Protamine Dose Research Articles

Method to Calculate the Protamine Dose Necessary for Reversal of Heparin as a Function of Activated Clotting Time in Patients Undergoing Cardiac Surgery

Activated clotting time (ACT) has been used to monitor coagulation and guide management of anticoagulation control in patients undergoing cardiac surgery for decades. However, reversal of heparin with protamine is typically empirically based on total heparin administered. Dose-related adverse effects of protamine are well described. The aim of this study was to evaluate a heparin reversal strategy based on calculation of the protamine dose based on ACT measurements. We present a method using a mathematical formula based on the dose–response line (1). To check the formula, we performed a retrospective observational cohort study of 177 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). The study group of 80 patients was administered the dose of protamine obtained using our formula, and the control group of 97 patients was administered the empirically calculated dose. The ACT returned to normal values in patients who were given doses of protamine that were calculated using our formula; all but two had a final ACT of 141. The application of the formula resulted in a significant reduction in the dose of protamine (p< .023). The formula we present is a valid method for calculating the dose of protamine necessary to neutralize heparin. This same method can be used working with a target ACT to adjust the dose of heparin. As a result of its functionality, it allows application on a daily basis standardizing the process. We believe that the formula we developed can be applied in all those procedures in which it is necessary to anticoagulate patients with heparin and later neutralization (cardiac surgery with or without CPB, vascular surgery, procedures of interventional cardiology, and extracorporeal depuration procedures).

Heparin Dose and Postoperative Bleeding in Patients Undergoing Cardiopulmonary Bypass

Heparin is the most widely used anticoagulant for cardiopulmonary bypass (CPB). Several authors suggest that lower doses of heparin during CPB would produce lower postoperative chest tube losses and fewer transfusion events. In the present study, a heparin dose–response (HDR) test was used to determine the heparin dose for each patient. We hypothesize that higher doses of heparin do not cause increased postoperative bleeding and transfusion events in postoperative patients undergoing CPB when the heparin dose is determined by a HDR test. This prospective observational study followed 66 patients undergoing CPB-supported primary coronary artery bypass grafting. Patients were placed in one of two groups, sensitive (n = 37) or resistant (n = 29) based on the result of a HDR test slope. Data on patient characteristics, secondary outcomes, transfusion, and the primary outcome, chest tube losses, were collected. Patient characteristics differed in the baseline activated coagulation time (ACT) and thromboelastograph G parameter as well as number of patients with hypercholesterolemia. The resistant group had lower postheparin and postprotamine ACTs and heparin sensitivity index. Initial heparin dose, total heparin dose, heparin dose per kilogram, HDR, and protamine dose were higher in the heparin-resistant group. The primary outcome, postoperative chest tube loss volume, was collected at four time points and the two groups were then compared. The heparin-resistant group was noninferior to the sensitive group and had clinically fewer transfused patients and transfusion events. The resistant group was noninferior to the sensitive group with respect to chest tube losses at all measured time points. Higher doses of heparin determined by a HDR test do not cause increased postoperative chest tube losses or increased transfusion events.

Intentional Overdose With Tinzaparin: Management Dilemmas

BackgroundLow-molecular-weight heparin (LMWH) is increasingly being prescribed for prophylaxis and treatment of thromboembolic diseases. Despite the fact that its therapeutic use is considered to be safe, it can be complicated by major hemorrhage and, in contrast to unfractionated heparin, it can only partially be neutralized by protamine. Recent reports of LMWH overdose illustrate the need for a consensus on its management. ObjectivesTo describe a case of self-poisoning with a very large dose of tinzaparin and discuss management options in patients with LMWH overdose. Case ReportA 69-year-old woman was brought to the Emergency Department 2 h after injecting herself with 280,000 IU of tinzaparin subcutaneously in an attempt to commit suicide. Despite an unrecordable activated partial thromboplastin time (APTT > 180 s) and prolonged prothrombin time, there was no evidence of active bleeding. She was given an intravenous infusion of 100 mg protamine sulfate and was admitted to the intensive care unit, where further infusions of protamine were administered. Normalization of the APTT occurred 40–50 h post admission, reflecting normal tinzaparin clearance rather than neutralization by protamine. No hemorrhagic complications occurred during her hospitalization except for prolonged bleeding from venipuncture sites. ConclusionIn this case of massive tinzaparin overdose, conventional doses of protamine failed to rapidly normalize the deranged coagulation parameters. The favorable clinical outcome suggests that, regardless of the LMWH amount injected, no active treatment is needed in the absence of hemorrhage. This is in accordance with the limited published data concerning cases of overdose with other LMWHs.

