Heparin Reversal Research Articles

Heparin reversal for coronary artery perforation

Abstract Background/Introduction In the management of coronary artery perforation (CAP) during percutaneous coronary intervention (PCI), heparin reversal can provide hemostatic effects but raises concerns about potential coronary thrombosis if an intracoronary artery guidewire or balloon is in place. Purpose We aimed to evaluate the safety and efficacy of heparin reversal during device insertion for CAP. We also aimed to determine the optimal target activated clotting time (ACT) to maintain when performing heparin reversal. Methods We analyzed cases of CAP which occurred during PCI procedures in a single center from January 2006 to October 2023. Patients were assigned to two groups according to whether they received heparin reversal with a device in place. The safety outcome was the periprocedural myocardial infarction (creatine kinase-MB >5 times the upper normal limit), and the efficacy outcome was successful hemostasis at the end of the procedures (complete absence of CAP on angiography). Results Among the 22,368 cases, 368 (1.6%) developed CAP, consisting of main vessels 45%, distal vessels 43%, and collateral vessels 12%. Heparin reversal with a device in place was implemented in 211 (57%) cases. Of these, 16 (7.6%) experienced coronary thrombosis. After adjusting covariates by the multivariable logistic regression model, heparin reversal with a device in place was significantly associated with a higher incidence of periprocedural myocardial infarction (11% vs 4.5%; adjusted OR: 3.11; 95% CI: 1.24–7.78; P = 0.015) and a higher rate of successful hemostasis (91% vs 73%; adjusted OR: 2.78; 95% CI: 1.27–6.09; P = 0.011). In the analysis of cases where minimum ACT value was available (n = 251), this value was significantly correlated with coronary thrombosis (r = −0.16, P = 0.012). When the cutoff values of minimum ACT were set at 200, 150, and 120 seconds as a binomial variable, the correlation coefficient was r = −0.08 (P = 0.158), r = −0.16 (P = 0.009), r = −0.20 (P = 0.001), respectively. Conclusions Heparin reversal after CAP with an intracoronary artery device in place was significantly associated with a higher incidence of periprocedural MI but also a higher rate of successful hemostasis. A minimum ACT value <150 seconds was significantly correlated with coronary thrombosis. These results propose a novel algorithm for CAP management strategies.Management algorithm for CAP

Onyx prevents the bleeding of ruptured aneurysms during interventional embolization.

Endovascular treatment has been acknowledged as an effective treatment for intracranial aneurysms, showcasing favorable clinical outcomes and providing robust protection against rebleeding and rupture. Notably, during the endovascular procedure, significant complications include intraprocedural aneurysmal rupture (IAR) induced by microcatheters, microguidewires, or spring coils, along with thromboembolic events, significantly escalating patient mortality and disability. Current approaches against for IARs involve various strategies such as heparin reversal, compression of the common carotid artery or upstream soft guidewire to mitigate blood flow, management of intracranial pressure and blood pressure, and balloon-assisted or unassisted rapid dense embolization of the aneurysm. Nevertheless, these measures may prove insufficient in halting hemorrhage, especially in scenarios where additional coils cannot be added for dense embolization due to inherent limitations. In this context, we introduce a novel strategy for the prompt, safe, and effective cessation of aneurysm bleeding, which involves injecting an appropriate quantity of Onyx into the aneurysm through a microcatheter while safeguarded by an aneurysm-carrying arterial braided stent. Initially, we attempted dense embolization by filling multiple coils. However, in cases where continued coil filling proved unfeasible or failed to sufficiently prevent contrast agent extravasation, we opted for Onyx injection into the aneurysm. Utilizing Onyx effectively prevented further blood extravasation without adversely impacting the aneurysm-carrying artery or distal vessels, leading to favorable prognoses for all patients. This article delineates our embolization strategy, highlighting the efficacy and safety of Onyx injection as an alternative or complementary measure in managing complications arising from endovascular coil embolization.

