Protamine dosing and its impact in cardiac surgery transfusion practice-A retrospective bi-institutional analysis.

BACKGROUND: Bleeding after cardiac surgery is common and continues to require 10-20% of the national blood supply. Transfusion of allogeneic blood is associated with increased morbidity and mortality. Excessive protamine in the absence of circulating heparin after weaning off CPB can cause anticoagulation and precipitate bleeding. Hence, adequate dose calculation of protamine is crucial yet under evaluated. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a retrospective bi-institutional analysis of cardiac surgical patients who underwent cardiopulmonary bypass (CPB)-assisted cardiac surgery to assess the impact of protamine dosing in transfusion practice. Total 762 patients were identified from two institutions using electronic medical records and the Society of Thoracic Surgery (STS) database who underwent cardiac surgery using CPB. Patients were similar in demographics and other baseline characteristics. We divided patients into two groups based on mg of protamine administered to neutralize each 100 U of unfractionated heparin (UFH)-low-ratio group (Protamine: UFH ≤ 0.8) and high-ratio group (Protamine: UFH > 0.8). RESULTS: We observed a higher rate of blood transfusion required in high-ratio group (ratio >0.8) compared with low-ratio group (ratio ≤0.8) (p < .001). The increased requirement was consistently demonstrated for intraoperative transfusions of red blood cells, plasma, platelets, and cryoprecipitate. CONCLUSION: High protamine to heparin ratio may cause increased bleeding and transfusion in cardiac surgical patients. Protamine to heparin ratio of 0.8 or lower is sufficient to neutralize circulating heparin after weaning off cardiopulmonary bypass.

Evaluating a unique enhanced recovery protocol in laparoscopic donor nephrectomy: A single center experience.

INTRODUCTION: Enhanced recovery after surgery (ERAS) protocols have been associated with a reduction in opioid consumption and a hastening in recovery in abdominal surgery. However, their impact on laparoscopic donor nephrectomy (LDN) has not been fully elucidated. The aim of this study is to evaluate opioid consumption and other relevant outcome measures before and after implementation of a unique LDN ERAS protocol. METHODS: 244 LDN patients were included in this retrospective cohort study. Forty-six underwent LDN prior to implementation of ERAS, whereas 198 patients received ERAS perioperative care. The primary outcome was daily oral morphine equivalent (OME) consumption averaged over the entire postoperative stay. Due to removal of preoperative oral morphine from the protocol partway through the study period, the ERAS group was further subdivided into morphine recipients and non-recipients for subgroup analysis. Secondary outcomes included the incidence of postoperative nausea and vomiting (PONV), length of stay, pain scores, and other relevant measures. RESULTS: ERAS donors consumed significantly fewer average daily OMEs than Pre-ERAS donors (21.5 vs. 37.6, respectively; p < .0001). There were no statistically significant differences in OME consumption between morphine recipients and non-recipients. The ERAS group experienced less PONV (44.4% requiring one or more rescue antiemetic postoperatively, vs. 60.9% of Pre-ERAS donors; p = .008). CONCLUSIONS: A protocol pairing lidocaine and ketamine with a comprehensive approach to preoperative PO intake, premedication, intraoperative fluid management and postoperative pain control is associated with reduced opioid consumption in LDN.

Roles of Four-Factor Prothrombin Complex Concentrate in the Management of Critical Bleeding.

