microg/kg, and 4 received two doses of 10 microg/kg. Treatment groups did not differ demographically. Median DeltaACT 9 min later was 11, 7, and 4 s for the 5, 7, and 10 microg/kg groups, respectively. No adverse hemodynamic changes occurred with heparinase-I administration. The authors conclude that heparinase-I effectively restored the ACT after cardiopulmonary bypass. This effect appeared to be dose dependent., Implications: Heparinase-I (Neutralase(TM)) successfully restored activated coagulation time with no adverse hemodynamic events in patients undergoing coronary artery surgery with cardiopulmonary bypass in an open-label dose-determining trial.

Implications: We conducted a randomized study in 147 pediatric patients undergoing cardiopulmonary bypass to determine when there are any differences in hemodynamic effects if CaCl(2) 20 mg/kg and protamine 5mg/kg are mixed together and infused over 10 min versus administering half of the calcium dose (10 mg/kg) as a bolus followed by a 10-min infusion of protamine 5 mg/kg and CaCl(2) 10mg/kg.

Objective: The heparin-protamine titration method that uses the Hepcon hemostasis management system (Medtronic HemoTec Inc, Englewood, Colo) reduced blood loss in cardiac surgery in previous reports, but the mechanism is not fully understood. This study tests the hypothesis that reduced protamine administration preserves platelet function in human cardiac surgery., Methods: Platelet count, alpha-granule secretion, and aggregation to thrombin before and after cardiopulmonary bypass in human beings were evaluated. In the control group (n = 14), a fixed dose of protamine (3 mg/kg) was administered. In the titration group (n = 20), protamine doses were based on the heparin concentration measured by the Hepcon system., Results: Heparin concentrations before protamine administration were higher in the titration group (P =.0012), but protamine doses of patients in the titration group were markedly lower than those of the control group (P <.0001). During protamine infusion at a rate of 0.3 mg. kg(-1). min(-1), the percentage of granule membrane protein-140-positive platelets significantly increased in the control group compared with the titration group (18.8% +/- 8.6% vs 13.0% +/- 5.3%, P =.0188). After protamine administration, aggregation of washed platelets to thrombin recovered almost to the preoperative level in the titration group; however, it remained lower in the control group (20% +/- 20% vs 55% +/- 18%, P =.0009)., Conclusion: Low-dose administration of protamine, based on a heparin-protamine titration method, restores not only the blood coagulation but also the platelet responses to thrombin and attenuates platelet alpha-granule secretion during heparin neutralization. Overdose of protamine activates platelets and may predispose patients to excessive bleeding after cardiac surgery.

In this study we investigated the effects of isoproterenol and enoximone on protamine cardiotoxicity because administration of protamine for heparin reversal during open heart surgery depresses left ventricular function. Eighteen mongrel dogs were entered into this study. After induction of general anesthesia and a stabilization period, a thermodilution catheter was inserted via the jugular vein. Another 2 catheters were inserted into the left ventricle and femoral artery. Heparin and protamine were used in all animals. Heparin dosage was 300 U/kg, and protamine dosage was 4.5 mg/kg. The animals were divided into 3 groups. Six animals received enoximone (5 micrograms/kg per min), 6 animals received isoproterenol (0.05 microgram/kg per min), and 6 animals received no inotropic agent. Measurements were performed before treatment, 5 min after protamine administration, and at 15-min intervals for 1 h. Cardiac output (CO), mean arterial pressure, pulmonary capillary wedge pressure, first derivative of left ventricular pressure (1 +/-) left ventricular systolic pressure, and heart rate were measured. CO was 1582 +/- 34 ml/min in the isoproterenol group (I + P), 1684 +/- 61 ml/min in the enoximone group (E + P), and 1471 +/- 37 ml/min in the protamine group (P) (p < 0.05 E + P vs I + P and P) 60 min after protamine administration. The first derivative of left ventricular pressure (dP/dt) was 1995 +/- 61 mmHg/sec in the I + P group, 2320 +/- 85 mmHg/sec in the E + P group, and 1816 +/- 48 mmHg/sec in the P group (p < 0.05 E + P vs I + P and P). In our experimental study, the isoproterenol and protamine combination did not increase hemodynamic activity. However, isoproterenol alone significantly increased hemodynamic activity as determined by dP/dt values. Protamine administration impairs the effects of beta agonists on the myocardium. In the protamine group, CO and pressure-dependent values were significantly reduced. Isoproterenol administration did not reverse this deterioration because of the loss of the beta-receptor activity. Inotropic agents acting through the beta-adrenergic system have partial effects on myocardium. Enoximone, a phosphodiesterase inhibitor, reverses deterioration of cardiac function after protamine administration because it increases myocardial function via the phosphodiesterase system.