Protamine Dosing for Heparin Reversal Following Cardiopulmonary Bypass: A Double-Blinded Prospective Randomized Control Trial Comparing Two Strategies.

Drug shortages are a frequent challenge in current clinical practice. Certain drugs, (e.g., protamine) lack alternatives and inadequate supplies can limit access to services. Conventional protamine dosing uses heparin ratio-based calculations for heparin reversal following CPB and may result in excess protamine utilization, and potential harm due to its intrinsic anticoagulation. We hypothesized that a fixed 250-mg protamine dose would be comparable, as measured by the activated clotting time, to a 1:1 (1 mg for every 100 U) protamine to heparin ratio-based strategy for heparin reversal and that protamine would be conserved. In a single-center, double-blinded trial, consenting elective adult cardiac surgical patients without pre-existing coagulopathy or ongoing anticoagulation, and a calculated initial heparin dose of ≥ 27500 U were randomized to receive, following CPB, protamine as a fixed dose (250 mg) or a ratio-based dose (1 mg:100 U heparin). The primary outcome was the activated clotting time following initial protamine administration, assessed by Student's t-test. Secondary outcomes included total protamine, the need for additional protamine, and the cumulative 24-h chest tube output. There were 62 and 63 patients in the fixed- and ratio-based dose groups, respectively. The mean post-protamine ACT was not different between groups (-2.0 s, 95% CI -7.2 to 3.3 s, P = 0.47). Less total protamine per case was administered in the fixed-dose group (2.1 50-mg vials, 95% CI -2.4 to -1.8, P < 0.0001). There was no difference in the cumulative 24-h chest tube output (difference = -77 ml, 95% CI 220 to 65 ml, P = 0.28). A 1: 1 heparin ratio-based protamine dosing strategy compared to a fixed 250-mg dose resulted in the administration of a larger total dose of protamine no difference in either the initial ACT or the amount postoperative chest-tube bleeding.

Systematic review of clinical guidelines and consensus statements concerning heparin and protamine dosing and monitoring of anticoagulation levels for non-cardiac arterial procedures.

This systematic review was performed to examine all published practice Guidelines and Consensus Statements (together: GCS) on heparin dosing and monitoring during non-cardiac arterial procedures (NCAP). The objective was to scrutinize the recommendations and advice outlined within these GCS documents and to evaluate the supporting evidence for these recommendations. Additionally, the use of the activated clotting time (ACT) and target ACT values were explored. This systematic review was performed in accordance with the PRISMA Guidelines. Medline and Embase databases were searched to identify all GCSs in the English language on NCAP. The final literature search was performed in January 2023. This search was supplemented by searching websites of relevant professional vascular surgical organizations for GCSs. Titles and abstracts were assessed by two independent reviewers. Of 9716 titles identified, 27 GCSs met the predefined inclusion criteria: six GCSs regarding carotid intervention, seven regarding procedures for aneurysmal disease of the abdominal aorta and iliac arteries, 12 regarding interventions for acute and chronic peripheral arterial occlusive disease and two regarding open and endovascular interventions of thoraco-abdominal aortic aneurysms. Administration of heparin is advised for al NCAP. There was high variability concerning heparin dose: both standard dose as weight based dosing (30-150 IU/kg) was advised. Recommendations on repeated doses, ACT monitoring and heparin reversal using protamine also varied widely. In none of the GCSs, the type of the ACT measuring device or used cartridges were specified. Large variability was found between the included GCSs with regard to the recommendations on heparin dose and target ACT values during NCAP. Advice and recommendations in GCSs were based on low-quality studies or without providing any reference at all. The described variability in recommendations emphasizes the need for large prospective (randomized) studies or the incorporation of data on heparin and the use of ACT monitoring into verified vascular surgery registries, to develop evidence-based, practical and uniform applicable recommendations.

Safety and Efficacy of Management for Intraprocedural Rupture During Endovascular Treatment for Intracranial Aneurysms.