Four-factor prothrombin complex concentrate (4F-PCC) is the term used to describe a pathogen-reduced, lyophilized concentrate that contains therapeutic amounts of at least 4 coagulation factors: Factor II (FII), Factor VII (FVII), Factor IX (FIX), and Factor X (FX). 4F-PCC has proven to be an effective hemostatic agent compared to plasma transfusion in several prospective randomized trials in acute warfarin reversal. In recent years, 4F-PCC has been used in various acquired coagulopathies including post-cardiopulmonary bypass bleeding, trauma-induced coagulopathy, coagulopathy in liver failure, and major bleeding due to anti-FXa (anti-Xa) inhibitors (eg, rivaroxaban and apixaban). As transfusion of frozen plasma (FP) has not been found efficacious in the above critical bleeding scenarios, there is increasing interest in expanding the use of 4F-PCC. However, efficacy, safety, and clinical implications of expanded use of 4F-PCC have not been fully elucidated. Prothrombin time and international normalized ratio are commonly used to assess dose effects of 4F-PCC. Prothrombin time/international normalized ratio are standardly use for warfarin titration, but they are not suited for real-time monitoring of complex coagulopathies. Optimal dosing of 4F-PCC outside of the current approved use for vitamin K antagonist reversal is yet to be determined. In this review, we will discuss the use of 4F-PCC in four critical bleeding settings: cardiac surgery, major trauma, end-stage liver disease, and oral anti-Xa reversal. We will discuss recent studies in each area to explore the dosing, efficacy, and safety of 4F-PCC.

Clotting Time Results Are Not Interchangeable Between EXTEM and FIBTEM on Rotational Thromboelastometry.

OBJECTIVE: To explore how cytochalasin D (CyD) affects clot initiation and to compare clotting times (CTs) of EXTEM and FIBTEM on rotational thromboelastometry in cardiac surgical patients undergoing cardiopulmonary bypass (CPB). DESIGN: Retrospective cohort study with translational in vitro coagulation experiments. SETTING: Single-center, tertiary, academic medical center. PARTICIPANTS: Patients who underwent cardiac surgery with CPB between November 2015 and August 2017. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study's primary measurements were CTEXTEM and CTFIBTEM before and after CPB. Additionally, the authors performed translational in vitro coagulation experiments using commercial plasma. In these experiments, the impact of CyD on in vitro thrombin generation (TG) was assessed using 10 platelet-rich plasma (PRP) samples and calibrated automated thrombogram. The impact of CyD on ROTEM-CT also was evaluated in vitro using the same 10 PRP samples. One hundred fifty-three patients had clinical CTEXTEM and CTFIBTEM measurements. CTFIBTEM was shorter than CTEXTEM before and after CPB by 6.8% (95% confidence interval [CI], 5.5-8.1) and 8.9% (95% CI, 4.7-13.0), respectively. These results correlated with in vitro experiments, where TG lag time was shortened by CyD and CTFIBTEM was shorter than CTEXTEM. CONCLUSION: CyD shortens the onset of TG and clot formation, resulting in shorter CTFIBTEM than CTEXTEM. The authors' data suggest that CTEXTEM and CTFIBTEM are not interchangeable. Additional clinical studies are warranted to assess if CTFIBTEM can be used to optimize the indication for plasma transfusion.

Reversal of Vasodilatory Shock: Current Perspectives on Conventional, Rescue, and Emerging Vasoactive Agents for the Treatment of Shock.

Understanding the different mechanisms of vasoconstrictors is crucial to their optimal application to clinically diverse shock states. We present a comprehensive review of conventional, rescue, and novel vasoactive agents including their pharmacology and evidence supporting their use in vasodilatory shock. The role of each drug in relation to the Surviving Sepsis Guidelines is discussed to provide a context of how each one fits into the algorithm for treating vasodilatory shock. Rescue agents can be utilized when conventional medications fail, although there are varying levels of evidence on their clinical effectiveness. In addition, novel agents for the treatment of vasodilatory shock have recently emerged such as ascorbic acid and angiotensin II. Ascorbic acid has been used with some success in vasoplegia and is currently undergoing a more rigorous evaluation of its utility. Angiotensin II (Ang-2) is the newest available vasopressor for the treatment of vasodilatory shock. In addition to its catecholamine-sparing properties, it has been shown to hold promising mortality benefits in certain subsets of critically ill patients.

