A Randomized Trial of Intravenous Amino Acids for Kidney Protection.

BACKGROUND: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. METHODS: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. RESULTS: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. CONCLUSIONS: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).

Perfusion quality odds (PEQUOD) trial: validation of the multifactorial dynamic perfusion index as a predictor of cardiac surgery-associated acute kidney injury.

OBJECTIVES: The multifactorial dynamic perfusion index was recently introduced as a predictor of cardiac surgery-associated acute kidney injury. The multifactorial dynamic perfusion index was developed based on retrospective data retrieved from the patient files. The present study aims to prospectively validate this index in an external series of patients, through an on-line measure of its various components. METHODS: Inclusion criteria were adult patients undergoing cardiac surgery with cardiopulmonary bypass. Data collection included preoperative factors and cardiopulmonary bypass-related factors. These were collected on-line using a dedicated monitor. Factors composing the multifactorial dynamic perfusion index are the nadir haematocrit, the nadir oxygen delivery, the time of exposure to a low oxygen delivery, the nadir mean arterial pressure, cardiopulmonary bypass duration, the use of red blood cell transfusions and the peak arterial lactates. RESULTS: Two hundred adult patients were investigated. The multifactorial dynamic perfusion index had a good (c-statistics 0.81) discrimination for cardiac surgery-associated acute kidney injury (any stage) and an excellent (c-statistics 0.93) discrimination for severe patterns (stage 2-3). Calibration was modest for cardiac surgery-associated acute kidney injury (any stage) and good for stage 2-3. The use of vasoconstrictors was an additional factor associated with cardiac surgery-associated acute kidney injury. CONCLUSIONS: The multifactorial dynamic perfusion index is validated for discrimination of cardiac surgery-associated acute kidney injury risk. It incorporates modifiable risk factors, and may help in reducing the occurrence of cardiac surgery-associated acute kidney injury.

Plasma-Free Strategy for Cardiac Surgery with Cardiopulmonary Bypass in Infants < 10 kg: A Retrospective, Propensity-Matched Study.

BACKGROUND: Infants < 10 kg undergoing cardiac surgery with cardiopulmonary bypass (CPB) may receive either fresh frozen plasma (FFP) or other solutions in the CPB priming volume. The existing comparative studies are controversial. No study addressed the possibility of total avoidance of FFP throughout the whole perioperative course in this patient population. This retrospective, non-inferiority, propensity-matched study investigates an FFP-free strategy compared to an FFP-based strategy. METHODS: Among patients <10 kg with available viscoelastic measurements, 18 patients who received a total FFP-free strategy were compared to 27 patients (1:1.5 propensity matching) receiving an FFP-based strategy. The primary endpoint was chest drain blood loss in the first 24 postoperative hours. The level of non-inferiority was settled at a difference of 5 mL/kg. RESULTS: The 24-h chest drain blood loss difference between groups was -7.7 mL (95% confidence interval -20.8 to 5.3) in favor of the FFP-based group, and the non-inferiority hypothesis was rejected. The main difference in coagulation profile was a lower level of fibrinogen concentration and FIBTEM maximum clot firmness in the FFP-free group immediately after protamine, at the admission in the ICU and for 48 postoperative hours. No differences in transfusion of red blood cells or platelet concentrate were observed; patients in the FFP-free group did not receive FFP but required a larger dose of fibrinogen concentrate and prothrombin complex concentrate. CONCLUSIONS: An FFP-free strategy in infants < 10 kg operated with CPB is technically feasible but results in an early post-CPB coagulopathy that was not completely compensated with our bleeding management protocol.

The Long Term Residual Effects of COVID-Associated Coagulopathy.