Although intraprocedural rupture (IPR) is rare, it is a devastating complication of endovascular treatment (EVT) for intracranial aneurysms. Very few studies have been conducted on IPR, and the safety and efficacy of management techniques of IPR have not been investigated. Patients who experienced IPR during EVT between 2013 and 2022 were enrolled from a multicenter observational registry. We examined the safety and efficacy of the management of IPR using imaging markers, including increased hemorrhage and ischemic lesions, which were evaluated using postoperative computed tomography and diffusion-weighted imaging, respectively. Of the 3269 EVTs for intracranial aneurysms, 74 patients who experienced IPR (2.26%) were analyzed. Fifty-five patients (3.36%) experienced IPR among 1636 EVT cases for ruptured aneurysms. Multivariate analysis revealed that increased hemorrhage was significantly associated with poor outcomes (odds ratio [OR], 6.37 [95% CI, 1.00-40.51], P = .050), whereas ischemic lesions were not. Regarding management techniques of IPR, antihypertensive medication use was significantly associated with increased hemorrhage (OR, 14.16 [95% CI, 2.35-85.34], P = .004). Heparin reversal was an independent factor for ischemic lesions (OR, 8.92 [95% CI, 1.54-51.58], P = .014). Although the setting of IPR may be miscellaneous, and optimal management varies depending on individual cases, heparin reversal might be associated with ischemic complications, and its role in the successful hemostasis in IPR during EVT for ruptured aneurysms remains unclear.

Assessment of Perioperative Protamine Reactions in Patients With Fish Allergies: A Retrospective Observational Study

ObjectivesThis study retrospectively assessed the incidence and severity of perioperative protamine reactions in adult patients with documented history of fish allergy. DesignRetrospective, observational. SettingLarge, academic tertiary referral center. ParticipantsAdults with fish allergies undergoing surgeries involving protamine, from January 1, 2008, to March 1, 2018. InterventionsPerioperative protamine administration in patients with documented fish allergy. Measurements and Main ResultsWe reviewed perioperative protamine and anaphylactic reactions. A diagnosis of anaphylaxis or protamine reaction was based on clinical suspicion, perioperative events, and postoperative evaluations. Among 214 patients, two cases (<1%) of anaphylaxis or protamine reactions occurred. Cardiac procedures were most common (67%). Median intraoperative heparin dosage was 46,000 IU, and protamine dosage was 310 mg. Nearly all patients (99%) were admitted to the ICU postoperatively, with a median hospital stay of 6.5 days [5.2, 14.6]. There were three deaths (1%) within 30 days and 15 (7%) within a year. ConclusionsOur study suggests that in patients with history of fish allergy, cross-reactivity with protamine is unlikely, as anaphylaxis and/or protamine reactions were rare among this patient population in the perioperative environment. Based on the findings herein, this study does not recommend avoiding protamine solely based on a history of fish allergy when heparin reversal is required during surgery.

Heparin reversal through an entire encapsulation strategy by giant macrocycles

Heparin reversal through an entire encapsulation strategy by giant macrocycles

Objective randomised blinded investigation of therapeutic ablation versus cardioversion for persistent atrial fibrillation- outcomes of the feasibility