Unlabelled: Coagulopathies in children after cardiopulmonary bypass (CPB) are complex. There are very limited data correlating coagulation tests with postoperative bleeding. We evaluated coagulation changes after CPB and after the administration of coagulation products to 75 children. Baseline coagulation tests were obtained and repeated after protamine administration, after transfusion of individual coagulation products, and on arrival in the intensive care unit (ICU). Regression analysis demonstrated no baseline coagulation test to predict postoperative chest tube drainage. Weight and duration of CPB were determined to be the only predictors of bleeding. Further analyses demonstrated that children <8 kg had more bleeding and required more coagulation products than children >8 kg. Postprotamine platelet count and fibrinogen level correlated independently with 24-h chest tube drainage in children <8 kg, whereas postprotamine platelet count and thrombelastographic values did so in patients weighing >8 kg. Platelet administration alone was found to restore effective hemostasis in many patients. With ongoing bleeding, cryoprecipitate improved coagulation parameters and limited blood loss. Fresh-frozen plasma administration after platelets worsened coagulation parameters and was associated with greater chest tube drainage and more coagulation product transfusions in the ICU. Objective data to guide post-CPB component therapy transfusion in children are suggested., Implications: Children <8 kg can be expected to have more severe coagulopathies, require more coagulation product transfusions, and bleed more after cardiopulmonary bypass. Correlations between coagulation tests and postoperative chest tube drainage are defined. Platelets and, if necessary, cryoprecipitate optimally restore hemostasis. Fresh-frozen plasma offers no benefits in correcting postcardiopulmonary bypass coagulopathies in children.

Objective: To investigate whether heparin reversal after carotid endarterectomy reduces the incidence of haemorrhagic complications., Design: A randomised prospective trial., Methods: Sixty-four patients randomised to reversal of heparin or no reversal, of whom 31 received protamine titrated to the residual circulating heparin at closure of arteriotomy. Measurements included serial activated clotting times (ACTs), wound drainage, neck swelling using duplex Doppler imaging to measure the depth from skin to carotid bifurcation, and the recording of all complications., Results: Wound drainage volumes were significantly reduced by protamine reversal (68.5 ml compared to 35 ml, p < 0.001), but neck swelling was not (72 mm compared to 70 mm, p = 0.77). Two patients who were not reversed developed neck haematomas requiring evacuation. More importantly, two patients receiving protamine, thrombosed the operated internal carotid artery (ICA) postoperatively and died despite urgent thrombectomy. A further patient who was not randomised in this study but who received protamine also developed ICA thrombosis within the same 3 month period., Conclusions: Reversing heparin with protamine reduces postoperative wound drainage after carotid surgery but may predispose to ICA thrombosis and stroke. This is in keeping with a previous retrospective study published during our trial.

