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Background: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery., Methods: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL., Results: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates., Conclusions: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

The short-acting platelet glycoprotein IIb/IIIa antagonist tirofiban is beneficial when used in the context of cardiac surgery. Tirofiban has an elimination half-life of 2 h. Renal failure prolongs the half-life and continues inhibition of platelet aggregation refractory to transfusions of platelets. Extracorporeal elimination is necessary to prevent excessive hemorrhage in this condition. We assessed the elimination of tirofiban by hemofiltration in an in vitro model of cardiopulmonary bypass (CPB). Two hemofilters and one plasmapheresis filter were assessed. Three separate filters of each type were tested serially. The CPB circuit was primed with a total volume of 1000 mL. Tirofiban was added to a calculated concentration of 200 ng/mL. Portions of 50 mL of filtrate were retrieved from the dialyzer, and equal amounts of fluid were substituted in the circuit. After each filtration, the tirofiban blood level was analyzed. The procedure was repeated 16 times. Peak tirofiban concentrations ranged from 160 to 260 ng/mL. The elimination of tirofiban followed an exponential decay curve with fast clearance of the large therapeutic concentrations of 250 to 50 ng/mL. The subsidence coefficient b revealed no significant differences in elimination between the filter systems. These data suggest that ultrafiltration is an effective means for extracorporeal elimination of therapeutic levels of tirofiban.

Unlabelled: Cardiac surgery involving cardiopulmonary bypass (CPB) leads to activation of the hemostatic/inflammatory system. We compared the influence of a half-dose aprotinin regimen on postoperative blood loss and the activation of the hemostatic/inflammatory system during CPB, when used during a heparin-level-based heparin management for cardiac surgery. Two-hundred patients (n = 100 in each group) were enrolled in this randomized prospective study. In Group I only heparin was given according to the results of the Hepcon HMS Plus. In Group II aprotinin was added with a bolus of 1 x 10(6) kallikrein inhibiting units (KIU) for the patient immediately before initiation of CPB, 1 x 10(6) KIU in the priming solution of the CPB, and a continuous infusion of 250,000 KIU/h during CPB. Postoperative blood loss was determined after 12 h. Heparin and antithrombin activity were evaluated by an anti-Xa assay and measurement of antithrombin III activity. Hemostatic activation was evaluated by adenosine diphosphate-stimulated platelet aggregometry and by measurements of the generation/release of beta-thromboglobulin (beta-TG), soluble P-selectin (sPS), thrombin (TAT), prothrombin 1 and 2 fragments (PTF1+2), factor XIIa (FXIIa), plasmin (PAP), and D-dimers. Inflammatory response was evaluated by measuring complement factors 5b-9 (C5b-9), interleukin (IL)-6, and neutrophil elastase (NE). There were no differences in the pre-CPB values or duration of CPB between the two groups. There were no differences in the post-CPB values for platelet count, platelet aggregation, beta-TG, sPS, TAT, PTF1+2, C5b-9, NE, or IL-6. The additional use of aprotinin resulted in a significant decrease of PAP, D-dimers, and 12 h postoperative blood loss, whereas generation of the contact factor XIIa was increased. The administration of aprotinin significantly reduced postoperative blood loss after cardiac surgery and CPB. This most likely has to be attributed to the antifibrinolytic effects of aprotinin. No effects on thrombin generation, platelet activation, inflammatory response, or clinical outcome were noted., Implications: The use of half-dose aprotinin and heparin-level-based anticoagulation management during cardiopulmonary bypass leads to a significant reduction of postoperative blood loss after cardiac surgery. This effect can most likely be attributed to the antifibrinolytic effects of aprotinin, as we did not observe effects on other variables of activation of the hemostatic/inflammatory system.

Implications: Bivalirudin is a new, direct thrombin inhibitor. We investigated the extracorporeal elimination rate of different hemofilters and one plasmapheresis filter for bivalirudin. Our data show that bivalirudin can be effectively eliminated via hemofiltration and plasmapheresis, although there were significant differences in the elimination rates among the filter systems investigated.