Abstract Background Patients with persistent atrial fibrillation (pers.AF) commonly undergo catheter ablation (CA) for symptom relief and improved quality of life(QoL). However,the benefits of CA compared to DC cardioversion (DCCV) or medical therapy lack substantial evidence from blinded randomized trials. Purpose Conducting such a large-scale trial presents substantial challenges in terms of recruitment, maintaining blinding, and implementation.To address this, we conducted a pilot study prior to a definitive larger study. Methods This feasibility trial is a single-centre, prospective, randomised, double-blinded placebo control study. Patients with early pers AF (&amp;lt;2 years) eligible for pulmonary vein isolation (PVI) or DCCV were enrolled. Twenty patients were recruited, accounting for 10% of the proposed larger trial based on power calculation. The intervention arm (PVI + DCCV) and placebo arm (Placebo + DCCV) were randomised in a 1:1 manner after ultrasound-guided vascular access with local anaesthetic and deep sedation (Midazolam + opioid). All procedures were performed as day cases on uninterrupted oral anticoagulation. Phrenic nerve pacing was performed in the Placebo group, mimicking lab interactions and fluoroscopy system movements. Implantable loop monitors were inserted immediately after heparin reversal and groin sheath removal. A 6-week(wk) blanking period was observed post-procedure. Blinding was assessed using Bang's blinding index (BI) for both patients and medical staff and a successful blinding is considered BI between -0.2 to 0.2. Health-related quality of life (HRQoL) was evaluated using SF12, EQ5D-5L, and AF PROMS. The study obtained ethical approval (REC ref 19/LO/0775),adhered to the principles of the Declaration of Helsinki,and obtained written informed consent from all participants. Results A remarkable 92% of patients approached, expressed a willingness to participate in the study. Procedure time and time to discharge were similar between groups. The study successfully achieved blinding among the patients at day0 (BI = PVI-0.2 vs placebo- 0) and was maintained throughout the 6-wk and 3M follow-up, among the patients as well as clinical staff. HRQoL improved in the active group in terms of AF PROMS [Improved difference from baseline PVI 23 (±22); vs Placebo 2 (±10), p=&amp;lt;0.001 and SF-12 mental component (MCS) at 12M (PVI 11.8 (±11) vs placebo 8.54(±11.5), p= 0.017). Over a follow up period of 12M, there was a trend towards greater recurrence (60% vs 30%; p=0.07) and repeat procedures (70% vs 40%; p=0.4) in the placebo group. Conclusion: Performing a blinded placebo-controlled interventional study to assess the efficacy of PVI is feasible and high recruitment rates are achievable. CA appears to result in better arrhythmic and QoL outcomes;a full-scale follow-on study will assess the true efficacy of CA in patients with early pers.AF and allow consideration of whether there is a role for DCCV in many patients.

Case report: Tenecteplase for acute ischemic stroke after heparin reversal

Intravenous thrombolysis can be administered to appropriate patients with suspected acute ischemic strokes who are on intravenous heparin infusions after its rapid reversal with protamine sulfate. Several case reports suggest the safety of tissue-type plasminogen activator, or alteplase, in these scenarios. Noting the increasing preferential use of tenecteplase over alteplase for intravenous thrombolysis of acute ischemic stroke, the safe and efficacious use of tenecteplase following heparin reversal has not been demonstrated in the literature. Our case demonstrates successful use of intravenous tenecteplase in a patient who was anticoagulated with therapeutic heparin. The patient had no hemorrhagic complications and had an excellent neurological outcome.

External Trigger Free Charge Switchable Cationic Ligands in the Design of Safe and Effective Universal Heparin Antidote.

Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin-based anticoagulants such as unfractionated heparin, low-molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA-approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin-binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.

INHIBITORS OF INORGANIC POLYPHOSPHATE AND NUCLEIC ACIDS ATTENUATE IN VITRO THROMBIN GENERATION IN PLASMA FROM TRAUMA PATIENTS.

Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Effect of Retrograde Autologous Priming on Coagulation Assessed by Rotation Thromboelastometry in Patients Undergoing Valvular Cardiac Surgery