During the acute phase of COVID-19, many patients experience a complex coagulopathy characterized by a procoagulant pattern. The present study investigates the persistence of hemostatic changes in post-COVID patients at a long-term follow up, and the link with the persistence of physical and neuropsychological symptoms. We completed a prospective cohort study on 102 post-COVID patients. Standard coagulation and viscoelastic tests were performed, along with an assessment of persistent symptoms and recording of acute phase details. A procoagulant state was adjudicated in the presence of fibrinogen > 400 mg/dL, or D-dimer > 500 ng/mL, or platelet count > 450,000 cells/µL, or a maxim clot lysis at viscoelastic test < 2%. A procoagulant state was identified in 75% of the patients at 3 months follow up, 50% at 6 months, and 30% at 12-18 months. Factors associated with the persistence of a procoagulant state were age, severity of the acute phase, and persistence of symptoms. Patients with major physical symptoms carry a procoagulant state relative risk of 2.8 (95% confidence interval 1.17-6.7, p = 0.019). The association between persistent symptoms and a procoagulant state raises the hypothesis that an ongoing process of thrombi formation and/or persistent microthrombosis may be responsible for the main physical symptoms in long-COVID patients.

The Very Long COVID: Persistence of Symptoms after 12-18 Months from the Onset of Infection and Hospitalization.

According to the World Health Organization's definition, long COVID is the persistence or development of new symptoms 3 months after the initial infection. Various conditions have been explored in studies with up to one-year follow-up but very few looked further. This prospective cohort study addresses the presence of a wide spectrum of symptoms in 121 patients hospitalized during the acute phase of COVID-19 infection, and the association between factors related to the acute phase of the disease and the presence of residual symptoms after one year or longer from hospitalization. The main results are as follows: (i) post-COVID symptoms persist in up to 60% of the patient population at a mean follow-up of 17 months; (ii) the most frequent symptoms are fatigue and dyspnea, but neuropsychological disturbances persist in about 30% of the patients (iii) when corrected for the duration of follow-up with a freedom-from-event analysis; only complete (2 doses) vaccination at the time of hospital admission remained independently associated with persistence of the major physical symptoms, while vaccination and previous neuropsychological symptoms remained independently associated with persistence of major neuropsychological symptoms.

The Rise and Fall of Antithrombin Supplementation in Cardiac Surgery.

Various cohort studies, both retrospective and prospective, showed that low antithrombin levels after cardiac surgery (at the arrival in the intensive care unit and during the next days) were associated with a number of adverse outcomes, including surgical reexploration and thromboembolic events, eventually leading to prolonged stay in the intensive care. Values lower than 58% to 64% of antithrombin activity were indicative of this higher morbidity with good sensitivity and specificity. The scenario generated the hypothesis that low antithrombin levels needed to be corrected by supplementation to improve postoperative outcome. However, randomized controlled studies run to test this idea failed to demonstrate any benefit of antithrombin supplementation, showing no effects on outcome, neither as preemptive preoperative strategy nor for treating postoperative low antithrombin values. In addition, randomized trials highlighted that those patients who received antithrombin experienced significantly higher incidence of acute kidney injury with a pooled odds ratio of 4.41 (95% CI, 1.90-10.23; P = .001). A strongly decreased thrombin activity after antithrombin correction may eventually affect the efficiency of the glomerular filtration and cause the deterioration of kidney function, but underlying biological mechanisms remain unclear. In conclusion, low levels of antithrombin activity after cardiac surgery should be considered as a marker of greater severity of the patient's conditions and/or of the complexity of the surgical procedure. There are no indications for antithrombin supplementation in cardiac surgery unless for correcting heparin resistance.

Clopidogrel Resistance and Ticagrelor Replacement in Dual Antiplatelet Therapy for Carotid Artery Stenting.