Hepcon HMS Plus® reduced intraoperative protamine dosages following weaning from cardiopulmonary bypass

Hepcon HMS Plus® reduced intraoperative protamine dosages following weaning from cardiopulmonary bypass

A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents

Despite widespread use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH), protamine sulfate remains the only reversal agent for UFH that is approved by the Food and Drug Administration within the US. Availability of new reversal agents for approved anticoagulants and those in development may improve patient safety and care. Delparantag (PMX-60056) is a novel small molecule that shows ability to neutralize the anticoagulation effects of UFH and LMWH in animals and humans. This study examined the 1-year utilization of protamine within an acute care hospital in order to determine the need for a novel reversing agent like delparantag. All patients having documented protamine administration within a 1-year period were included. Pharmacy automated dispensing machines and computerized medication management systems were queried for all doses of protamine withdrawn, billed for, or dispensed. Scanned medical records were reviewed and protamine and anticoagulant information was abstracted. Primary procedural group categorizations for protamine patients were coronary artery bypass graft, cardiac valve surgeries, abdominal aortic aneurysm and other open abdominal surgeries, fistula placement, non-cardiac vascular, cardiac catheter and electrophysiology lab, and "other." Average doses of protamine administered were 439, 423, 126, 26, 46, 36, and 35mg in these groups, respectively. Four major bleeds and one serious adverse event occurred over the year period. Protamine is used in a wide array of procedures. Evaluating protamine's current use may be beneficial in identifying roles for future UFH and LMWH reversal agent use.

Immediate effects of individualized heparin and protamine management on hemostatic activation and platelet function in adult patients undergoing cardiac surgery with tranexamic acid antifibrinolytic therapy

This randomized prospective study was initiated to clarify whether individualized heparin and protamine dosing has immediate effects on hemostatic activation and platelet function in adult cardiac surgery. Sixty adults undergoing elective coronary artery bypass grafting (CABG) were assigned to receive individualized heparin and protamine (HMS group, n= 29) or a standard dose (ACT group, n=24). Measures of thrombin generation and Multiplate (Verum Diagnostica, Munich, Germany) platelet function tests were performed before and after cardiopulmonary bypass (CPB). HMS patients received higher heparin (p = 0.006) and lower protamine (p<0.001) doses. Post-CPB, HMS managed patients showed significantly lower thrombin generation (thrombin-antithrombin (TAT) p<0.02) than the ACT group. Moreover, HMS managed patients had a better preservation of platelet function (COL p = 0.013; ADP p = 0.04; TRAP p = 0.04). An individualized and stable heparin concentration and appropriate dosing of protamine can reduce thrombin generation and preserve platelet function, even in short-time CPB.