ObjectivesTo investigate the effect of retrograde autologous priming (RAP) on coagulation function using rotation thromboelastometry (ROTEM) in patients undergoing valvular heart surgery. DesignProspective, randomized, patient- and outcome assessor-blinded study. SettingSingle-center university hospital. ParticipantsPatients aged 20 years or more undergoing valvular heart surgery. Interventions104 patients were allocated to the RAP or control group (1:1 ratio). In the RAP group, the prime was displaced into the collection bag before bypass initiation. ROTEM was performed at the induction of anesthesia, at the beginning of rewarming, and after the reversal of heparinization. Allogeneic plasma products and platelet concentrates were transfused according to ROTEM-based algorithms. Measurements and Main ResultsAn average volume of 635 ± 114 mL was removed using RAP (from the 1,600 mL initial prime volume). The hematocrit 10 min after CPB was 24.7 ± 3.5% in the control group and 26.1 ± 4.1% in the RAP group (P=0.330). ROTEM including EXTEM, INTEM, and FIBTEM showed prolonged clotting time and decreased maximal clot firmness after CPB in both groups, without intergroup differences. The number of patients who received intraoperative erythrocyte (27% vs. 25%, control vs. RAP, P=0.823), fresh frozen plasma (14% vs. 8%, control vs. RAP, P=0.339), cryoprecipitate (21% vs. 12%, control vs. RAP, P=0.185), or platelet concentrate transfusion (19% vs. 12%, control vs. RAP, P=0.277) did not differ between the groups. ConclusionsCPB induced impaired coagulation function on ROTEM. However, RAP did not improve coagulation function when compared with conventional priming in patients undergoing valvular heart surgery.

Negative Effects Of Protamine On Myocardium In Paediatrics Patients Undergoing Cardiac Surgery Using A Cardiopulmonary Bypass Machine

The administration of protamine, a heparin reversal agent, is an integral part of cardiovascular bypass protocols, particularly in the post-bypass phase. In paediatric cases, protamine is administered in a titration dose. The use of protamine is associated with various adverse events, including myocardial impairment. Proper dosage adjustment is crucial during protamine administration, as excessive doses may result in the depression of myocardial function. Experimental studies examining protamine usage have revealed myocyte impairments, such as reduced myocyte contractility, dysfunction in signaling pathways, and alterations in cardiac receptors. Despite these findings, research on the impact of pediatric protamine on the myocardium remains limited and necessitates further investigation.

Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study.

It has been suggested that a larger heparin dose during cardiopulmonary bypass (CPB) is associated with reduced perioperative coagulopathy and thromboembolic complications. We investigated the effect of different heparin doses during routine elective cardiac surgery. Our primary outcomes include blood loss and transfusion and secondary outcomes investigate the effects on coagulation biomarkers. In this prospective pilot trial, we allocated 60 patients undergoing cardiac surgery on CPB in a single tertiary cardiac centre into three groups to receive an initial dose of 300, 400, or 500 units (U) per kilogram of intravenous heparin prior to the commencement of CPB. Blood was sampled after induction of anesthesia, at 30 and 60min of CPB, and three minutes after heparin reversal with protamine. Samples were analyzed for fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimer, and thrombin-antithrombin (TAT) complexes. Postoperative blood loss and transfusion was measured for the first 24-hr period after surgery. The total mean (95% CI) administered heparin dose in the 300U·kg-1, 400U·kg-1, and 500U·kg-1 groups were 39,975 (36,528 to 43,421) U, 43,195 (36,940 to 49,449) U and 47,900 (44,807 to 50,992) U, respectively. There were no statistically significant differences in FPA, FPB or D-dimer levels at the measured time intervals. There was a trend towards lower TAT levels while on CPB with greater heparin dosing, which was statistically significant after the administration of protamine. The clinical significance appears to be negligible, as there is no difference in overall blood loss and amount of packed red blood cell transfusion or other blood product transfusion. This pilot study indicates that, while larger heparin dosing for routine cardiac surgery results in subtle biochemical changes in coagulation, there is no demonstrable benefit in postoperative blood loss or transfusion requirements.

Safety and efficacy of protamine administration for prevention of bleeding complications in patients with recent PCI undergoing TAVR