BACKGROUNDS: Resistance to the pharmacological effect of clopidogrel in patients undergoing dual antiplatelet therapy for carotid stenting may increase the risk of periprocedural neurological events. The purpose of the study was to describe the phenomenon of clopidogrel resistance in a series of patients undergoing carotid stenting. METHODS: Data of patients who consecutively underwent carotid stenting from November 2016 to December 2020 for a significant stenosis and who underwent a dual antiplatelet therapy using acetyl-salicylic acid and clopidogrel were prospectively collected. Patients who were already taking a different thienopyridine were excluded. The effectiveness of antiplatelet drugs was assessed by the impedance aggregometry test. Primary endpoint was to evaluate the incidence of clopidogrel resistance and the effectiveness of ticagrelor as alternative therapy. P values < 0.05 were considered statistically significant. RESULTS: Two-hundred patients (80 females, 40%) underwent stenting for carotid stenosis (94% asymptomatic). The phenomenon of clopidogrel resistance was observed in 38 patients (19%), in whom clopidogrel was replaced by ticagrelor (90 mg/bis in die) with 100% effectiveness at aggregometry test. Platelet counts was associated to clopidogrel resistance (P = 0.001). There was no stent thrombosis at 30 days, neither major hemorrhagic events; a total of 12/200 major adverse cardiovascular events occurred (6%), including 1 in the group of patients who took ticagrelor and 11 in group of patients under clopidogrel (2.6% versus 6.7%, P = 0.55). CONCLUSIONS: Clopidogrel was ineffective in 19% of patients undergoing carotid stenting. Platelet count seemed to affect this phenomenon. In these patients, clopidogrel was effectively replaced by ticagrelor.

Association of miR-144 levels in the peripheral blood with COVID-19 severity and mortality.

Coronavirus disease-2019 (COVID-19) can be asymptomatic or lead to a wide symptom spectrum, including multi-organ damage and death. Here, we explored the potential of microRNAs in delineating patient condition and predicting clinical outcome. Plasma microRNA profiling of hospitalized COVID-19 patients showed that miR-144-3p was dynamically regulated in response to COVID-19. Thus, we further investigated the biomarker potential of miR-144-3p measured at admission in 179 COVID-19 patients and 29 healthy controls recruited in three centers. In hospitalized patients, circulating miR-144-3p levels discriminated between non-critical and critical illness (AUCmiR-144-3p = 0.71; p = 0.0006), acting also as mortality predictor (AUCmiR-144-3p = 0.67; p = 0.004). In non-hospitalized patients, plasma miR-144-3p levels discriminated mild from moderate disease (AUCmiR-144-3p = 0.67; p = 0.03). Uncontrolled release of pro-inflammatory cytokines can lead to clinical deterioration. Thus, we explored the added value of a miR-144/cytokine combined analysis in the assessment of hospitalized COVID-19 patients. A miR-144-3p/Epidermal Growth Factor (EGF) combined score discriminated between non-critical and critical hospitalized patients (AUCmiR-144-3p/EGF = 0.81; p < 0.0001); moreover, a miR-144-3p/Interleukin-10 (IL-10) score discriminated survivors from nonsurvivors (AUCmiR-144-3p/IL-10 = 0.83; p < 0.0001). In conclusion, circulating miR-144-3p, possibly in combination with IL-10 or EGF, emerges as a noninvasive tool for early risk-based stratification and mortality prediction in COVID-19.

Are Viscoelastic Tests Clinically Useful to Identify Platelet-Dependent Bleeding in High-Risk Cardiac Surgery Patients?

