Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney injury after cardiac surgery?

INTRODUCTION: Postoperative acute kidney injury (AKI) is a frequently observed complication after on-pump cardiac surgery (CS) and is associated with adverse patient outcomes. Early identification of patients at risk is essential for the prevention of AKI after CS. In this study, we analysed whether urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) combined with urine insulin-like growth factor binding protein 7 (IGFBP-7) ([TIMP-2] × [IGFBP-7]) is an adequate diagnostic test to identify early AKI after on-pump CS. METHODS: In 42 patients undergoing coronary artery bypass graft surgery, we surveyed individual risk factors for AKI and defined AKI by applying the Kidney Disease: Improving Global Outcomes (KDIGO) classification during the day of surgery and the following 2 days after surgery. Concentrations of urinary TIMP-2 multiplied by IGFBP-7 were recorded at four time points: at baseline pre-surgery, at the end of surgery, 4 hours after cardiopulmonary bypass (CPB) and at 8:00 AM on the first postoperative day. RESULTS: In total, 38% of the patients experienced AKI. The results showed a median baseline [TIMP-2] × [IGFBP-7] concentration of 0.3 (ng/ml)(2)/1,000, decreasing at the end of surgery and then increasing at the next measurement point 4 hours after CPB and further on the first postoperative day. On the first postoperative day, patients with AKI had significantly higher concentrations of [TIMP-2] × [IGFBP-7]. On the day of surgery, the concentration did not significantly differ between patients classified as KDIGO 0 or KDIGO 1 or 2. Previously published cutoff points of 0.3 and 2 were not confirmed in our study cohort. CONCLUSION: [TIMP-2] × [IGFBP-7] concentration can be used as a diagnostic test to identify patients at increased risk of AKI after CS on the first postoperative day. At earlier time points, no significant difference in [TIMP-2] × [IGFBP-7] concentration was found between patients classified as KDIGO 0 or KDIGO 1 or 2. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00005457. Registered 26 November 2013.

Assessment of hemostatic changes after initiation of continuous venovenous hemodialysis.

BACKGROUND: Continuous renal replacement therapy (CRRT) is a standard therapy in critically ill patients suffering from acute kidney injury (AKI). Extracorporeal circulation and exposure to foreign surfaces during CRRT may induce disturbances in hemostasis, particularly in platelet function. The present study described the hemostatic changes associated with CRRT and aimed to identify the independent predictors of premature clotting of the circuit. METHODS: In a prospective cohort mono-center study, patients were assessed for eligibility if they were i) diagnosed with AKI and ii) assigned to receive CRRT for the first time. Patients were included in the study if their platelet count was greater than 100/nL prior to inclusion in the study. After initiation of CRRT, aggregometric [Multiplate, Roche, Grenzach, Germany: Arachidonic acid (ASPItest)-, ADP (ADPtest)- and Thrombin (TRAPtest)-induced platelet aggregation] and viscoelastic (ROTEM; TEM International, Munich, Germany) analyses were performed immediately before (Baseline, T1) and 6 hours (T2), 12 hours (T3), 24 hours (T4), and 48 hours (T5) after initiation of CRRT. Conventional laboratory coagulation analyses were routinely performed twice a day. Arachidonic acid- and ADP-induced platelet aggregations were defined as primary endpoints. RESULTS: A total of 127 patients were screened for eligibility, and 50 patients were enrolled in this study. Aggregometric analyses showed that arachidonic acid-induced platelet aggregation was significantly reduced at T2 [532 (210/1105) median (25th/75th percentile) AU*min] compared to the Baseline at T1 [780 (297/1156), p = 0.007] and remained unchanged from T2 onward. Platelet aggregation in the ADPtest and TRAPtest remained unchanged during the study period. Viscoelastic and conventional coagulation analyses indicated a progredient increase of clot firmness. In total, 76 filter sets (an average of 1.5 per patient) were used, and 26 filter sets occluded prematurely after an average treatment time of 17 ± 12 hours. No predictors for premature clotting of the circuit were identified. CONCLUSIONS: The results of the present study indicate that CRRT may lead to impaired primary hemostasis as shown by a decrease in ex vivo arachidonic acid-induced platelet aggregation. Moreover, viscoelastic measure indicate a fibrinogen-associated trend of increasing clot firmness during the study period. Further studies are needed to analyze whether these findings are of hemostatic relevance.

Response to dual antiplatelet therapy in patients with peripheral artery occlusive disease suffering from critical limb ischemia.