Protamine Overdose and Its Impact on Coagulation, Bleeding, and Transfusions After Cardiopulmonary Bypass

We assessed the effects of protamine overdosing on thrombelastometry, bleeding, and transfusions in patients after cardiopulmonary bypass (CPB). In group 1 (n = 15), representing the clinical standard, the protamine dose was based on the initial heparin dose, and group 2 (n = 15) received protamine based on the heparin concentration measured after CPB. Primary end points were thromboelastometric parameters. Secondary end points were perioperative blood loss and utilization of blood products. During CPB, heparin concentrations decreased by 40%, resulting in overdosing of protamine in group 1. Thromboelastometry revealed longer clotting time (CT) in group 1 (P values < .05). Four patients in group 1 but none in group 2 had excessive prolonged CT values (>360 seconds) and concomitant microvascular bleeding, requiring substantial replacement of coagulation factors. Heparin dose-based protamine management leads to protamine overdosing with inhibition of the coagulation process. Protamine management guided by heparin concentration avoids these complications.

Impact of protamine dose on activated clotting time and thromboelastography in infants and small children undergoing cardiopulmonary bypass

To study the effect of two protamine-dosing strategies on activated clotting time (ACT) and thromboelastography (TEG). Protamine dosage based on neutralizing heparin present in the combined estimated blood volumes (EBVs) of the patient and cardiopulmonary bypass (CPB) pump may result in excess protamine and contributes toward a coagulopathy that can be detected by ACT and TEG in pediatric patients. A total of 100 pediatric patients 1 month to ≤5 years of age undergoing CPB were included in this retrospective before/after design study. Combined-EBV group consisted of 50 consecutive patients whose protamine dose was calculated to neutralize heparin in the combined EBVs of the patient and the pump. Pt-EBV group consisted of the next 50 consecutive patients whose protamine dose was calculated to neutralize heparin in the patient's EBV. Baseline and postprotamine ACTs were similar between groups. Postprotamine heparin assay (Hepcon) showed the absence of residual heparin in both groups. Postprotamine kaolin-heparinase TEG showed that R was prolonged by 7.5 min in the Combined-EBV group compared with the Pt-EBV group (mean R of 20.17 vs. 12.4 min, respectively, P < 0.001). Increasing doses of protamine were associated with a corresponding, but nonlinear increase in R. There was no significant difference in the changes for K, alpha, and MA between the groups. Automated protamine titration with a protamine dosage based on Pt-EBV can adequately neutralize heparin as assessed by ACT while minimizing prolonging clot initiation time as measured by TEG.

Protamine dosage effects on complement activation and sonoclot coagulation analysis after cardiac surgery

Background: An optimal dosage and infusion regime for protamine reversal of heparin after cardiopulmonary bypass is important. Methods: Protamine dosages of either 2mg/kg or 4mg/kg bodyweight were compared in 40 patients after first time coronary arterial bypass grafting. Protamine was infused with a syringe driver over 20 minutes. Arterial blood sampling was performed prior to and during surgery, before and at 0.3, 0.6, 1, 3, 6 and 25h after the protamine infusion. C3a-desArg and C4a-desArg were analysed by radioimmunoassay. Coagulation was assayed with Sonoclot and activated clotting time. Results: Significantly higher inter-group plasma levels of C3a-desArg were seen with the greater protamine dose from 0.3- 0.6h, but none for C4a-desArg. Sonoclot parameters and leucocyte count differed significantly between the groups up to 6h, indicating hypercoagulabilty with the higher protamine dose. Significantly longer ACT in the low protamine dosage group indicited unblocked heparin with nonsignificant increased drainage bleeding and transfusions. There were no signs of allergic or anaphylactic reactions in any of the groups. Conclusion: Keeping the protamine dose low, minimizes complement activation with less viscoelastic signs of hypercoagulability. However there is an increased risk for drainage bleeding and unnecessary transfusion if heparin is not fully reversed with protamine post cardiopulmonary bypass. The present study was underpowered to detect significant differences in bleeding. (Less)

The Effect of Acute Sleep Deprivation and Fatigue in Cardiovascular Perfusion Students: A Mixed Methods Study