BACKGROUND: Postoperative use of platelet function testing to rule out microvascular bleeding due to platelet dysfunction after cardiac surgery still lacks strong reference data and reliable cutoff values, yielding a clinically adequate sensitivity and specificity. The present study aims to investigate the performance of two different point-of-care viscoelastic devices and platelet aggregometry in expressing surgery-dependent platelet dysfunction and anticipating postoperative major bleeding in a cohort of high-risk patients. METHODS: Prospective cohort study of 50 adult patients who were on antiplatelet drugs discontinued for no more than 7 days (clopidogrel and prasugrel) or 5 days (ticagrelor) undergoing cardiac surgery with cardiopulmonary bypass (CPB). Coagulation and platelet function testing, including QUANTRA, ROTEM, and Multiplate, were assessed preoperatively and postoperatively. Chest drain blood loss was measured in the first 12 postoperative hours. Perioperative bleeding was assessed using a modified version of the Universal Definition of Perioperative Bleeding (UDPB) in cardiac surgery, modified to not consider anemia-correcting packed red cells transfusions in the absence of bleeding >600 mL/12 h. Major bleeding was identified as UDPB class II or higher. RESULTS: Multiplate adenosine diphosphate (ADPtest) was significantly ( P = .001) reduced after CPB, whereas TRAPtest was not. The platelet component (PC) as extrapolated by ROTEM data (EXTEM MCF-FIBTEM MCF) was unchanged after CPB, while the A10 PC (PC at 10 minutes) was significantly ( P = .001) reduced. The QUANTRA platelet contribution to clot stiffness (PCS) was significantly ( P = .001) reduced, as well. At the ROC analysis for the predictive ability of the post-CPB platelet function testing, the best discrimination was obtained by the QUANTRA PCS, with an area under the curve (AUC) (95% confidence interval [CI]) of 0.80 (0.66-0.91), P = .001, followed by the ROTEM A10 PC with AUC (95% CI) of 0.75 (0.51-0.99), P = .004, and PC with AUC (95% CI) of 0.74 (0.50-0.99), P = .009. The Multiplate ADPtest had an AUC (95% CI) of 0.67 (0.42-0.91), and the TRAPtest had an AUC (95% CI) of 0.62 (0.37-0.86). The cutoff values identified were 13 hPa for the QUANTRA PCS, 40 mm for the ROTEM A10, and 48.5 mm for the ROTEM PC, with negative predictive values of 84%, 81%, and 86%, respectively, and positive predictive values of 55%, 53%, and 69%, respectively. CONCLUSIONS: QUANTRA PCS, ROTEM A10 PC, and Multiplate ADPtest showed a significant decrease after CPB, whereas ROTEM PC and Multiplate TRAPtest did not. Major bleeding was predicted with a moderate to good discrimination by the post-CPB viscoelastic tests (PCS, PC, and A10 PC).

Microcirculatory Alterations in Critically Ill Patients with COVID-19-Associated Acute Respiratory Distress Syndrome.

BACKGROUND: Presently, a number of specific observations have been performed on microcirculatory function in a coronavirus disease-19 (COVID-19) setting. We hypothesized that, in the critically ill, endothelial dysfunction secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the subsequent inflammation and coagulopathy may lead to microcirculatory alterations, further exacerbated by the hypoxemic state. A dysfunctional microcirculation may represent the hidden motor underlying the development of COVID-19's clinical manifestations. METHODS: A single center, prospective, observational study. We analyzed bedside sublingual microcirculation in twenty-four consecutive COVID-19-associated acute respiratory distress syndrome (ARDS) patients mechanically ventilated in an Intensive Care Unit (ICU), together with macro-hemodynamics, clinical parameters, echocardiography, and laboratory data at a single time-point after ICU admission. All participants were recruited between March and May 2020. RESULTS: The microcirculatory pattern was characterized by increased values of total vessel density and perfused vessel density, a reduced value of proportion of perfused vessels and microvascular flow index, and high values of heterogeneity index. The duration of mechanical ventilation before microcirculation assessment was inversely associated with the proportion of perfused vessels (p = 0.023). Within the macro-hemodynamic parameters, the right ventricle end-diastolic diameter was inversely associated with proportion of perfused vessels and microvascular flow index (p = 0.039 and 0.014, respectively) and directly associated with the heterogeneity index (p = 0.033). CONCLUSIONS: In COVID-19-associated ARDS patients, the microcirculation showed impaired quality of flow parameters coupled with a high vessel density.

A Comparative Study of Multiple Electrode Aggregometry Technologies in Cardiac Surgery: Different Values, Same Clinical Relevance.