BACKGROUND: Failure to reach the level of therapeutic anticoagulation represents a risk factor for occlusive events in patients suffering from peripheral arterial disease. Our study aimed to analyze the prevalence of nonresponse to dual antiplatelet therapy in a group of patients admitted to our hospital with critical limb ischemia (CLI) following stent-thrombosis. METHODS: This prospective study was approved by the local Ethics Review Board. Patients with critical limb ischemia following stent thrombosis were included if dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel per day had been administered over three months prior to enrollment. The antiaggregatory effects were analyzed using the Multiple Electrode Aggregometry (MEA, Multiplate®, Roche AG, Grenzach, Germany). The primary endpoints were the area under the aggregation curve (AUC) of the ex-vivo-induced platelet aggregation following stimulation with adenosine diphosphate (ADP, ADPtest) and arachidonic acid (ASPItest). RESULTS: Sixty patients were enrolled in this study. Platelet aggregation was 39.6 (24/54) [median (25th/75th percentile)] U in the ADPtest and 22.4 (13/35) U in the ASPItest. Effective aspirin- and ADP-induced therapeutic inhibition of platelet aggregation was confirmed in 78% and 53% of our patients, respectively. Effective dual platelet inhibition was achieved in 27 patients (45%). A non-response to both of the antiaggregatory drugs was found in 14% of the patients. CONCLUSIONS: The results of the present study indicate a high prevalence of nonresponse to antiaggregatory medication in our study collective. Further studies are needed to confirm our hypothesis that individual adjustments of both aspirin and clopidogrel dosages may potentially reduce the incidence of CLI in patients suffering from peripheral arterial occlusive disease.

A prospective, blinded evaluation of a video-assisted '4-stage approach' during undergraduate student practical skills training.

BACKGROUND: The 4-stage approach (4-SA) is used as a didactic method for teaching practical skills in international courses on resuscitation and the structured care of trauma patients. The aim of this study was to evaluate objective and subjective learning success of a video-assisted 4-SA in teaching undergraduate medical students. METHODS: The participants were medical students learning the principles of the acute treatment of trauma patients in their multidiscipline course on emergency and intensive care medicine. The participants were quasi- randomly divided into two groups. The 4-SA was used in both groups. In the control group, all four steps were presented by an instructor. In the study group, the first two steps were presented as a video. At the end of the course a 5-minute objective, structured clinical examination (OSCE) of a simulated trauma patient was conducted. The test results were divided into objective results obtained through a checklist with 9 dichotomous items and the assessment of the global performance rated subjectively by the examiner on a Likert scale from 1 to 6. RESULTS: 313 students were recruited; the results of 256 were suitable for analysis. The OSCE results were excellent in both groups and did not differ significantly (control group: median 9, interquantil range (IQR) 8-9, study group: median 9, IQR 8-9; p = 0.29). The global performance was rated significantly better for the study group (median 1, IQR 1-2 vs. median 2, IQR 1-3; p < 0.01). The relative knowledge increase, stated by the students in their evaluation after the course, was greater in the study group (85% vs. 80%). CONCLUSION: It is possible to employ video assistance in the classical 4-SA with comparable objective test results in an OSCE. The global performance was significantly improved with use of video assistance.

Factor XIII Activity Might Already Be Impaired before Veno-Venous ECMO in ARDS Patients: A Prospective, Observational Single-Center Cohort Study.

Direct complications in patients receiving extracorporeal (veno-venous) membrane oxygenation (vvECMO) are mainly either due to bleeding or thromboembolism. We aimed to evaluate the course of routine coagulation parameters and the activity of different coagulation factors-with special focus on factor XIII (F XIII)-before, during and after vvECMO in acute respiratory distress syndrome (ARDS) patients. The activity of coagulation factors and rotational thrombelastometry were analyzed in 20 ECMO patients before (T-1) and 6 h (T0), one (T1), three (T3) and seven days (T7) after the implantation, as well as one and three days after the termination of ECMO. F XIII activity was already severely decreased to 37% (30/49) before ECMO. F XIII activity was the only coagulation factor continuously declining during vvECMO, being significantly decreased at T3 (31% (26/45) vs. 24% (18/42), p = 0.0079) and T7 (31% (26/45) vs. 23% (17/37), p = 0.0037) compared to T0. Three days after termination of vvECMO, platelet count and fibrinogen nearly doubled and factors II, V, XI and XIII showed spontaneous significant increases. Severe ARDS patients showed a considerably diminished factor XIII activity before vvECMO initiation and its activity continuously declined later on. Thus, incorporation of F XIII monitoring into the regular hemostaseologic routine during vvECMO therapy seems advisable. Due to the potential development of a hypercoagulatory state after the termination of vvECMO, tight hemostasiologic monitoring should persist in the initial phase after ECMO termination.