Unlabelled: The standard celite or kaolin activated clotting time (ACT) correlates poorly with heparin levels during cardiopulmonary bypass (CPB). We compared a modified kaolin ACT, in which plasma was supplemented, to a standard undiluted kaolin ACT for monitoring heparin levels during CPB. Fifteen patients undergoing normothermic CPB were enrolled in this prospective study. Heparin management was performed according to the Hepcon HMS results (Medtronic, Minneapolis, MN). The ACTs were performed with the ACT II device (Medtronic). Hepcon HMS calculations, standard kaolin ACTs, and plasma supplemented modified ACTs (mACTs), prepared by diluting blood samples 1:1 with human plasma (Behring, Marburg, Germany), were measured every 30 min during CPB. The data obtained were correlated to the plasma chromogenic anti-Xa activity as a reference assay for heparin levels. A total of 64 samples were evaluated. The chromogenic anti-Xa activity ranged from 0.2 to 5.5 IU/mL. The Hepcon HMS calculations ranged from 2.7-8.2 IU/mL of heparin, the standard ACT ranged from 424 to >999 s, and the mACT ranged from 210 to 801 s. The correlation to the chromogenic anti-Xa method was r = 0.43 for the standard kaolin ACT and r = 0.69 for the plasma mACT. The plasma mACT provided an improved correlation to chromogenically measured levels of anti-Xa activity during CPB. The improved correlation most likely results from a correction of the effects of the impairment of the coagulation system caused by hemodilution and consumption of procoagulants on extracorporeal surfaces., Implications: During cardiopulmonary bypass, the plasma modified kaolin activated clotting time (ACT) provides a better correlation with heparin levels than the standard kaolin ACT.

Unlabelled: Cariporide (HOE 642) ameliorates myocardial ischemia/reperfusion (I/R) injury, by the well established reduction of cytosolic [Ca(2+)] in cardiac myocytes through inhibition of Na(+)/H(+) exchange. However, postischemic inflammation also contributes to I/R injury. We tested the hypothesis that cariporide also modulates the inflammatory response. The effect of cariporide on L-selectin expression by human leukocytes in vitro and leukocyte adhesion and emigration in the reperfused rat cremaster muscle in vivo were studied. The rat cremaster muscle was exteriorized for intravital videomicroscopy, induction of ischemia (90 min), and reperfusion (90 min). Eleven rats were pretreated with cariporide (9 mg/kg body weight IV) whereas 11 rats received saline. Leukocyte adhesion was quantified offline. Human venous blood was incubated with cariporide (3 micromol/L) or saline, stimulated with formyl- methionine-leucine-phenylalanine (10(-10)-10(-6) mol/L), and granulocyte L-selectin expression was analyzed by flow cytometry. Cariporide reduced leukocyte rolling and adhesion by approximately 35% and 45%, respectively, after 30 min of reperfusion. Leukocyte extravasation was decreased by approximately 85% after 90 min. Cariporide increased L-selectin shedding at each formyl-methionine-leucine-phenylalanine concentration, reducing the 50% effective dose from 9.95 to 4.68 nmol/L. Thus, cariporide may ameliorate I/R injury not only by the known reduction of cytosolic [Ca(2+)] in cardiomyocytes, but also by attenuating leukocyte-dependent inflammatory responses. Promotion of L-selectin shedding from activated leukocytes may present a mechanism underlying this newly detected effect., Implications: This study provides evidence that inhibition of Na(+)/H(+) exchange by cariporide (HOE 642) attenuates the postischemic inflammatory response. Leukocyte adhesion and emigration, assessed by in vivo microscopy, were markedly reduced in rat cremaster muscle, possibly because of increased L-selectin shedding of activated leukocytes as demonstrated by flow cytometry.