OBJECTIVES: The assessment of platelet function in cardiac surgery patients who recently received dual-antiplatelet therapy is considered in the existing guidelines. Among available devices, Multiplate (MP) and ROTEM Platelet (RP) are both based on electrical impedance. This study aimed to determine the agreement between MP and RP in cardiac surgery patients under dual-antiplatelet therapy discontinued before surgery. Secondarily, it compared the ability of the MP and RP in predicting postoperative bleeding and the need for platelet transfusion. DESIGN: A prospective cohort study. SETTING: A hospital in Milan, Italy. PARTICIPANTS: Fifty adult patients preoperatively and postoperatively tested. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were studied with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP) testing on both of the devices. The mean preoperative ADP tests were below the respective lower limit of the reference value, thus reflecting a good ability of these tests to detect the residual or ongoing effects of antiplatelet drugs acting on the P2Y12 receptor. The agreement between the 2 methodologies was very poor for both the ADP and TRAP tests, with a percentage error of 80%. The preoperative ADP tests were predictive for the need of platelet concentrate transfusion, with cut-off values at 35 U for the ADP-MP and 60 Ω/min for the ADP-RP. No correlation was found for postoperative bleeding. CONCLUSION: Both technologies seemed to offer potential benefits in the surgical approach to patients who preoperatively received antiplatelet drugs. However, the results of these tests are not interchangeable, and different cut-off values should be applied.

Covid-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome.

Background: Coronavirus Disease 2019 (COVID-19)-associated coagulopathy is characterized by a prothrombotic state not yet comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS), comparing patients who survived to those who did not. Methods: In this prospective cohort study on 20 COVID-19 ARDS patients, the following biomarkers were measured: thrombin generation (prothrombin fragment 1 + 2 (PF 1 + 2)), fibrinolysis activation (tissue plasminogen activator (tPA)) and inhibition (plasminogen activator inhibitor 2 (PAI-2)), fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex (PAP) and D-dimers). Measurements were done upon intensive care unit (ICU) admission and after 10-14 days. Results: There was increased thrombin generation; modest or null release of t-PA; and increased levels of PAI-2, fibrinopeptide A, PAP and D-dimers. At baseline, nonsurvivors had a significantly (p = 0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range (IQR) 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly (p = 0.025) reduced in survivors (PF 1 + 2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in nonsurvivors. Fibrinolysis inhibition at follow-up remained stable in survivors and increased in nonsurvivors, leading to a significant (p = 0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1088 pg/mL, IQR 177-1565). Conclusion: Severe patterns of COVID-19 ARDS are characterized by a thrombin burst and the consequent coagulation activation. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. This pattern ameliorates in survivors, whereas it worsens in nonsurvivors.

Sensitivity of Viscoelastic Tests to Platelet Function.

Viscoelastic tests provide a dynamic assessment of coagulation, by exploring the time to clot formation and the clot strength. Using specific activators or inhibitors, additional factors can be explored, like the fibrinogen contribution to clot strength. Since the early days, various attempts have been done to measure platelet function with viscoelastic test. In general, the difference between the maximum clot strength and the fibrinogen contribution is considered an index of platelet contribution. However, this parameter does not clearly split platelet count from function; additionally, the extensive thrombin generation of standard activated viscoelastic tests activates platelet through the protease activated receptors, bypassing the other pathways. For this reason, standard viscoelastic tests cannot be used to assess platelet reactivity under the effects of aspirin or P2Y12 inhibitors. To overcome this limitation, a specific test was developed (thromboelastography platelet mapping). This test has been compared with the gold standard of light transmission aggregometry and with other point-of-care tests, with conflicting results. In general, the use of viscoelastic tests to assess the effects of antiplatelet agents is still limited. Conversely, platelet contribution to clot strength in the setting of coagulopathic bleeding is considered an important parameter to trigger platelet transfusion or desmopressin.

The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.

