Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Proyecto de biomarcadores y perfiles clínicos personalizados en la enfermedad pulmonar obstructiva crónica (proyecto BIOMEPOC) / The BIOMEPOC Project: Personalized Biomarkers and Clinical Profiles in Chronic Obstructive Pulmonary Disease

La enfermedad pulmonar obstructiva crónica (EPOC) es una entidad de presentación heterogénea. Por ello, se han intentado perfilar diferentes fenotipos y endotipos, que permitirían un manejo más diferenciado. El objetivo del proyecto Biomarcadores en la EPOC (BIOMEPOC) es identificar biomarcadores sanguíneos útiles para tipificar mejor a los enfermos. Se analizarán datos clínicos y muestras sanguíneas en un grupo de pacientes y controles sanos. El proyecto constará de fases de prospección y de validación. Se realizarán determinaciones analíticas sanguíneas con técnicas convencionales y de diversas ciencias «ómicas» (transcriptómica, proteómica y metabolómica). Las primeras se realizarán orientadas por hipótesis, mientras que con las segundas se realizará una exploración sin dicho condicionante. Finalmente se realizará un análisis multinivel. En el momento actual se han reclutado 269 pacientes y 83 controles, y se está iniciando el procesamiento de muestras. Con los resultados obtenidos se espera identificar nuevos biomarcadores que, en solitario o combinados, permitan una mejor tipificación de los pacientes

Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain ‘omics’ (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients

The BIOMEPOC Project: Personalized Biomarkers and Clinical Profiles in Chronic Obstructive Pulmonary Disease. / Proyecto de biomarcadores y perfiles clínicos personalizados en la enfermedad pulmonar obstructiva crónica (proyecto BIOMEPOC).

Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain 'omics' (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients.

Cystatin C estimated glomerular filtration rate to assess renal function in early stages of autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: Height-adjusted total kidney volume (htTKV) is the best marker of disease progression in early autosomal dominant polycystic kidney disease (ADPKD) when renal function still remains normal. The usefulness of cystatin-C as a biomarker to assess renal function according to renal volume has not been studied in ADPKD patients. METHODS: Observational and cross-sectional study of 62 ADPKD patients. htTKV, creatinine and cystatin-C estimated glomerular filtration rate (eGFR) were determined. Correlations between htTKV and eGFR were studied. A control group was used to determine the association between renal function differences and htTKV. RESULTS: htTKV significantly correlated with cystatin-C-eGFR (r = -0.384, p = 0.002) but not with creatinine-eGFR (r = -0.225, p = 0.078). With htTKV stratified into tertiles, a significant difference of cystatin-C-eGFR but not in creatinine-eGFR was detected in the third tertile when compared with the first tertile group (110.0±22.2 vs 121.3±7.2; p = 0.023 and 101.8±17.2 vs 106.9±15.1; p = 0.327 respectively). When cystatin-C-eGFR of the controls was used as the reference, htTKV above 605 ml/m identified with a 75% sensitivity and 84.9% specificity those patients with a significant worse kidney function. However, this cut-off value could not be identified using creatinine-eGFR. CONCLUSIONS: Cystatin-C-eGFR but not creatinine-eGFR correlated with htTKV in ADPKD patients in early stages of the disease. Differences in cystatin-C-eGFR but not in creatinine-eGFR have been identified through htTKV tertiles. A htTKV above 605 ml/m is associated with a worse renal function only if cystatin-C-eGFR is used. Cystatin-C-eGFR should be studied in prospective studies of early stages of ADPKD to determine its usefulness as an early marker of disease progression.

Impact of monopolar radiofrequency coagulation on intraoperative blood loss during liver resection: a prospective randomised controlled trial.

PURPOSE: To evaluate the impact of using monopolar thermal coagulation based on radiofrequency (RF) currents on intraoperative blood loss during liver resection. MATERIALS AND METHODS: A prospective randomised controlled trial was planned. Patients undergoing hepatectomy were randomised into two groups. In the control group (n = 10), hemostasis was obtained with a combination of stitches, vessel-sealing bipolar RF systems, sutures or clips. In the monopolar radiofrequency coagulation (MRFC) group (n = 18), hemostasis was mainly obtained using an internally cooled monopolar RF electrode. RESULTS: No differences in demographic or clinical characteristics were found between groups. Mean blood loss during liver resection in the control group was more than twice that of the MRFC group (556 ± 471 ml vs. 225 ± 313 ml, p = .02). The adjusted mean bleeding/transection area was also significantly higher in the control group (7.0 ± 3.3 ml/cm2 vs. 2.8 ± 4.0 ml/cm2, p = .006). No significant differences were observed in the rate of complications between the groups. CONCLUSIONS: The findings suggest that the monopolar electrocoagulation created with an internally cooled RF electrode considerably reduces intraoperative blood loss during liver resection.