Is There a "Blind Spot" in Point-of-Care Testing for Residual Heparin After Cardiopulmonary Bypass? A Prospective, Observational Cohort Study.

Identifying the cause of a bleeding complication after cardiac surgery can be crucial. This study sought to clarify whether the application of unprocessed autologous pump blood influences anti-factor Xa activity after cardiac surgery and evaluated 2 point-of-care methods regarding their ability to identify an elevated anti-factor Xa activity at different timepoints after cardiopulmonary bypass. Anti-factor Xa activity, heparin/protamine titration and the clotting time ratio of thromboelastometry in the INTEM and HEPTEM were measured at baseline (T1), after the application of protamine (T2) and after the complete application of autologous pump blood (T3). Anti-factor Xa activity decreased significantly between T2 and T3 as well did the absolute number of patients with an elevated anti-factor Xa activity. Receiver Operating Curve analyses were performed for both point-of-care methods. At T2 neither could identify patients with an elevated anti-factor Xa activity, while both methods were able to do so at T3 with high sensitivity and specificity. This difference suggests that an interference in the detection of residual heparinization with point-of-care methods exists right after the application of protamine, which seems to subside after a short time span. Nevertheless, results of point-of-care testing for residual heparinization after cardiopulmonary bypass need to be interpreted considering the protamine-heparin ratio and the timepoint of protamine administration.

Platelet Function Disturbance During Veno-Venous ECMO in ARDS Patients Assessed by Multiple Electrode Aggregometry-A Prospective, Observational Cohort Study.

Extracorporeal (veno-venous) membrane oxygenation (vvECMO) has been shown to have negative effects on platelet number and function. This study aimed to gain more information about the impact of vvECMO on platelet function assessed by multiple electrode aggregometry (MEA). Twenty patients with the indication for vvECMO were included. Platelet function was analyzed using MEA (Multiplate®) before (T-1), 6 h (T0), one (T1), two (T2), three (T3), and seven (T4) days after the beginning of vvECMO. Median aggregational measurements were already below the normal reference range before vvECMO initiation. Platelet aggregation was significantly reduced 6 h after vvECMO initiation compared to T-1 and spontaneously recovered with a significant increase at T2. Platelet count dropped significantly between T-1 and T0 and continuously decreased between T0 and T4. At T4, ADP-induced platelet aggregation showed an inverse correlation with the paO2 in the oxygenator. Platelet function should be assessed by MEA before the initiation of extracorporeal circulation. Although ECMO therapy led to a further decrease in platelet aggregation after 6 h, all measurements had recovered to baseline on day two. This implies that MEA as a whole blood method might not adequately reflect the changes in platelet function in the later stages of extracorporeal circulation.

Association between perioperative hypothermia and patient outcomes after thoracic surgery: A single center retrospective analysis.

Hypothermia due to anaesthetic-induced impairment of thermoregulatory control and exposure to a cool environment is common in surgical patients. Peripheral vasodilation due to neuroaxial blockade may aggravate hypothermia. There is few data on perioperative hypothermia in patients undergoing thoracic surgery under combined general and regional anesthesia. We reviewed all thoracic surgical patients between 2006 and 2011 to determine the incidence and extent of hypothermia with or without an epidural anesthesia and evaluated its effect.Around 339 patients underwent lung resection procedures with intraoperative forced-air warming: 197 with general and epidural anesthesia (GA + EPI), 199 with general anesthesia alone (GA). Statistical analyses were performed to determine the association between hypothermia (T < 36°C) and transfusion requirements, length of stay (LOS) in the intensive care unit (ICU), hospital LOS, and in hospital mortality.The overall incidence of hypothermia was 64.3%. Multivariate regression analysis revealed three significant risk factors for the development of hypothermia: long induction time (P = .011), small body surface area (P = .003), and application of more fluid intraoperatively (P < .001). Factors determining the extent of hypothermia were: receiving an open thoracotomy (P = .009), placement and use of an epidural catheter (P = .002), and a lower body mass index (BMI) (P < .001). Additional epidural anesthesia reduced core temperature by 0.26°C (95% CI -0.414 to -0.095°C, P < .05). There was no difference in transfusion requirements, ICU LOS or mortality between both groups. Hospital LOS was longer in patients with hypothermia.More than half of all thoracic patients suffered from hypothermia. A long induction time, small body surface area, and large intraoperative fluid application were independent risk factors for the development of perioperative hypothermia. Additional epidural anesthesia to general anesthesia did not increase the incidence of hypothermia but decreased body core temperature to an-albeit not clinically significant-degree. Patients scheduled for thoracic surgery will probably benefit from an additional period of prewarming prior to induction to reduce the high incidence of perioperative hypothermia.