Coagulation Factor Levels and Underlying Thrombin Generation Patterns in Adult Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: There is a paucity of data on the underlying procoagulant-anticoagulant balance during extracorporeal membrane oxygenation (ECMO). We hypothesized that adult ECMO patients would have an imbalance between procoagulant and anticoagulant factors, leading to an abnormal underlying thrombin generation (TG) pattern. METHODS: Twenty adult venoarterial (VA) ECMO patients had procoagulant and anticoagulant factor levels measured temporally on ECMO day 1 or 2, day 3, and day 5. In heparin-neutralized plasma, underlying TG patterns, and sensitivity to activated protein C were assessed using calibrated automated thrombogram. TG parameters including lag time, peak TG, and endogenous thrombin potential (ETP) were compared against 5 normal plasma controls (3 males and 2 females) obtained from a commercial supplier. Thrombomodulin (TM) was added to some samples to evaluate for activated protein C resistance. RESULTS: Procoagulant factors (factor [F] II, FV, and FX) were mostly in normal reference ranges and gradually increased during the first 5 ECMO days (P = .022, <.001, <.001). FVIII levels were elevated at all time points and did not change (P = .766). In contrast, FXI was in the low-normal range but did not increase during ECMO (P = .093). Antithrombin (AT) and protein C levels were below normal but increased during the first 5 ECMO days (P = .002 and P = .014). Heparinase-treated samples showed prolonged lag time, increased peak TG, and increased ETP compared to controls; mean difference in lag time on ECMO day 1 or 2 = 6.0 minutes (99% confidence interval [CI], 2.8-9.2), peak TG = 193.4 (99% CI, 122.5-264.3), and ETP = 1170.4 (99% CI, 723.2-1617.6). After in vitro TM treatment, differences in TG parameters were accentuated and ECMO samples appeared insensitive to TM treatment; mean difference in lag time on ECMO day 1 or 2 = 9.3 minutes (99% CI, 6.2-12.4), peak TG = 233.0 (99% CI, 140.9-325.1), and ETP = 1322.5 (99% CI, 764.8-1880.2). Similar differences in TG parameters were observed on ECMO days 3 and 5. CONCLUSIONS: Contact activation occurs during ECMO, but procoagulant factor levels are generally preserved. Although heparin-neutralized TG is delayed, peak TG and ETP are supranormal in the setting of high FVIII and low AT and protein C levels. Resistance to TM is also apparent. These changes demonstrate a possible mechanism for hypercoagulability during adult VA ECMO.

Perioperative clinical utility of myocardial deformation imaging: a narrative review.

Preoperative cardiac function is an important predictor of postoperative outcomes. Patients with heart failure are at higher risk of perioperative morbidity and mortality. Left ventricular ejection fraction, derived by standard echocardiography, is most frequently used to assess cardiac function in the intraoperative and postoperative periods. Myocardial strain analysis, a measurement of myocardial deformation, can provide additional information to left venricular eject fraction estimation. Here, we provide an overview of myocardial strain and different methods used to evaluate strain, including speckle tracking echocardiography. Speckle tracking echocardiography is an imaging modality that can analyse and track small segments of the myocardium, which provides greater detail for assessing global and regional cardiac motion and function. We further review the literature to illustrate the value of speckle tracking echocardiography-derived myocardial strain in describing cardiac function and its association with adverse surgical outcomes in the perioperative period, including low cardiac output states, need for inotropic support, postoperative arrhythmias, subclinical myocardial ischaemia, and length of hospital stay.

Clinical Impact of Protamine Titration-Based Heparin Neutralization in Patients Undergoing Coronary Bypass Grafting Surgery.