Comparison of the performances of cardiac troponins, including sensitive assays, and copeptin in the diagnostic of acute myocardial infarction and long-term prognosis between women and men.

BACKGROUND: Concerns have been raised about possible gender disparities in cardiac investigations and/or outcome. This study sought to examine and compare the diagnostic and prognostic performance of selected cardiac biomarkers in women versus men. METHODS: In a prospective, multicenter cohort of patients with acute chest pain cardiac troponin T (cTnT) (fourth-generation Roche assay), high-sensitivity cTnT (hs-cTnT), and copeptin were measured at presentation. RESULTS: Of 1,247 patients, 420 were women and 827 were men. Although the rate of acute myocardial infarction was similar in women (14.5%) and men (16.6%, P = .351), women more frequently had cardiac but noncoronary causes of chest pain (17.4% vs 10.8%, P = .001) and less frequently had unstable angina (8.8% vs 16.6%, P = .002) than men. Diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (AUC) for acute myocardial infarction in women was 0.90 (95% CI 0.84-0.95) for cTnT, which was lower than the AUC for hs-cTnT alone (0.94, 95% CI [0.91-0.98]), the combination of cTnT with copeptin (0.96, 95% CI [0.94-0.98]) or the combination of hs-cTnT with copeptin (0.96, 95% CI [0.93-0.98]) (P = .008, P = .006, and P = .002, respectively). Prognostic accuracy as quantified by the AUCs for 1-year mortality was 0.69 (0.56-0.83), 0.86 (0.79-0.93), 0.87 (0.81-0.94), and 0.87 (0.80-0.94), respectively. No relevant gender differences in AUCs were observed. CONCLUSION: The diagnostic and prognostic performance of cTnT, hs-cTnT, and copeptin is as good in women as in men. High-sensitivity cTnT and the combination of cTnT and copeptin outperform cTnT alone, both in women and men.

Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.

BACKGROUND: We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED). METHODS AND RESULTS: In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%-99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%-99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%. CONCLUSIONS: Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays.

Uric acid for diagnosis and risk stratification in suspected myocardial infarction.

BACKGROUND: Hypoxia precedes cardiomyocyte necrosis in acute myocardial infarction (AMI). We therefore hypothesized that uric acid - as a marker of oxidative stress and hypoxia - might be useful in the early diagnosis and risk stratification of patients with suspected AMI. MATERIALS AND METHODS: In this prospective observational study, uric acid was measured at presentation in 892 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by two independent cardiologists. Patients were followed 24 months regarding mortality. Primary outcome was the diagnosis of AMI, secondary outcome was short- and long-term mortality. RESULTS: Uric acid at presentation was higher in patients with AMI than in patients without (372 µM vs. 336 µM; P < 0·001). The diagnostic accuracy of uric acid for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0·60 (95%Cl 0·56-0·65). When added to cardiac troponin T (cTnT), uric acid significantly increased the AUC of cTnT from 0·89 (95%Cl 0·85-0·93) to 0·92 (95%Cl 0·89-0·95, P = 0·020 for comparison). Cumulative 24-month mortality rates were 2·2% in the first, 5·4% in the second and the third and 15·6% in the fourth quartile of uric acid (P < 0·001 for log-rank). Uric acid predicted 24-month mortality independently. Adding uric acid to TIMI and GRACE risk score improved their prognostic accuracy as shown by an integrated discrimination improvement of 0·04 (P = 0·007) respective 0·02 (P = 0·021). CONCLUSIONS: Uric acid, an inexpensive widely available biomarker, improves both the early diagnosis and risk stratification of patients with suspected AMI.

[Predictive factors for pneumonia in adults infected with the new pandemic A (H1H1) influenza virus]. / Factores predictivos de neumonía en pacientes infectados por el nuevo virus de la gripe A (H1N1) pandémica.