Abstract Background Despite major advances, TAVR is still associated with vascular and bleeding complications, that have an impact on mortality. Recent studies have shown that heparin antagonization using protamine resulted in lower bleeding rates in patients undergoing TAVR as compared to those without heparin reversal. However, there are only limited data on the safety of protamine regarding thromboembolic complications including in-stent thrombosis in TAVR patients who have had a recent PCI. Accordingly, daily practice varies between Centers. Purpose The aim of this multicentre study was to evaluate the safety and efficacy of protamine administration in patients who have had a recent PCI undergoing subsequent TAVR. Methods Our study included 1838 patients undergoing TAVI between 2017 and 2020. Of the patients included, 173 (9.4%) had a recent PCI (≤30 days), 319 (17.4%) had an intermediately (≥30 days) and 303 (16.5%) a previously performed PCI (≥6 months). Standardized vascular access management included the use of preclosure devices and PTA or implantation of a stent-graft, if necessary. The primary endpoint was a composite of one-year mortality and myocardial infarction at 30 days. Secondary endpoints included 30-day mortality and VARC-3-defined complications. Results The overall study population had a mean age of 81.1±6.2 years. Among patients with recent PCI, 134 (77.5%) patients received protamine for heparin reversal during the TAVR procedure. In the group of patients with intermediately and previously performed PCI 258 (80.9%) and 249 (82.2%) patients received protamine, respectively. In the recent PCI group, the occurrence of the primary endpoint was comparable between patients with protamine administration (24.6%) as compared to patients without heparin reversal (30.8%, p=0.53, Figure 1). Similarly, among patients with intermediately as well as previously performed PCI, the rates of the primary endpoint were comparable irrespective of protamine administration (20.1 vs 16.4%, p=0.59; 17.3 vs 27.7%, p=0.08, respectively, Figure 2). Moreover, among all three groups, the incidence of myocardial infarction at 30 days after TAVR was low and comparable between patients with and without heparin reversal (p&amp;gt;0.50). Overall, protamine administration was associated with decreased life-threatening bleeding (3.2 vs 9.4%, p&amp;lt;0.01) and major vascular complications (4.4 vs 7.9%, p=.02). Regarding safety endpoints, no overall differences were observed in the incidence of stroke between patients with and without protamine administration (1.5 vs 2.9%, p=0.13). Conclusion Protamine administration during the TAVR procedure did not increase the rate of myocardial infarction or one-year mortality in patients who have had a recently or intermediately performed PCI. Overall, heparin reversal using protamine resulted in significantly lower rates of life-threatening bleeding and major vascular complications, without increasing the incidence of stroke.Figure 1Figure 2

Does heparin rebound lead to postoperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass?

Heparin rebound is a common observed phenomenon after cardiac surgery with CPB and is associated with increased postoperative blood loss. However, the administration of extra protamine may lead to increased blood loss as well. Therefore, we want to investigate the relation between heparin rebound and postoperative blood loss and the necessity to provide extra protamine to reverse heparin rebound. We searched PubMed, Cochrane, EMBASE, Google Scholar and Web of Science to review the question: "Does heparin rebound lead to postoperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass." Combination of search words were framed within four major categories: heparin rebound, blood loss, cardiac surgery and cardiopulmonary bypass. All studies that met our question were included. Quality assessment was performed using the Cochrane risk of bias (RoB2) tool for randomized controlled trials and the risk of bias in non-randomized studies of intervention (ROBINS-I) for non-randomised trials. 4 randomized and 17 non-randomized studies were included. The mean incidence of heparin rebound was 40%. The postoperative heparin levels, due to heparin rebound, were often below or equal to 0.2 IU/mL. We could not demonstrate an association between heparin rebound and postoperative blood loss or transfusion requirements. However the quality of evidence was poor due to a broad variety of definitions of heparin rebound, measured by various coagulation tests and studies with small sample sizes. The influence of heparin rebound on postoperative bleeding seems to be negligible, but might get significant in conjunction with incomplete heparin reversal or other coagulopathies. For that reason, it might be useful to get a picture of the entire coagulation spectrum after cardiac surgery, as can be done by the use of a viscoelastic test in conjunction with an aggregometry test.

Safety and efficacy of the CELT ACD femoral arteriotomy closure device in the office-based laboratory.