OBJECTIVES: A hemostasis management system (HMS) is a point-of-care method for heparin and protamine titration. The authors hypothesized that protamine dosing over the HMS estimate would be associated with elevated activated clotting time (ACT), increased bleeding, and transfusion owing to protamine's anticoagulant activity. DESIGN: A retrospective cohort study. SETTING: Single-center university hospital. PARTICIPANTS: One hundred eighty-nine patients undergoing elective coronary artery bypass grafting surgery. INTERVENTIONS: Patients were stratified into 3 groups per ratio of actual total administered protamine versus the HMS-derived protamine estimate: (1) low-ratio (≤66% of HMS estimate), (2) moderate-ratio (66%-100% of HMS estimate), and (3) high-ratio (>100% of HMS estimate). MEASUREMENTS AND MAIN RESULTS: The primary endpoints were post-protamine ACT, and residual heparin levels on HMS among the 3 groups in addition to bleeding and transfusion. There were 54 (28.6%) patients in the low, 95 (50.3%) in the moderate, and 40 (21.2%) in the high-ratio group. The high-ratio patients who were overdosed with protamine relative to the HMS estimate had elevated ACT, international normalized ratio, and activated partial thromboplastin time values, and subsequently received more red blood cell (RBC) and non-RBC transfusions compared to lower-ratio groups. Higher actual/HMS protamine ratios were associated independently with post-protamine ACT elevations after adjustment for sex, body mass index (BMI), and cardiopulmonary bypass (CPB) time. CONCLUSION: Most patients received the protamine dose sufficiently close to the HMS estimate, but protamine dosing above the HMS estimate occurred in both obese and nonobese patients, which was associated independently with prolonged ACT after adjusting for sex, BMI, and CPB time.

Von Willebrand Factor-GP1bα Interactions in Venoarterial Extracorporeal Membrane Oxygenation Patients.

OBJECTIVE: Evaluate extracorporeal membrane oxygenation (ECMO) patients' platelet adhesion and aggregation under shear stress and determine whether addition of von Willebrand factor (VWF) concentrate improves platelet function. Also, explore whether reduced platelet adhesion and aggregation is associated with clinical bleeding during ECMO. DESIGN: Prospective observational cohort study with translational component. SETTING: Academic medical center. PARTICIPANTS: Consecutive venoarterial (VA) ECMO patients were screened and 20 patients enrolled. INTERVENTIONS: VWF multimers, VWF antigen, ristocetin cofactor activity, and plasma glycocalicin levels were measured and values were compared at study points: ECMO day 1 or 2, day 3, and day 5. Platelet adhesion and aggregation were measured in vitro using the total thrombus analysis system. Platelet function was expressed as area under the flow-pressure curve (AUC). VWF concentrate was added in vitro and the AUC after VWF supplementation (VWF AUC) was compared with baseline AUC. Further, baseline AUCs and VWF AUCs were compared between patients who experienced bleeding during ECMO and those who did not. MEASUREMENTS AND MAIN RESULTS: ECMO patients had high VWF antigen levels, high ristocetin cofactor activity, and large VWF multimer loss. Platelet counts fell over the first 5 days on ECMO, and plasma glycocalicin levels were elevated mildly. ECMO patients had severely low platelet adhesion and aggregation in vitro: median AUC = 5.8 (3.5-9.7) ECMO day 1 or 2, median AUC = 6.3 (5.3-11.1) day 3, and median AUC = 5.5 (4.1-8.1) day 5. There was no significant change in AUC over time (p = 0.47). Addition of VWF concentrate increased the AUC compared to baseline at each point (all p < 0.05), but VWF AUC values remained low. Patients with bleeding during ECMO had a low VWF AUC at all points, whereas those without bleeding had a higher VWF AUC on ECMO day 3. CONCLUSIONS: VA ECMO patients have severely impaired platelet function, which improved but did not normalize with VWF concentrate. The data suggest that GP1bα receptor loss of dysfunction also contributes to impaired platelet adhesion and aggregation during ECMO. Based on these findings, clinical bleeding in ECMO patients is unlikely to be correctable with VWF supplementation alone.

Recent update on coagulation management and hemostatic therapies in liver transplantation.

Liver transplantation is an ever-evolving field and understanding coagulation management and hemostatic therapies is essential for good outcomes. In this review, we discuss current monitoring tools available in the operating room and the hemostatic agents available to control hemostasis. Multifactorial coagulation defects are discussed and point-of care monitoring is reviewed to guide selection of hemostatic agents when indicated.