BACKGROUND: On April 2009 a new A (H1N1) influenza virus was identified with a higher incidence of severe outcome in younger people, most of them with pneumonia. The objective of our study was to identify the predictive risk factors of pneumonia in patients with the new A (H1N1) influenza virus infection. METHODS: Prospective cohort study of adults infected with the new A (H1N1) influenza virus, admitted in a universitary hospital, from june 2009 to January 2010. Pneumonia was defined as the presence of any pulmonary infiltrate of any distribution with no other evident cause, in the chest radiography. A comparative analysis was made with patients with A (H1N1) influenza without pneumonia. RESULTS: 281 patients with influenza A (H1N1) were treated. Thirty of them (10.6%) had pneumonia and 11 (3.9%) required intensive care. The global mortality was 0.7%. For the comparative analysis, 42 patients with influenza A (H1N1) without pneumonia were analysed (20 hospitalized and 22 nonhospitalised). In the multivariate analysis, obesity (BMI>30), (OR: 3.8; IC 95%: 0.99-15.0), time since symptom onset until hospital admission (OR 1.34; IC 95% 1.04-1.72), serum C reactive protein levels (OR:1.10; IC 95%: 0.98-1.24) and serum IgG2 levels (OR:1.08; IC 95%: 1.0- 1.01), were identified as independent risk factors for pneumonia. CONCLUSION: Obesity, delay in medical care and higher levels of C reactive protein and IgG2 were predictive factors for pneumonia in adult patients with A (H1N1) influenza infection.

Factores predictivos de neumonía en pacientes infectados por el nuevo virus de la gripe A (H1N1) pandémica / Predictive factors for pneumonia in adults infected with the new pandemic A (H1H1) influenza virus

Introducción: en abril de 2009 se identificó un nuevo virus de la gripe A H1N1 con mayor incidencia de casos graves en pacientes jóvenes, con afectación pulmonar en forma de neumonía en la mayoría de ellos. El objetivo de este estudio fue identificar los factores predictivos de neumonía en pacientes infectados por el nuevo virus de la gripe A (H1N1). Métodos: estudio de cohortes prospectivo de casos de infección por el virus de la gripe A (H1N1), en adultos, de junio de 2009 a enero de 2010, en un hospital universitario. Se definió neumonía como la presencia de infiltrado de cualquier tipo y distribución en la radiografía de tórax, sin otra causa evidente. Se realizó un análisis comparativo con pacientes con gripe A (H1N1) sin neumonía. Resultados: Se atendieron 281 pacientes adultos con gripe A (H1N1). De ellos 30 (10.6%) tenían neumonía. y 11 (3,9%) precisaron cuidados intensivos. La mortalidad global fue del 0,7%. Para el análisis comparativo se analizaron 42 pacientes con gripe A H1N1 sin neumonía (20 ingresados y 22 ambulatorios). En el análisis multivariado se identificaron como factores de riesgo de neumonía un IMC >30 (OR: 3,8; IC 95%: 0,99- 15,0), los días transcurridos desde el inicio de los síntomas hasta el ingreso hospitalario (OR 1,34; IC 95% 1,04-1,72), los niveles de PCR (OR:1,10; IC 95%: 0,98-1,24) y de IgG subtipo 2 (OR: 1,08; IC 95%: 1,0- 1,01). Conclusiones: la obesidad, el retraso en la atención sanitaria, y unos niveles elevados de PCR e IgGsub2 fueron factores predictivos de neumonía en pacientes adultos con gripe A H1N1(AU)

Background: On April 2009 a new A (H1N1) influenza virus was identified with a higher incidence of severe outcome in younger people, most of them with pneumonia. The objective of our study was to identify the predictive risk factors of pneumonia in patients with the new A (H1N1) influenza virus infection. Methods: Prospective cohort study of adults infected with the new A (H1N1) influenza virus, admitted in a universitary hospital, from june 2009 to January 2010. Pneumonia was defined as the presence of any pulmonary infiltrate of any distribution with no other evident cause, in the chest radiography. A comparative analysis was made with patients with A (H1N1) influenza without pneumonia. Results: 281 patients with influenza A (H1N1) were treated. Thirty of them (10.6%) had pneumonia and 11 (3.9%) required intensive care. The global mortality was 0.7%. For the comparative analysis, 42 patients with influenza A (H1N1) without pneumonia were analysed (20 hospitalized and 22 nonhospitalised). In the multivariate analysis, obesity (BMI>30), (OR: 3.8; IC 95%: 0.99-15.0), time since symptom onset until hospital admission (OR 1.34; IC 95% 1.04-1.72), serum C reactive protein levels (OR:1.10; IC 95%: 0.98-1.24) and serum IgG2 levels (OR:1.08; IC 95%: 1.0- 1.01), were identified as independent risk factors for pneumonia. Conclusion: Obesity, delay in medical care and higher levels of C reactive protein and IgG2 were predictive factors for pneumonia in adult patients with A (H1N1) influenza infection(AU)