Sleep deprivation as a result of long working hours has been associated with an increased risk of adverse events in healthcare professions but not in cardiovascular perfusion. The purpose of this study is to investigate the impact of sleep deprivation on cardiovascular perfusion students. Testing with highfidelity simulation after 24 hours of sleep deprivation allowed investigators to assess user competency and the effect of fatigue on performance. After informed consent, seven senior perfusion students were enrolled in the study (three declined to participate). The qualitative portion of the study included a focus group session, whereas the quantitative portion included administration of questionnaires, including the Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS), as well as clinical skills assessment using high-fidelity simulation. Subjects were assessed at three different intervals of sleep deprivation over a 24-hour period: baseline (6:00am), 12 hours (6:00pm), 16 hours (10:00pm), and 24 hours (6:00am) of wakefulness. During each scenario, normally monitored bypass parameters, including mean arterial pressure, activated clotting times, partial pressures of oxygen, partial pressures of carbon dioxide, and venous flow, were manipulated, and the subjects were required to return the parameters to normal levels. In addition, the scenario required calculation of the final protamine dose (using a dose–response curve) and detection of electrocardiography changes. Each task was varied at the different simulation sessions to decrease the effect of learning. Despite any lack of sleep, we hypothesized that, because of repetition, the times to complete the task would decrease at each session. We also hypothesized that the ESS and SSS scores would increase over time. We expected that the students would anticipate which tasks were being evaluated and would react more quickly. The average ESS scores progressively increased at each time period: baseline, 12 hours, 16 hours, and 24 hours. At 24 hours, the ESS and SSS scores were the greatest and the standard deviation was low, suggesting that fatigue affected all participants. During the clinical task evaluations, a “flattening effect” on the learning curve over time was observed. Tasks that required a higher level of cognition had prolonged completion times. Sleep deprivation significantly affects clinical performance as assessed with high-fidelity simulation. To optimize patient and clinician safety, it is important that the question of length of working time be investigated further.

A randomized study of coronary artery bypass surgery performed with the Resting Heart System utilizing a low vs a standard dosage of heparin

Allogeneic blood transfusion and reoperation for postoperative bleeding after the coronary artery bypass grafting have a negative impact on the patient outcome. This study aimed at evaluating the effects of reduced doses of heparin and protamine on the patient outcome, using a heparin-coated mini-cardiopulmonary bypass (CPB) system. Sixty patients undergoing elective first-time CPB were prospectively randomized either to have a reduced systemic heparinization [activated clotting time (ACT) = 250 s] or to a control group perfused with a full heparin dose (ACT = 420 s). Blood transfusions, ventilation time, early postoperative bleeding, ICU stay, reoperations for bleeding, postoperative cognitive status and the level of mobilization were registered. Twenty-nine patients were randomized to the control group, 27 patients to the low-dose group and 4 patients were excluded because of protocol violations. Four patients in the control group received a total of 10 units of packed red blood cells, and in the low-dose group, no transfusions were given, P = 0.046. No patient was reoperated because of bleeding. The ICU stay was significantly shorter in the low-dose group (8.4 vs 13.7 h, P = 0.020), less dependent on oxygen on the first postoperative day (78 vs 97%, P = 0.034), better mobilized (89 vs 59%, P = 0.006) and had less pain (visual analogue scale 2.0 vs 3.5, P = 0.019) compared with the control group. The use of a mini-CPB system combined with a low dose of heparin reduced the need for blood transfusions and may facilitate the faster mobilization of the patients.

Subtle differences in commercial heparins can have serious consequences for cardiopulmonary bypass patients: A randomized controlled trial