We studied the inflammatory reaction related to cardiopulmonary bypass in 24 neonates (median age 6 days) undergoing the arterial switch operation for simple transposition of the great arteries, with respect to the development of postoperative capillary leak syndrome. Complement proteins, leukocyte count, tumor necrosis factor-alpha, and histamine levels were determined before, during, and after cardiopulmonary bypass. Additionally, protein movement from the intravascular into the extravascular space during cardiopulmonary bypass was assessed by the measurement of plasma concentrations of proteins with molecular weights ranging from 21,200 to 718,000. Capillary leak syndrome developed in 13 of the 24 neonates. Patients with capillary leak syndrome, as compared with those without, had preoperatively higher C5a levels (C5a, 3.0 +/- 0.6 microgram/L vs 0.9 +/- 0.2 microgram/L) (mean +/- standard error of the mean) (p < 0.05) and higher leukocyte counts (leukocytes, 17.9 +/- 2.1 X 10(3) cells/ml versus 11.7 +/- 0.8 X 10(3) cells/ml) (p < 0.05), suggesting in these neonates a preoperative inflammatory state. Preoperative clinical and operative data were identical in both patient groups. Before cardiopulmonary bypass, serum protein concentrations were similar in all patients. Ten minutes after institution of cardiopulmonary bypass, protein concentrations fell to significantly lower values in patients with capillary leak syndrome than in those without: albumin (19% +/- 1.5% vs 30% +/- 6% of the prebypass value, p < 0.05), immunoglobulin G (17% +/- 1.5% vs 29% +/- 5.5%, p < 0.001), and alpha 2-macroglobulin (15% +/- 1.2% vs 25% +/- 4%, p < 0.02). During cardiopulmonary bypass, albumin concentrations remained significantly lower in patients with capillary leak syndrome than in those without, whereas hematocrit values were similar in both groups. During cardiopulmonary bypass, patients with capillary leak syndrome also had lower concentrations of complement proteins C3 and C4 but not C1 inhibitor. C3d/C3 ratio and C5a levels were similar in both patient groups. In contrast, histamine liberation during cardiopulmonary bypass was significantly more pronounced in patients with capillary leak syndrome than in those without (725.2 +/- 396.7 pg/ml vs -54.1 +/- 58.4 pg/ml, p < 0.05). Tumor necrosis factor-alpha levels after protamine administration were also significantly higher in patients with capillary leak syndrome (38.1 +/- 10.0 pg/ml vs 15.3 +/- 3.4 pg/ml, p < 0.05). Leukocyte count during and after cardiopulmonary bypass was similar in both patient groups. This study demonstrates increased protein leakage as early as 10 minutes after initiation of.

There are no clinically available alternatives for reversing heparin in protamine-allergic patients. This study examined the ability of methylene blue, hexadimethrine, and vancomycin to reverse circulating heparin so that these compounds can be carefully examined in future placebo-controlled studies in humans. Heparin activity in blood obtained from extracorporeal circuits was reversed by adding protamine (13.5, 27.0, 81.1, 135.1, and 270.3 micrograms/mL), methylene blue (13.5, 27.0, 135.1, 202.7, 270.3, 337.8, 405.4, 473.0, 540.5, and 810.8 micrograms/mL), hexadimethrine (6.8, 13.5, 20.3, 27.0, 81.1, and 135.1 micrograms/mL), or vancomycin (13.5, 27.0, 135.1, 270.3, 540.5, and 810.8 micrograms/mL), and activated clotting times (ACTs) were measured with kaolin (n = 18). Heparinase-ACT was obtained to determine complete reversal. Heparin concentrations were 3.3 +/- 0.3 U/mL with ACT values of 485 +/- 97 s. The ACT at a protamine concentration of 81.1 micrograms/mL and at hexadimethrine concentrations of 81.1 and 135.1 micrograms/mL was not statistically different from heparinase-ACT; however, methylene blue or vancomycin did not reverse the anticoagulation at any concentrations. Hexadimethrine can reverse heparin-induced anticoagulation after cardiopulmonary bypass as well as protamine, although methylene blue or vancomycin did not neutralize heparin in vitro.

Background: Cardioplegic arrest with rewarming and protamine administration have been implicated in causing transient left ventricular dysfunction perioperatively. However, whether interactive effects between cardioplegic arrest and rewarming with protamine occur with respect to myocyte contractile processes remains unclear. Accordingly, using an isolated myocyte model, the present study tested the hypothesis that simulated cardioplegic arrest with rewarming and protamine would have direct and interactive effects on myocyte contractile function., Methods: Left ventricular isolated myocyte contractile function was examined using computer-aided videomicroscopy under normothermic conditions (37 degrees C, cell medium; n = 183) and after simulated hypothermic, hyperkalemic cardioplegic arrest with rewarming (4 degrees C, 24 mEq/L K+, 2 hours; then 37 degrees C, cell medium, 5 minutes; n = 268). Myocyte function was then examined in the presence of protamine (10 to 40 micrograms/mL) under normothermic conditions (n = 102) and after cardioplegic arrest with rewarming (n = 175)., Results: Myocyte contractile function decreased by 43% from baseline after simulated cardioplegic arrest with rewarming. Under normothermic conditions, protamine (20 micrograms/mL) reduced myocyte contractile function by 43.9% +/- 4.3%, whereas myocyte contractile function decreased by only 31.1% +/- 2.7% with protamine (20 micrograms/mL) after cardioplegic arrest with rewarming. Thus, the negative effects of protamine on myocyte contractility were attenuated after cardioplegic arrest when compared with normothermic conditions., Conclusions: The present study demonstrated that simulated cardioplegic arrest with rewarming and protamine have direct and interactive effects on myocyte contractile function, which are not additive or synergistic.