BACKGROUND: Few observations exist with respect to the pro-coagulant profile of patients with COVID-19 acute respiratory distress syndrome (ARDS). Reports of thromboembolic complications are scarce but suggestive for a clinical relevance of the problem. OBJECTIVES: Prospective observational study aimed to characterize the coagulation profile of COVID-19 ARDS patients with standard and viscoelastic coagulation tests and to evaluate their changes after establishment of an aggressive thromboprophylaxis. METHODS: Sixteen patients with COVID-19 ARDS received a complete coagulation profile at the admission in the intensive care unit. Ten patients were followed in the subsequent 7 days, after increasing the dose of low molecular weight heparin, antithrombin levels correction, and clopidogrel in selected cases. RESULTS: At baseline, the patients showed a pro-coagulant profile characterized by an increased clot strength (CS, median 55 hPa, 95% interquartile range 35-63), platelet contribution to CS (PCS, 43 hPa; interquartile range 24-45), fibrinogen contribution to CS (FCS, 12 hPa; interquartile range 6-13.5) elevated D-dimer levels (5.5 µg/mL, interquartile range 2.5-6.5), and hyperfibrinogenemia (794 mg/dL, interquartile range 583-933). Fibrinogen levels were associated (R2  = .506, P = .003) with interleukin-6 values. After increasing the thromboprophylaxis, there was a significant (P = .001) time-related decrease of fibrinogen levels, D-dimers (P = .017), CS (P = .013), PCS (P = .035), and FCS (P = .038). CONCLUSION: The pro-coagulant pattern of these patients may justify the clinical reports of thromboembolic complications (pulmonary embolism) during the course of the disease. Further studies are needed to assess the best prophylaxis and treatment of this condition.

Platelet Contribution to Clot Strength in Thromboelastometry: Count, Function, or Both?

In thromboelastometry (ROTEMTM) the difference in amplitude between the EXTEM and the FIBTEM is considered an index of platelet contribution to clot strength (PCSamp). The difference in elasticity (PCSel) is rarely used. We investigated the ability of PCSamp and PCSel in reflecting platelet count and function in 103 patients undergoing cardiac surgery, simultaneously measuring ROTEM and platelet function tests (multiple electrode aggregometry ADPtest and TRAPtest, MultiplateTM). PCSamp and PCSel were tested for association with platelet count and function. The PCSamp showed a low (R coefficient 0.32-0.39) association with platelet count and function (ADPtest), whereas the PCSel showed higher values of association (R coefficient 0.55-0.71) with the same variables. No association was found between PCS and TRAPtest. In a multivariable model, both the platelet count (R coefficient 0.60, P = 0.001) and the ADPtest (R coefficient 0.36, P = 0.001) were independently associated with the PCSel. The discrimination properties of the PCSel for the prediction of a low platelet count/function were very good (c-statistics 0.837). In clinical practice, the difference in elasticity between EXTEM and FIBTEM should replace the difference in amplitude.

Antenatal maternal antidepressants drugs treatment affects S100B levels in maternal-fetal biological fluids in a dose dependent manner.

BACKGROUND: The increased use of antidepressant treatment during pregnancy occurred without firm evidence on safety/efficacy. The present study investigated the correlation among S100B and paroxetine blood levels with the occurrence of short-term post-natal neurological abnormalities. METHODS: We conducted a cross-sectional study in 50 pregnant women using paroxetine because of depression and in 150 controls. Standard laboratory parameters and S100B were measured at seven monitoring time-points (maternal blood: T1, 16-20 wks; T2, 27-30 wks; T3, 35-40 wks; T4, at delivery; amniotic fluid, T5; venous and arterial cord blood, T6-T7). Paroxetine levels were measured at T1-T6. Neurological outcome was set at 7th day from birth. RESULTS: Higher S100B concentrations at T1-T7 were found in the paroxetine-treated group. S100B correlated with paroxetine blood levels. The paroxetine/S100B ratio cut-off of 1.31 at T2 achieved sensitivity 100%, specificity 96.5% and positive/negative predictive values 87.5-100, respectively, as a single marker to predict adverse neonatal neurological outcome. CONCLUSIONS: The present study offers additional support to the usefulness of longitudinal S100B and drug level monitoring in depressed pregnant women and in the early detection of cases at risk for short-term neurological abnormalities. Results open the way at further investigations correlating antidepressant drugs and neurobiomarkers in the maternal bloodstream.