To compare the potency, reversibility, and perioperative bleeding risk of Hepalean with those of PPC heparin. Because invitro testing failed to detect differences in the potency or protamine reversibility of the 2 heparin preparations, we conducted a parallel group, single-center, double-blind, randomized, controlled trial to compare the anticoagulant effects of Hepalean to those of PPC heparin in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. From June 1, 2011, to June 30, 2011, we randomly assigned 11 patients to receive PPC heparin and 10 to receive Hepalean. Despite similar initial doses of heparin, the median initial activated clotting time was numerically lower in the PPC heparin group than in the Hepalean group (median, 516.0 seconds; interquartile range, 481.0-633.0; vs median, 584.0 seconds, interquartile range, 520.0-629.0; P=.418). Those given PPC heparin required a greater total heparin dose (median, 46,000.0 U; interquartile range, 39,500.0-60,000.0 vs median, 34,500.0 U; interquartile range, 32,250.0-37,000.0; P=.011) and a greater dose of heparin per kilogram than those given Hepalean (median, 572.9 U/kg; interquartile range, 443.0-659.7 vs median, 401.1 U/kg; interquartile range, 400.0-419.4; P=.003). The key secondary results included an increased median total protamine dose (median, 600.0 mg; interquartile range, 550.0-700.0; vs median, 500.0 mg; interquartile range, 425.0-542.5; P=.026) and a trend toward increased chest tube output within 24 hours (median, 830.0 mL; interquartile range, 425.0-1135.0; vs median, 702.5 mL; interquartile range, 550.0-742.5; P=.324). PPC heparin use was associated with greater heparin and protamine dose requirements than Hepalean. These findings indicate that heparin preparations are not interchangeable and suggest that a direct comparison of the potency with the brand in use is needed if a change is made to ensure that the agents exert similar anticoagulant effects invivo.

Protamine Dosage Based on Two Titrations Reduces Blood Loss After Valve Replacement Surgery: A Prospective, Double-Blinded, Randomized Study

BackgroundPostoperative hemorrhage following cardiopulmonary bypass in heart valve replacement patients may be caused by a mismatch of protamine and heparin. We hypothesized that a 2-titration-guided protamine dose would reduce protamine-heparin mismatch and bleeding in those patients. MethodsPatients scheduled for elective cardiac valve replacement surgery (N = 60) were randomly divided into 3 groups. All patients received 2 titrations: the first at termination of cardiopulmonary bypass and the second at 5 minutes after the initial dose of protamine. In the control group, the initial protamine dose was based on the heparin dose received; the supplemental protamine dose was empirically determined. In the single-titration group, the initial dose was based on the first titration, while supplemental dose was empirically determined. In the 2-titration group, both initial and supplemental doses were based on titrations. Bleeding volumes were recorded from the time of first protamine dose to 24 hours after surgery. ResultsMost patients needed supplemental protamine according to second titrations. In the 2-titration group, 12 patients received supplemental protamine, whereas only 1 patient in the single-titration group and 6 in the control group received supplemental protamine (P = 0.003). The blood loss was significantly less in the 2-titration group (526 ± 131 mL) than in the control group (730 ± 385 mL; P = 0.019). ConclusionsA higher dosage of protamine based on 2 titrations reduced blood loss after surgery, supporting the hypothesis that inadequate dosage of protamine contributes to hemorrhage after valve replacement surgery.

Anticoagulation monitoring during extracorporeal circulation with the Hepcon/HMS device

The objective of our study was to compare the standard protocol of anticoagulation to the Hepcon/HMS. This study included forty-four patients who underwent coronary bypass grafting surgery (CABG), or biological aortic valve replacement (AVR). Unfractionated heparin (UH) was used for patients who underwent operations in the control group (n = 22) (300U/Kg of UH with a goal of an ACT of 400s). The heparin was antagonized dose/dose by protamine. For the patients who underwent operations in the HMS group (n = 22), the heparin and protamine doses were assessed by the Hepcon/HMS device. The sex ratio amounted to 1.93 (29 men and 15 women) and the mean age was 70 ± 11 years. The patients in the HMS group had a chest closure time that was significantly shorter than patients in the control group. The times were, respectively, 42 ± 15 minutes and 68 ± 27 minutes (p = 0.001). The protamine/heparin ratio was significantly lower in the HMS group (0.62 ± 0.13 vs. 1 ± 0.11) (p = 0.0001). The postoperative bleeding amounted to 804 ± 729 ml in the HMS group versus 1416 ± 1103 in the control group (p = 0.016). In multivariate linear regression analysis, only two independent factors were significantly associated with bleeding: the Hepcon/HMS (OR = 0.1-p = 0.03) and the preoperative hemoglobin rate (OR = 1.4 - p = 0.05). Postoperatively, within 72 hours, the red blood cell transfusion was 1.04 ± 1.5 units for the HMS group and 2.1 ± 1.87 units for the control group (p = 0.05). During cardiac surgery under CPB, heparin and protamine titration with the Hepcon/HMS device could predict a lower protamine dose and lower postoperative bleeding without higher thromboembolic events, and lower perioperative red blood cell transfusion with a shorter chest closure time.