The Prevalence and Clinical Relevance of ASA Nonresponse After Cardiac Surgery: A Prospective Bicentric Study.

We aimed to identify the prevalence of acetylsalicylic acid (ASA) nonresponse in patients after coronary artery bypass graft (CABG) surgery and the possible consequences for the rate of major cardiovascular events. This prospective, observational, bicentric cohort study was conducted in two German University hospitals. A total of 400 patients (200 in each study center) undergoing elective CABG surgery were enrolled after written informed consent. Platelet function was analyzed on day 3 (d3) and day 5 (d5) postoperatively following stimulation with arachidonic acid (ASPItest) and with thrombin receptor-activating peptide 6 (TRAPtest) using multiple electrode aggregometry (Multiplate). Individuals with an ASPItest ≥40 AU·min were categorized as ASA nonresponders. A 1-year follow-up recorded the combined end point of cardiovascular events, hospital admissions, or deaths related to cardiovascular disease. The prevalence of ASA nonresponse was 51.5% on d3, and it significantly increased to 71.3% on d5 ( P = .0049). The area under the aggregation curve in the TRAPtest ( P < .0001), the platelet count on d5 ( P = .009), and the cardiopulmonary bypass time ( P = .01) were identified as independent predictors of an ASA nonresponse. A 1-year follow-up recorded 54 events fulfilling criteria for the combined end point with no difference between ASA responders and nonresponders. This study indicates a high incidence of perioperative ASA nonresponse in patients following CABG. No effect on the incidence of cardiovascular events was recorded in the 1-year follow-up. Therefore, a randomized dosage adjustment trial should elucidate whether a tailored ASA treatment after CABG surgery represents a useful concept.

IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study.

INTRODUCTION: Sepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin® [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters. METHODS: Patients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit's standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating "control" and "IgM-IVIg" groups. EA assays, thrombelastometry (ROTEM®) and impedance aggregometry (Multiplate®) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit's standards. RESULTS: Data from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 ±0.06 vs. 0.26 ±0.07, p<0.05 and 0.51 ±0.06 vs. 0.25 ±0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 ±0.07 vs. 0.43 ±0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl ±43 vs. 87/nl ±20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl ±37 vs. 475 mg/dl ±47 (p = 0.015)) and day 4 (307 mg/dl ±35 vs. 420 mg/dl ±16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed. CONCLUSION: Treatment with IgM-enriched immunoglobulin attenuates the EA levels in patients with severe sepsis and might have an effect on septic thrombocytopenia and fibrinogen depletion. Viscoelastic, aggregometric or inflammatory parameters were not influenced. TRIAL REGISTRATION: clinicaltrials.gov NCT02444871.

The pre-hospital administration of tranexamic acid to patients with multiple injuries and its effects on rotational thrombelastometry: a prospective observational study in pre-hospital emergency medicine.

BACKGROUND: Hyperfibrinolysis (HF) is a major contributor to coagulopathy and mortality in trauma patients. This study investigated (i) the rate of HF during the pre-hospital management of patients with multiple injuries and (ii) the effects of pre-hospital tranexamic acid (TxA) administration on the coagulation system. METHODS: From 27 trauma patients with pre-hospital an estimated injury severity score (ISS) ≥16 points blood was obtained at the scene and on admission to the emergency department (ED). All patients received 1 g of TxA after the first blood sample was taken. Rotational thrombelastometry (ROTEM) was performed for both blood samples, and the results were compared. HF was defined as a maximum lysis (ML) >15 % in EXTEM. RESULTS: The median (min-max) ISS was 17 points (4-50 points). Four patients (15 %) had HF diagnosed via ROTEM at the scene, and 2 patients (7.5 %) had HF diagnosed via ROTEM on admission to the ED. The median ML before TxA administration was 11 % (3-99 %) vs. 10 % after TxA administration (4-18 %; p > 0.05). TxA was administered 37 min (10-85 min) before ED arrival. The ROTEM results before and after TxA administration did not significantly differ. No adverse drug reactions were observed after TxA administration. DISCUSSION: HF can be present in severely injured patients during pre-hospital care. Antifibrinolytic therapy administered at the scene is a significant time saver. Even in milder trauma fibrinogen can be decreased to critically low levels. Early administration of TxA cannot reverse or entirely stop this decrease. CONCLUSIONS: The pre-hospital use of TxA should be considered for severely injured patients to prevent the worsening of trauma-induced coagulopathy and unnecessarily high fibrinogen consumption. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01938768 (Registered 5 September 2013).