Anti-Factor Xa-Based Anticoagulation during Extracorporeal Membrane Oxygenation: Potential Problems and Possible Solutions.

Choices for monitoring of unfractionated heparin (UFH) anticoagulation in extracorporeal membrane oxygenation (ECMO) patients include activated clotting time, activated partial thromboplastin time, reaction times of viscoelastic tests, and anti-factor Xa activity (between 0.3 and 0.7 IU/mL). Recent studies propose the anti-factor Xa to be the gold standard for monitoring UFH anticoagulation in ECMO. However, many extraneous factors combined question the utility of anti-factor Xa as the sole method of monitoring of UFH effects in ECMO. Anti-factor Xa is a chromogenic assay, which may be biased by the frequently elevated values of bilirubin and free hemoglobin in ECMO patients. The test may alternatively underestimate UFH effects in cases of low antithrombin values. More importantly, the anti-factor Xa assay is a plasma-based test which does not take into account the role of platelets and fibrinogen in forming a stable clot. Thrombocytopenia and platelet dysfunction are common features in ECMO patients, and underestimating their role may lead to over-anticoagulation, should only anti-factor Xa guiding be used to adjust the UFH dose. Conversely, fibrinogen is an acute phase protein, and some patients may experience high levels of fibrinogen during the ECMO course. In this case, an UFH monitoring based on anti-factor Xa is insensitive to this condition, although it may potentially be associated with thrombotic complications. Finally, the generally suggested range of 0.3 to 0.7 IU/mL is a somewhat arbitrary estimate, based on the desired range for treating and preventing thrombotic events in non-ECMO patients. In conclusion, anti-factor Xa may offer useful information on the real effects of UFH only when combined with a whole blood test capable of assessing the relative contribution of platelets and fibrinogen to clot formation.

Trials and Tribulations of Viscoelastic-Based Determination of Fibrinogen Concentration.

Acquired fibrinogen deficiency is a major determinant of severe bleeding in different clinical conditions, including cardiac surgery, trauma, postpartum hemorrhage, liver surgery, and transplantation. The existing guidelines recommend to supplement fibrinogen in patients with severe bleeding when the fibrinogen concentration is <1.5 g/L. Viscoelastic tests (VETs) provide a fast determination of the fibrinogen contribution to clot firmness and allow prompt treatment of acquired fibrinogen deficiency. However, different VET devices are presently available on the market, based on different technologies and different activators and platelet inhibitors. The available tests are the functional fibrinogen (FF, thromboelastography), the fibrinogen contribution to clot firmness (fibrinogen determination [FIBTEM], thromboelastometry), and the fibrinogen contribution to clot strength (FCS, sonorheometry). All these tests have a moderate to very good correlation with the Clauss fibrinogen assays; however, when comparing VET-based fibrinogen contribution to clot firmness with Clauss fibrinogen concentration, strong differences occur within the same test under different conditions and between different tests. The most widely studied test is the thromboelastometric FIBTEM; the best predictor of a Clauss fibrinogen <1.5 g/L is placed at a maximum clot firmness around 8 mm of amplitude. Fewer data are available for thromboelastographic FF, but the correspondent value is in the range of 12 mm. Overall, due to an incomplete inhibition of platelet contribution, FF overestimates the fibrinogen contribution with respect to FIBTEM. Data on sonorheometry FCS are limited and conflicting. When addressing the correlation between different tests, it is good in general, but no fixed conversion factors can be proposed, due to a considerable dispersion of the experimental points. In conclusion, VET-based fibrinogen tests are certainly powerful tools that are presently suggested by the existing guidelines; however, when using them for clinical decision-making, users should consider the possible sources of bias, which include the different level of platelet inhibition, the role of platelet count and function, the possible different degrees of blood activation with tissue factor, the important role of factor XIII in stabilizing the fibrin clot, and others.