A Novel Polymer Based Antidote for Reversing the Anticoagulation Effect of Clinically Used Heparins,

Abstract 3359 IntroductionAnticoagulation is one of the most widely used and essential clinical practices in modern medicine. Heparins are universally used for the prevention of blood coagulation in surgical procedures and for the treatment of diseases such as venous thromboembolism (VTE). Unfractionated heparin (UFH), low and ultra-low molecular weight heparins (LMWHs&ULMWHs) and synthetic pentasaccharides such as fondaparinux and idraparinux are the most commonly used clinical anticoagulants. Heparin is the second most widely used drug after insulin. However, it is associated with bleeding complications and heparin induced thrombocytopenia. Hence a careful monitoring and neutralization of heparins is essential. Protamine is the only clinically approved antidote to UFH, but it has several side effects and is not effective against LMWHs and synthetic pentasaccharides. Hence there is an unmet clinical need to develop safer and more efficient antidotes for all these anticoagulants. Here, we report a novel polymer based antidote, heparin binding synthetic polyvalent cationic macromolecule (HBSPCM), that completely neutralizes UFH and LMWHs in vitro and in vivo and is highly biocompatible and non-toxic in the required therapeutic dose range. ExperimentalHBSPCMs were synthesized by the polymerization of glycidol and methoxy polyethylene glycol and functionalized with multifunctional tertiary amines as binding groups. Blood compatibility of HBSPCM was evaluated by activated partial thromboplastin time (APTT), prothrombin time (PT), thromboelastography (TEG), platelet and complement activation assays. Cell viability of HBSPCM was evaluated in human umbilical vein endothelial cells and fibroblast cells. Single dose tolerability in mice was studied by injecting escalating doses of HBSPCM and monitoring the body weights over a period of 29 days. HBSPCMs were tested for in vitro heparin neutralization by measuring the APTT in human plasma. An anti-fXa assay was used to study the in vivo neutralization of heparins by HBSPCM in a rat model. Pharmacokinetics and biodistribution of 3H-labeled HBSPCM was studied by bolus i.v. injection in female Balb/c mice and measuring the radioactivity in major organs at different time points. Results and DiscussionThe newly designed antidotes, HBSPCMs, alone do not show any adverse effect on blood coagulation, platelet and complement activation and cytotoxicity that reveal their excellent blood and cell compatibilities. When injected in mice, HBSPCMs were well-tolerated up to the maximum injected dose of 200 mg/kg, which is ten-fold higher than the maximum tolerated dose of protamine (20 mg/kg) (Figure 1). HBSPCMs were 20-times more efficient than protamine for neutralizing heparins in vitro, and unlike protamine they do not show anticoagulant effect at higher concentrations. In vivo studies in rats revealed complete neutralization of both UFH and LMWHs by HBSPCMs, and the neutralization activities for LMWHs were significantly higher than that of protamine (Figure 2). HBSPCMs and their heparin complexes showed rapid clearance through urine, without significant accumulation in major organs. [Display omitted] [Display omitted] Conclusions and SignificanceIn order to overcome the challenges associated with heparin based anticoagulation therapy, there is an increasing demand to develop safer, stable, effective, economical and universal antidotes which could neutralize all the available heparin anticoagulants. The developed polymer based antidote, HBSPCM, represents a major breakthrough towards this goal and could be a potential replacement for protamine. This polymer based therapeutic agent opens the scope for the development of non-toxic antidotes for all heparin based drugs. Disclosures:No relevant conflicts of interest to declare.

Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

BackgroundIn cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR).MethodsWe performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).Results160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.ConclusionsProlonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.Current Controlled Trials numberISRCTN: ISRCTN84413719

416 Improved surgical outcomes with the universal use of individualized heparin and protamine management system for pediatric cardiac surgery with cardiopulmonary bypass

In a recent clinical trial we established that the use of the Hemostatic Management System (HMS) with a pediatric-specific protocol, for the individualized management of heparin and protamine dosing during cardiac surgeries performed on patients <1 year of age resulted in enhanced anticoagulation and improved surgical outcomes. Based on the results of this study the HMS system was thereafter employed for all cardiac surgeries. We sought to determine whether the universal use of the HMS was associated improved program-wide post-operative outcomes. A total of 622 pediatric cardiac surgeries performed between April 2009 and August 2010 using the HMS were compared to 1,542 surgeries performed between July 2004 and December 2007, using standard weight-based heparin dosing using the activated clotting time for monitoring (HMS was evaluated/deployed between those 2 periods). Outcomes between the 2 periods were compared with adjustments for multiple patients and surgical characteristics in multivariable regression models. Patients and surgical characteristics between the pre-HMS and post-HMS era were similar. The HMS failed to achieve sufficiently high heparin blood concentration after the initial heparin bolus in 52% of cases and required an additional heparin bolus prior to bypass initiation. Most patients (361, 58%) received additional heparin during the surgery, despite normal activated clotting time (>400s). Patients in the post-HMS era required significantly lower amount of allogeneic red blood cell (87ml/kg vs. 118 ml/kg, P < 0.001) and platelets (8ml/kg vs. 14ml/kg, P < 0.001). Use of recombinant factor VIIa in post-operative period was less likely in the post-HMS era (1.1% vs. 3.5%, P = 0.03). Intubation time (9 vs. 27 hours, P < 0.001), intensive care unit stay (2 vs. 3 days, P = 0.009) and hospital stay (6.3 vs. 8.0 days, P = 0.02) were all shorter in the post-HMS period. Failure of the HMS system to achieve sufficient blood heparin concentration after the initial dose shows that further refinements in the pediatric protocol are necessary. Even considering this, the use of the HMS system for all pediatric cardiac surgeries was associated with system-wide improvement in post-surgical outcomes. Although the effect cannot be entirely ascribed to the use of the HMS because of additional concurrent changes in surgical and post-operative protocols, the reduction of allogeneic blood transfusions and bleeding-related complications suggest that the HMS system was a contributor to the improved surgical outcomes observed between the 2 periods.

Low‐Dose Protamine to Facilitate Earlier Sheath Removal from the Femoral Artery After Peripheral Endovascular Intervention

This study aimed to evaluate the safety of low-dose protamine administration to facilitate earlier vascular sheath removal. Vascular access complications are the most common cause of postprocedural morbidity in patients undergoing peripheral endovascular intervention (PEI). Prolonged manual compression and closure devices do not eliminate these complications. A consecutive series of 166 patients who underwent PEI were retrospectively compared to an all-comers control group of 136 patients who did not receive protamine. The study population received an intravenous dose of protamine based upon the dose of heparin received and the length of the procedure. The arterial sheath was removed when activated clotting time was less than 220 seconds. Primary end-points included bleeding complications, comprised of groin hematomas and retroperitoneal bleeding, and vascular complications, comprised of pseudoaneurysms, access vessel thrombosis, and arteriovenous fistula formation. The study population on average was older than the control group (71 vs. 67 years) and had a higher incidence of hypercholesterolemia (89.8% vs. 76.5%, P = 0.002). The average dose of protamine was 1.9 ± 0.83 mg, with a total dose of heparin of 5371 ± 1327 units. The time until sheath removal was 8.9 ± 8.6 minutes in the protamine group versus 188 ± 118 minutes in the control group (P < 0.001). There were no episodes of protamine anaphylaxis or adverse reactions. The access site complication rate between the 2 groups was statistically insignificant. This strategy offers an inexpensive, safe, and reliable method to achieve hemostasis and facilitate earlier sheath removal in patients undergoing PEI.