Background: Protamine is used to reverse the anticoagulant effects of heparin, but it can have important side effects. Platelet factor 4 (PF4) is a protein found in platelet alpha granules that binds to and thereby neutralizes heparin. We evaluated the safety and effectiveness of intravenous recombinant PF4 to neutralize heparin anticoagulation after cardiac catheterization in a phase 1, open-label trial., Methods and Results: The study group consisted of 18 patients having diagnostic cardiac catheterization. Heparin (5000 U) was given after vascular access was obtained. In the first 12 patients, additional heparin was given at the conclusion of the procedure so that all patients had activated coagulation times > 300 seconds before rPF4 was given. Three patients each received 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 over a period of 3 minutes at the conclusion of the catheterization procedure. In 6 additional patients, extra heparin was not given at the conclusion of the procedure, and 1.0 mg/kg rPF4 was given. Hemodynamic measurements, cardiac output, and serial blood tests were performed 5, 10, 20, and 30 minutes after rPF4 and then into the next 24 hours. There were no serious side effects in any patient, despite transient rPF4 levels as high as 14,870 ng/mL in the patients receiving 5.0 mg/kg. One patient receiving 2.5 mg/kg had a slight transient rise in liver enzymes possibly related to the rPF4. There were no important hemodynamic effects of rPF4 administration at any dose used. Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the anticoagulant effect of heparin. At lower doses, rPF4 neutralized the effects of heparin in most but not all patients. Pharmacokinetic analysis suggested a monophasic and one-compartment clearance of the PF4-heparin complex. No neutralizing factors to rPF4 were detected in the samples collected 7 days after dosing., Conclusions: rPF4, in doses ranging from 0.5 to 5.0 mg/kg over 3 minutes, had no serious side effects. Given in sufficient amounts, rPF4 can completely and rapidly reverse the anticoagulant effects of heparin.

Severe pulmonary hypertension after protamine neutralization of heparin is an infrequent but life-threatening event following cardiopulmonary bypass. The effect of left ventricular infusion of protamine on pulmonary hypertension as well as a possible role of platelet-activating factor (PAF) or histamine in the heparin-protamine reaction was investigated in 30 pigs in four different groups during general anesthesia. Group 1 animals received 250 IU/kg heparin, followed by 100 mg protamine intravenously after 15 min. In group 2 protamine was infused into the left ventricle. Group 3 animals received the histamine H1- and H2-antagonists clemastine and ranitidine 5 min before protamine infusion. In group 4 the PAF receptor blocker WEB 2086 was given 5 min before protamine. Platelet-activating factor was measured by a bioassay in serum samples of group 1 and group 4 animals. In all four groups protamine caused severe pulmonary hypertension, thromboxane A2 release, and a transient decrease in leukocyte counts. No PAF release was detected after protamine infusion. Neither left ventricular infusion of protamine nor histamine or PAF antagonists prevented or attenuated the reactions after protamine infusion. The authors conclude that left ventricular infusion of protamine provides no protection from pulmonary hypertension, and that histamine and PAF are not involved in the acute pulmonary vasoconstriction after protamine neutralization of heparin.