Factores predictivos de infección por el virus de la gripe H1N1 2009 en pacientes con síndrome gripal / Predictive factors of 2009 H1N1 virus infection in patients with influenza syndrome

Introducción: La técnica de reacción en cadena de la polimerasa en frotis nasofaríngeo es uno de los mejores métodos para la detección de virus gripales. El objetivo de este estudio es conocer el porcentaje de frotis nasofaríngeos positivos durante la pandemia de gripe de 2009 y determinar si existe algún factor predictor de positividad para el virus H1N1 2009. Métodos: Estudio retrospectivo de todos los pacientes que consultaron en Urgencias por síndrome gripal entre el 15 de julio y el 15 de diciembre de 2009 a los que se realizó un frotis nasofaríngeo. Se identificaron aquellos casos en los que el frotis estaba correctamente solicitado. Se dividieron en dos grupos según la positividad para el virus H1N1 2009. Resultados: Se realizó un frotis nasofaríngeo a 362 pacientes. En 87 casos estaba incorrectamente indicado. De los 275 restantes, fue positivo en 141. Los pacientes con frotis positivo eran más jóvenes (36,1(15) años vs 42,3(18); p=0,002), tenían menor recuento de leucocitos, neutrófilos y linfocitos, menor valor de proteína C reactiva (5,15(5) vs 10,5(12); p<0,001) y menor incidencia de infiltrados radiológicos (20,5% vs 33%; p=0,036). La regresión logística identificó la edad, una proteína C reactiva baja y un recuento linfocitario bajo como factores independientes de infección por el virus H1N1 2009. Conclusiones: En pacientes con síndrome gripal, el porcentaje de positividades del frotis para detectar H1N1 2009 se sitúa en el 50%. La edad, los niveles de proteína C reactiva y el recuento linfocitario son factores independientes para predecir el resultado(AU)

Introduction: Polymerase chain reaction (PCR) testing is one of the better techniques for viral detection in nasopharyngeal swabs. The objective of this study was to assess the percentage of positive swabs and to determine whether there were differences according to PCR positivity. Material and Methods: A retrospective study of 362 patients with flu syndrome attended at the Emergency Department between July 15 and December 15, 2009, in whom PCR of nasopharyngeal swabs for the detection of H1N1 2009 influenza virus was performed. Those cases in which swab testing was adequately requested were identified, and patients were divided into two groups according to positive or negative results for H1N1 2009 influenza virus. Results: Nasopharyngeal swab was inadequately ordered in 87. In the remaining 275 patients, PCR was positive in 141. Patients with positive nasopharyngeal swabs were younger (mean [SD] age 36.1 [15] vs 42.3 [18] years, P = 0.002), had lower white blood cell, neutrophil and lymphocyte counts, lower serum concentrations of C-reactive protein (5.15 [5] vs 10.5 [12] mg/dL, P = 0.036) and lower incidence of radiological infiltrates (20.5% vs 33%, P = 0.036). In the logistic regression analysis, age, serum C-reactive protein levels, and lymphocyte count were independently associated with a positive nasopharyngeal swab. Conclusions:About 50% of patients with flu syndrome had positive nasopharyngeal swabs for H1N1 2009 influenza virus. Age, C-reactive protein, and lymphocyte count were independent predictors of positivity(AU)

NT-proBNP: a cardiac biomarker to assess prognosis in non-Hodgkin lymphoma.

NT-proBNP provides diagnostic and prognostic information in heart syndromes but its role in cancer has not yet been established. The prognostic value of NT-proBNP was prospectively studied in 104 non-Hodgkin lymphoma (NHL) patients treated with chemotherapy. Echocardiography and NT-proBNP were determined prior to treatment. In multivariate analysis, NT-proBNP ≥ 900 pg/ml was the variable with higher risk of death (adjusted hazard ratio 11.1; 95% CI 3.8-32.9; P<0.001). The C statistic for NT-proBNP ≥ 900 pg/ml was significantly better than IPI score for prediction of survival. These findings suggest that NT-proBNP ≥ 900 pg/ml could be considered a useful marker for risk assessment in NHL patients treated with chemotherapy.