Unlabelled: We developed a quick and easy method to perform anti-Xa-activity-based whole blood assay and assessed its reliability for online monitoring of unfractionated heparins (UFHs) during cardiopulmonary bypass. Seventy-five microliters of a mixture of 1:3 large- and small-range Heptest reagent were transferred into blank cartridges of the ACT II device. The plastic flags for clot detection and stirring the sample and reagent were inserted and overlaid with 75 microL of Recalmix for recalcification. One-hundred fifty microliters of citrated whole blood were added and measurements performed. In vitro, the linearity of the test over a range of 1-8 IU/mL UFH, as well as the influence of variations in hematocrit (60%, 30%, and 20%), plasma coagulation factors (50%, 30%, and 20%) and platelets (100, 50, and 20 x 10(3)/microL) on the test results were assessed. In vivo measurements performed during cardiopulmonary bypass were compared with the chromogenic assay. The test revealed linearity to concentrations of 6 IU/mL of UFH and was not significantly influenced by the variations in the in vitro set-up despite a prolongation in samples with a hematocrit of 60%. In vivo, the correlation to the chromogenic test was R: = 0.90. The ACT II anti-Xa-UFH assay performed in whole blood was reliable when used over a wide range of conditions that could be encountered clinically. Although the test is useful for point-of-care monitoring, the necessity of individual calibrations and pipetting in the operation room requires further automation before its use in clinical practice., Implications: The ACT II anti-Xa-unfractionated heparin assay allows for reliable monitoring of large concentrations of UFH over a wide range of hematocrit, platelet, and coagulation factor levels. Further evaluation of this point-of-care device is indicated.

Unlabelled: Recombinant hirudin (r-hirudin) is being used increasingly in patients with heparin-induced thrombocytopenia type II. Renal failure has been demonstrated to prolong the half-life of r-hirudin and to cause bleeding in patients who have undergone cardiopulmonary bypass (CPB). We assessed the ability of different filter systems for modified ultrafiltration to eliminate r-hirudin in vitro using simulated CPB. r-Hirudin concentration was measured (chromogenic laboratory standard plus ecarin clotting time) before and after filtration, and its elimination was calculated using both controlled system flow and arterial inflow (separate pump). Four hemofilters (Renoflow II, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Iostra) and two plasmapheresis filter systems (ASAHI Plasmaflow OP, Diamed; and PF 2000 N, Gambro) were assessed (5 filters of each brand = 30 filters) in a closed in vitro CPB system applying conditions usually occurring during CPB. Ten plasmapheresis filters showed a greater ability than 20 hemofilters to eliminate r-hirudin (60%-70% vs 15%-42%) within the shortest time (80 vs 180 s). Among the four hemofilter systems, the Arylane H4 filter provided the most effective (42%) r-hirudin elimination. Elimination of r-hirudin was markedly improved using plasmapheresis systems, compared with hemofilter systems. Our findings may be relevant to patients with impaired renal function, who have been administered r-hirudin during CPB., Implications: Modified ultrafiltration may enhance the elimination of recombinant-hirudin, although plasmapheresis systems provide the most rapid and complete elimination of recombinant-hirudin during simulated cardiopulmonary bypass. The decision to use a specific system will ultimately depend on the prevailing clinical situation and overall health of the patient.

Unlabelled: The electroencephalogram (EEG) and middle latency auditory evoked responses (MLAER) have been proposed for assessment of the depth of anesthesia. However, a reliable monitor of the adequacy of anesthesia has not yet been defined. In a multicenter study, we tested whether changes in the EEG and MLAER after a tetanic stimulus applied to the wrist could be used to predict subsequent movement in response to skin incision in patients anesthetized with 1 minimum alveolar anesthetic concentration (MAC) isoflurane in N2O. We also investigated whether the absolute values of any of these variables before skin incision was able to predict subsequent movement. After the induction of anesthesia with propofol and facilitation of tracheal intubation with succinylcholine, 82 patients received 1 MAC isoflurane (0.6%) in N2O 50% without an opioid or muscle relaxant. Spontaneous EEG and MLAER to auditory click-stimulation were recorded from a single frontoparietal electrode pair. MLAER were severely depressed at 1 MAC isoflurane. At least 20 min before skin incision, a 5-s tetanic stimulus was applied at the wrist, and the changes in EEG and MLAER were recorded. EEG and MLAER values were evaluated before and after skin incision for patients who did not move in response to tetanic stimulation. Twenty patients (24%) moved after tetanic stimulation. The changes in the EEG or MLAER variables were unable to predict which patients would move in response to skin incision. Preincision values were not different between patients who did and did not move in response to skin incision for any of the variables. MLAER amplitude increased after skin incision. We conclude that it is unlikely that linear EEG measures or MLAER variables can be of practical use in titrating isoflurane anesthesia to prevent movement in response to noxious stimulation., Implications: Reliable estimation of anesthetic adequacy remains a challenge. Changes in spontaneous or auditory evoked brain activity after a brief electrical stimulus at the wrist could not be used to predict whether anesthetized patients would subsequently move at the time of surgical incision.