325 Regional Heparinization for Aquadex™ Ultafiltration System in Volume Overloaded Patients Using Heparin and Protamine

REGIONAL HEPARINIZATION FOR AQUADEX ULTAFILTRATION SYSTEM IN VOLUME OVERLOADED PATIENTS USING HEPARIN AND PROTAMINE Ruchir Trivedi, Andre A. Kaplan. University of Connecticut Health Center, Farmington, CT 06032 Regional anticoagulation with heparin-protamine or citrate has been successfully employed during CRRT. Citrate use is limited by the patient’s capacity to metabolize citrate, which is decreased if liver function or tissue perfusion is compromised. Citrate accumulation causes metabolic acidosis and resultant hypocalcemia can cause myocardial depression. We have previously described using regional heparinization with protamine during CRRT (Kaplan & Petrillo. Trans ASAIO 33:312, 1987). We now describe 2 patients with successful regional heparinization using the Aquadex ultrafiltration system. This system uses smaller, 6F dual lumen antecubital catheters with blood flows to 40 mL/min and ultrafiltration potential of 10-240 mL/hr. A 65 year old female with advance alcoholic cirrhosis and pulmonary hypertension presented with rapid onset edema, ascites and 25 Kg wt. gain. Low dose diuretic therapy resulted in rapid worsening of azotemia and creatinine. Patient was placed on ultrafiltration using Aquadex system with pre-filter heparinization at 800 IU/hr. and post-filter protamine at 8 mg/hr. Systemic PTT was monitored every 6 hours with operator modification of heparin and protamine dosage to keep systemic PTT 150 sec (166-200). Filter remained patent for 3 days. Renal function remained stable. These cases demonstrate that regional heparinization with protamine reversal in low flow ultrafiltration system is effective and safe with near normal systemic PTT and can be used in patients with cirrhosis where citrate based anticoagulation has significant potential toxicity.

The effects of protamine overdose on coagulation parameters as measured by the thrombelastograph

Protamine is routinely administered following cardiopulmonary bypass in order to neutralize the effects of heparin. An excess of protamine can contribute to coagulopathy, hence predisposing to bleeding with associated morbidity and mortality. Thromboelastography (TEG) is recognized as an invaluable bedside tool to detect coagulation parameters; however, the effects of protamine overdose on TEG parameters have not been fully established. Forty-six patients undergoing cardiac surgery using cardiopulmonary bypass were recruited in the study. Following heparinization, the patient's blood heparin level was measured using Hepcon HMS. Incremental doses of protamine [at a protamine-to-Hepcon-derived heparin ratio (PHR) of 1:1, 2:1 and 3:1] were added to patients' blood samples in vitro and four TEG coagulation parameters, including R (time to clot initiation), K (clot kinetics), alpha (clot kinetics) and maximum amplitude (ultimate clot strength), were monitored. Statistical analysis was performed using NCSS software. Protamine caused dose-dependent worsening of coagulation parameters on TEG; K was significantly elevated, whereas alpha and maximum amplitude showed significant reduction (P < 0.001) compared with baseline at a PHR of 2:1 and 3:1, respectively. R was significantly prolonged compared with baseline (P < 0.001) at a PHR of 3:1. Protamine adversely affects clot initiation time, clot kinetics and platelet function in a dose-dependent manner, which can predispose to bleeding.