Contemporary Single-Center Experience With Prophylactic Cerebrospinal Fluid Drainage for Thoracic Endovascular Aortic Repair in Patients at High Risk for Ischemic Spinal Cord Injury.

OBJECTIVE: To review rates of permanent paraplegia and lumbar drain-related complications in patients undergoing thoracic endovascular aortic repair (TEVAR) surgery with prophylactic cerebrospinal fluid (CSF) drainage at the authors' institution. DESIGN: Retrospective cohort study. SETTING: Tertiary care, academic medical center. PARTICIPANTS: Patients who underwent TEVAR with a high risk for ischemic spinal cord injury and prophylactic lumbar CSF drainage over a 5-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred and two patients underwent TEVAR with lumbar CSF drainage. Thirty-day mortality was 5.9%, and the rate of permanent paraplegia was 2%. Drain complications occurred in 4 (3.9%) patients, but no patient experienced permanent injury related to CSF drainage. Two patients in the cohort had complete resolution of paraplegia with increased CSF drainage and mean arterial blood pressure increases aimed to increase spinal cord perfusion pressure by 25%. A third patient experienced improvement in lower extremity strength but remained paraplegic, and a fourth patient demonstrated no improvement in symptoms. The 6 patients taking clopidogrel experienced no bleeding complications, and there were no apparent risk factors for bleeding in the 5 patients who had bloody drain output or in 1 patient who developed an epidural hematoma. CONCLUSION: Prophylactic CSF drainage was associated with low paraplegia and drain-related complication rates. These data further support the safety of prophylactic CSF drainage in patients undergoing TEVAR with a high risk for ischemic spinal cord injury.

Coagulation Management During Liver Transplantation: Use of Fibrinogen Concentrate, Recombinant Activated Factor VII, Prothrombin Complex Concentrate, and Antifibrinolytics.

Coagulation management, and transfusion practice in liver transplantation (LT) have been evolving in the recent years due to better understanding of coagulation abnormalities in end-stage liver disease, and clinical management of LT patients. Avoidance of allogeneic blood components is feasible in some patients, but multi-modal coagulation therapies may be necessary in others who develop complex coagulopathy due to hemorrhage, hemodilution, hypothermia, and acid-base disturbances. Transfusions of plasma and cryoprecipitate remain to be the mainstay therapy for procoagulant factor replacement during LT. Clinical efficacy and safety of these products are limited by logistic issues (eg, thawing), and mostly noninfectious complications. Considering potential alternatives to conventional transfusion is thus important to improve hemostatic resuscitation in complex LT cases. The present review is mainly focused on procoagulant properties of plasma and platelet transfusion, and currently available plasma-derived and recombinant factor concentrates, and antifibrinolytic agents in LT patients. The role of viscoelastic coagulation tests to guide specific component therapies will be also discussed.

Reduced Requirement for Prothrombin Complex Concentrate for the Restoration of Thrombin Generation in Plasma From Liver Transplant Recipients.

BACKGROUND: Plasma transfusion remains the mainstay hemostatic therapy during liver transplantation (LT) in most countries. However, a large volume is required for plasma to achieve clinically relevant factor increases. Prothrombin complex concentrate (PCC) is a low-volume alternative to plasma in warfarin reversal, but its efficacy has not been well studied in LT. METHODS: Blood samples were collected from 28 LT patients at baseline (T0) and 30 minutes after graft reperfusion (T1). Factor X and antithrombin levels were measured. Ex vivo effects of PCC (0.2 and 0.4 IU/mL) and 10% volume replacement with normal plasma were compared in LT and warfarin plasma by measuring lag time, thrombin peak, and endogenous thrombin potential (ETP) using thrombin generation (TG) assay. RESULTS: Coagulation status was worsened at T1 as international normalized ratio increased from 1.7 to 3.0, and factor X was decreased from 49% to 28%. TG measurements showed normal lag time and ETP at T0 and T1, but low-normal peak at T0, and below-normal peak at T1. Both doses of PCC increased peak and ETP, while 10% volume plasma had minimal effects on TG. Thrombin inhibition appears to be very slow after adding 0.4 IU/mL of PCC in LT plasma due to low antithrombin. The same doses of PCC and plasma were insufficient for warfarin reversal. CONCLUSIONS: Reduced TG in LT can be more effectively restored by using PCC rather than plasma. The required doses of PCC for LT patients seem to be lower than warfarin reversal due to slow thrombin inhibition.