Manual compression remains the gold standard for achieving hemostasis for percutaneous common femoral artery access. However, it requires prolonged bedrest and 20 to 30minutes or more of compression for hemostasis. Current arterial closure devices have emerged in recent years, but patients still require prolonged bedrest and time to ambulation and discharge, and these devices are associated with significant access device complications, including hematoma, retroperitoneal bleeding, transfusion requirement, pseudoaneurysm, arteriovenous fistula, and arterial thrombosis. A novel femoral access closure device, the CELT ACD (Vasorum Ltd, Dublin, Ireland), has been previously shown to reduce these complication rates and allow rapid hemostasis, require little or no bedrest, and shortened time to ambulation and discharge. This is especially advantageous in the outpatient setting. We report our initial experience with this device. A prospective single-center single-arm study was performed in an office-based laboratory setting to assess the safety and efficacy of the CELT ACD closure device. Patients underwent diagnostic and therapeutic peripheral arterial procedures from retrograde or antegrade common femoral artery access. Primary endpoints include device deployment success, time to hemostasis, and major or minor complications. Secondary endpoints include time to ambulation and time to discharge. Major complications were defined as bleeding requiring hospitalization or blood transfusion, device embolization, pseudoaneurysm formation, and limb ischemia. Minor complications were defined as bleeding not requiring hospitalization/blood transfusion, device malfunction, and access site infection. A total of 442 patients were enrolled with common femoral access only. Median age was 78years (range, 48-91years), and 64% were male. Heparin was given in all cases, with median heparin dose of 6000 units (range, 3000-10,000 units). Protamine reversal was used in 10 cases due to minor soft tissue bleeding. Average time to hemostasis was 12.1seconds (±13.2seconds), time to ambulation was 17.1minutes (±5.2minutes), and time to discharge was 31.7minutes (±8.9minutes). All devices (100%) were deployed successfully. No major complications occurred (0%). Ten minor complications (2.3%) occurred; all were minor soft tissue bleeding from the access site that resolved with protamine reversal of heparin and manual compression. The CELT ACD closure device is safe and easily deployed with a very low complication rate, and significantly reduces time to hemostasis, ambulation, and discharge in patients undergoing peripheral arterial intervention from a common femoral artery approach in the office-based laboratory setting. This is a promising device that deserves further evaluation.

Prognostic Factors for Postoperative Bleeding Complications and Prolonged Intensive Care after Percutaneous Hepatic Chemosaturation Procedures with Melphalan.

Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PurposePercutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.Materials and methodsAll patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).ResultsThromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.ConclusionOur retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Safety of routine protamine in the reversal of heparin in percutaneous coronary intervention: A systematic review and meta-analysis

ObjectivesTo determine the safety and efficacy of protamine in the reversal of heparin in percutaneous coronary intervention (PCI). BackgroundHeparin is routinely used for anticoagulation in PCI. Protamine is not used routinely to reverse heparin's effects in PCI, partly due to the perceived risk of stent thrombosis. MethodsRelevant studies published in English were searched for in PubMed, Embase, and Cochrane databases from inception to April 26th, 2023. Our primary outcome of interest was stent thrombosis in patients receiving PCI for all indications. Secondary outcomes included mortality, major bleeding complications, and hospitalization length. Dichotomous outcomes were analyzed using a Mantel-Haenszel random-effects model and expressed as odds ratios (OR) with their 95% confidence intervals (CI), while continuous outcomes were analyzed using an inverse variance random-effects model expressed as mean differences (MD) with their 95% CI. Results11 studies were included in our analysis. Protamine use was not associated with stent thrombosis: OR 0.58, 95% CI: 0.33, 1.01 (p = 0.05) nor with mortality (p = 0.89). Protamine administration was associated with a decreased incidence of major bleeding complications: OR 0.48; 95% CI: 0.25, 0.95 (p = 0.03) and decreased length of hospitalization (p < 0.0001). ConclusionsIn patients pre-treated with dual antiplatelet therapy (DAPT), protamine may be a safe and efficacious option to facilitate earlier sheath removal, reduce major bleeding complications, and reduce length of hospitalization without increased risk of stent thrombosis.