The effect of the rate of intravenous infusion of protamine on the acute hemodynamic and pulmonary effects of heparin neutralization was investigated in six adult sheep surgically instrumented for chronic studies. Bovine lung heparin at a dose of 200 IU/kg was injected intravenously over 10 sec, 5 min before the start of protamine administration. On separate experimental days, each sheep received protamine at the same dose of 2 mg/kg, but it was infused over four different time periods: 3 s, 30 s, 300 s, or 30 min. At an additional session, protamine was administered over 3 s without prior heparinization to assess the effect of protamine alone. The sequence of the sessions was randomized and performed blindly. Injecting protamine in unheparinized sheep produced no change in any of the measured variables. In contrast, when protamine was injected over 3 s in heparinized sheep, it induced a transient and significant (P less than 0.001) pulmonary hypertension (from 17.2 +/- 1.5 to 45.6 +/- 2.4 mmHg at 1 min) with an increased pulmonary (five-fold) and systemic (2.5-fold) vascular resistance; a decrease of cardiac output (from 3.85 +/- 0.43 to 1.93 +/- 0.29 l/min) without change in left atrial pressure (from 5.3 +/- 1.3 to 6.0 +/- 1.7 mmHg; P = NS); a significant (P less than 0.001) increase of plasma thromboxane B2 (TxB2) concentrations (from 349 +/- 131 to 974 +/- 218 pg/ml); leukopenia (76 +/- 4% of baseline white blood cell counts); and hypoxemia (PaO2 decreased from 81 +/- 3 to 63 +/- 4 mmHg at 2 min). Administering the same amount of protamine after heparin at a slower infusion rate significantly attenuated and delayed all components of the adverse response to protamine. This attenuation occurred in an infusion rate-dependent fashion, so that when protamine was infused over 30 min, no significant changes in any of the measured variables were noted. The time course of plasma heparin concentrations following protamine indicated that chemical heparin was completely neutralized over the time period of protamine infusion. These results demonstrate that the rate of generation of heparin-protamine complexes (as detected by changes of plasma concentrations of chemical heparin) during iv protamine infusion started 5 min after heparin administration is a factor involved in the generation of sufficient mediators required to initiate a characteristic physiologic response in sheep, including systemic and pulmonary vasoconstriction, TxB2 generation, and leukopenia. Infusing a neutralizing dose of protamine over 30 min avoids these adverse reactions in sheep.

The effect of protamine sulfate on several cardiovascular and biochemical variables was studied in man under clinical conditions. This study was performed to quantitate these effects in 15 adult patients who had undergone cardiopulmonary bypass for coronary artery bypass grafting. Protamine was administered in typical clinical doses (3 mg/kg) at typical clinical rates (total dose infused over 5 minutes). This infusion rate is greatly in excess of the 50 mg/10 min suggested in the protamine package insert. No statistically significant changes in mean arterial blood pressure, cardiac output, central venous pressure, total or ionized calcium, PaO2, PaCO2, pH, Na+, or K+ were found during or after administration of protamine sulfate. Hypotension was observed after administration of protamine to one patient, but no etiologic mechanism was apparent. Previous reports suggest cardiovascular depression by protamine in the dog, a species highly susceptible to these effects. Data obtained in man in this study do not corroborate the canine studies.

Postoperative heparin rebound was investigated in 50 adult patients undergoing cardiopulmonary bypass with the use of the Hepcon heparin analyzer. Prior to bypass each patient received 2 mg/kg of heparin. During bypass, the activated clotting time (ACT) was utilized to assess the need for additional heparin to maintain the value between 300 and 400 seconds. The average amount of heparin given was 160 mg. Once cardiopulmonary bypass was terminated the Hepcon unit was employed to determine the actual amount of active circulating heparin and to calculate the dose of protamine sulfate. The average amount of protamine administered intraoperatively was 200 mg. The overall mean ratio of protamine-to-heparin was 1.25 : 1. Once hemostasis was achieved, no circulating heparin was measured with the Hepcon unit, and the ACT value had returned to its baseline, the incisions were closed and the patients were transferred to the intensive care unit. One hour later a blood sample was obtained and analyzed by the Hepcon unit for any heparin rebound. We found that 26 patients (52%) had circulating heparin and required an additional dose of protamine, averaging 70 mg. Drainage from the thoracotomy tubes averaged 400 cc in the first 24 hours, and a mean of 2 units of packed cells was infused. Three patients (6%) did not require any blood transfusions. The use of the Hepcon unit has produced a safe and expedient method of analyzing and neutralizing active circulating heparin in patients following cardiopulmonary bypass. It is a useful adjunct in blood conservation because it reduces excessive postoperative blood loss associated with heparin rebound.