Epidural Versus Paravertebral Nerve Block for Postoperative Analgesia in Patients Undergoing Open Liver Resection: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Although many studies have found no difference between thoracic epidural block and unilateral thoracic paravertebral block after thoracotomy, no previous studies have compared epidural block with bilateral thoracic paravertebral block (bTPVB) in patients undergoing open liver resection. We aimed to investigate whether there was a significant analgesic advantage of thoracic epidural over bTPVB after liver resection. METHODS: This randomized, prospective, open-label study included adult patients undergoing elective open liver resection. Patients were randomized to receive either thoracic epidural block or bTPVB, through which ropivacaine (0.2%) was infused for 3 days. The primary outcome was pain Verbal Rating Scale (VRS) score (0-10) at rest and with postoperative incentive spirometry. Secondary outcomes included VRS at rest, inspired volumes during incentive spirometry, patient-controlled analgesia hydromorphone utilization, measures of hemodynamic stability, and postoperative bowel function. RESULTS: Eighty patients completed the study and received thoracic epidural block (n = 41) or bTPVBs (n = 39). No catheter-related complications were noted. The primary outcome, pain (VRS) with incentive spirometry, was significantly lower in the epidural group (epidural vs bTPVB, mean [SD]) (4.5 [2.7] vs 5.4 [2.7] at 24 hours postoperatively, and 3.2 [2.1] vs 4.6 [2.4] at 48 hours postoperatively). Maximal inspired volumes at 24 hours postoperatively (917 [379] vs 1042 [468] mL) and cumulative utilization of patient-controlled analgesia hydromorphone during the first 48 hours postoperatively (10.7 [7.9] vs 13.6 [8.5] mg) were not significantly different between groups. Decrease in mean arterial pressure from baseline at 24 hours postoperatively was greater for the epidural group (-12.6 [15.8] vs -3.8 [16.2]; P = 0.016). CONCLUSIONS: This study suggests that there is a modest analgesic advantage of thoracic epidural over bTPVBs for patients after open liver resection.

Ex vivo evaluation of 4 different viscoelastic assays for detecting moderate to severe coagulopathy during liver transplantation.

Prolonged prothrombin time (PT) and its ratio are routinely used for the assessment of candidates for liver transplantation (LT), but intraoperative coagulation management of transfusion is hindered by its long turnaround time. Abnormal reaction time (R time) on thromboelastography (TEG) or clotting time (CT) of rotational thromboelastometry (ROTEM) are presumably an alternative, but there is a paucity of clinical data on abnormal R time/CT values compared to PT during LT. After receiving institutional review board approval and informed consent, we obtained blood samples from 36 LT patients for international normalized ratio (INR), factor (F) X level, and viscoelastic tests (EXTEM/INTEM and kaolin/rapid TEG) at baseline and 30 minutes after graft reperfusion. Receiver operating characteristic (ROC) curves were calculated for INR > 1.5 and viscoelastic R time/CT thresholds to assess the ability to diagnose FX deficiency at the moderate (<50%) or severe (<35%) level. The FX deficiency data were calculated using cutoff values of INR (>1.5) and abnormal R time/CT for TEG and ROTEM. Tissue factor (TF)-activated INR and EXTEM-CT performed well in diagnosing FX below 50%, but rapid TEG with combined TF and kaolin activators failed. Improved performance of INTEM-CT in diagnosing FX below 35% underlies multifactorial deficiency involving both intrinsic and common pathways. In conclusion, the differences among different viscoelastic tests and clinical situations should be carefully considered when they are used to guide transfusion during LT.