Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Attributable mortality of acute respiratory distress syndrome: a systematic review, meta-analysis and survival analysis using targeted minimum loss-based estimation.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS. OBJECTIVE: To estimate the attributable mortality, if any, of ARDS. DESIGN: First, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method. RESULTS: In the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; p<0.001) with a numerically stronger association between ARDS and mortality in trauma than sepsis. In the survival analysis of three ICU cohorts enrolling 1203 critically ill patients, 658 septic patients were included. After controlling for confounders, ARDS was found to increase the mortality rate by 15% (95% CI 3% to 26%; p=0.015). Significant increases in mortality were seen for severe (23%, 95% CI 3% to 44%; p=0.028) and moderate (16%, 95% CI 2% to 31%; p=0.031), but not for mild ARDS. CONCLUSIONS: ARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit. PROSPERO REGISTRATION NUMBER: CRD42017078313.

Semi-quantitative visual assessment of chest radiography is associated with clinical outcomes in critically ill patients.

BACKGROUND: Respiratory pathology is a major driver of mortality in the intensive care unit (ICU), even in the absence of a primary respiratory diagnosis. Prior work has demonstrated that a visual scoring system applied to chest radiographs (CXR) is associated with adverse outcomes in ICU patients with Acute Respiratory Distress Syndrome (ARDS). We hypothesized that a simple, semi-quantitative CXR score would be associated with clinical outcomes for the general ICU population, regardless of underlying diagnosis. METHODS: All individuals enrolled in the Registry of Critical Illness at Brigham and Women's Hospital between June 2008 and August 2018 who had a CXR within 24 h of admission were included. Each patient's CXR was assigned an opacification score of 0-4 in each of four quadrants with the total score being the sum of all four quadrants. Multivariable negative binomial, logistic, and Cox regression, adjusted for age, sex, race, immunosuppression, a history of chronic obstructive pulmonary disease, a history of congestive heart failure, and APACHE II scores, were used to assess the total score's association with ICU length of stay (LOS), duration of mechanical ventilation, in-hospital mortality, 60-day mortality, and overall mortality, respectively. RESULTS: A total of 560 patients were included. Higher CXR scores were associated with increased mortality; for every one-point increase in score, in-hospital mortality increased 10% (OR 1.10, CI 1.05-1.16, p < 0.001) and 60-day mortality increased by 12% (OR 1.12, CI 1.07-1.17, p < 0.001). CXR scores were also independently associated with both ICU length of stay (rate ratio 1.06, CI 1.04-1.07, p < 0.001) and duration of mechanical ventilation (rate ratio 1.05, CI 1.02-1.07, p < 0.001). CONCLUSIONS: Higher values on a simple visual score of a patient's CXR on admission to the medical ICU are associated with increased in-hospital mortality, 60-day mortality, overall mortality, length of ICU stay, and duration of mechanical ventilation.

Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is characterized by the acute onset of hypoxemia and bilateral lung infiltrates in response to an inciting event, and is associated with high morbidity and mortality. Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for ARDS. We hypothesized that HSCT patients with ARDS would have a unique transcriptomic profile identifiable in peripheral blood compared to those that did not undergo HSCT. METHODS: We isolated RNA from banked peripheral blood samples from a biorepository of critically ill ICU patients. RNA-Seq was performed on 11 patients with ARDS (5 that had undergone HSCT and 6 that had not) and 12 patients with sepsis without ARDS (5 that that had undergone HCST and 7 that had not). RESULTS: We identified 687 differentially expressed genes between ARDS and ARDS-HSCT (adjusted p-value < 0.01), including IFI44L, OAS3, LY6E, and SPATS2L that had increased expression in ARDS vs. ARDS-HSCT; these genes were not differentially expressed in sepsis vs sepsis-HSCT. Gene ontology enrichment analysis revealed that many differentially expressed genes were related to response to type I interferon. CONCLUSIONS: Our findings reveal significant differences in whole blood transcriptomic profiles of patients with non-HSCT ARDS compared to ARDS-HSCT patients and point toward different immune responses underlying ARDS and ARDS-HSCT that contribute to lung injury.

Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells.

As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFN-γ typically helps microbial clearance, we found that increased plasma IFN-γ in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-γ suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-γ after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-γ production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in Cd1d-/- mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-γ axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-γ, which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.

Uric Acid and Acute Kidney Injury in the Critically Ill.

RATIONALE & OBJECTIVE: Uric acid is excreted by the kidney and accumulates in acute kidney injury (AKI). Whether higher plasma uric acid level predisposes to AKI or its complications is not known. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 2 independent cohorts of critically ill patients: (1) 208 patients without AKI admitted to the intensive care unit (ICU) at Brigham & Women's Hospital between October 2008 and December 2016; and (2) 250 participants with AKI requiring renal replacement therapy (RRT) who had not yet initiated RRT enrolled in the Acute Renal Failure Trial Network (ATN) Study. EXPOSURE: Plasma uric acid level upon ICU admission and before RRT initiation in the ICU and ATN Study cohorts, respectively. OUTCOMES: Incident AKI and 60-day mortality in the ICU and ATN Study cohorts, respectively. ANALYTICAL APPROACH: Logistic regression models were used to test the association of plasma uric acid level with incident AKI and 60-day mortality. RESULTS: In the ICU cohort, median plasma uric acid level was 4.7 (interquartile range [IQR], 3.6-6.4) mg/dL, and 40 patients (19.2%) developed AKI. Higher plasma uric acid levels associated with incident AKI, but this association was confounded by serum creatinine level and was not significant after multivariable adjustment (adjusted OR per doubling of uric acid, 1.50; 95% CI, 0.80-2.81). In the ATN Study cohort, median plasma uric acid level was 11.1 (IQR, 8.6-14.2) mg/dL, and 125 participants (50.0%) died within 60 days. There was no statistically significant association between plasma uric acid levels and 60-day mortality in either unadjusted models or after multivariable adjustment for demographic, severity-of-illness, and kidney-specific covariates (adjusted OR per doubling of uric acid, 1.15; 95% CI, 0.71-1.86). LIMITATIONS: Heterogeneity of ICU patients. CONCLUSIONS: Plasma uric acid levels upon ICU admission or before RRT initiation are not independently associated with adverse clinical outcomes in critically ill patients.

Leukocyte function assessed via serial microlitre sampling of peripheral blood from sepsis patients correlates with disease severity.

Dysregulated leukocyte responses underlie the pathobiology of sepsis, which is a leading cause of death. However, measures of leukocyte function are not routinely available in clinical care. Here we report the development and testing of an inertial microfluidic system for the label-free isolation and downstream functional assessment of leukocytes from 50 µl of peripheral blood. We used the system to assess leukocyte phenotype and function in serial samples from 18 hospitalized patients with sepsis and 10 healthy subjects. The sepsis samples had significantly higher levels of CD16dim and CD16- neutrophils and CD16+ 'intermediate' monocytes, as well as significantly lower levels of neutrophil-elastase release, O2- production and phagolysosome formation. Repeated sampling of sepsis patients over 7 days showed that leukocyte activation (measured by isodielectric separation) and leukocyte phenotype and function were significantly more predictive of the clinical course than complete-blood-count parameters. We conclude that the serial assessment of leukocyte function in microlitre blood volumes is feasible and that it provides significantly more prognostic information than leukocyte counting.

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness.

BACKGROUND: Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS: Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS: In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS: Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.

Efecto de las resinas secuestradoras de ácidos biliares en los desenlaces cardiovasculares y en los niveles séricos de lípidos: A systematic review / Effect of bile acid sequestrants on cardiovascular outcomes and seric lipids

Antecedentes: Las guías internacionales recientes proponen el uso de estatinas como piedra angular del manejo de la dislipidemia en adultos. Sin embargo, no se ha definido con claridad el tratamiento de los pacientes con intolerancia o efectos adversos asociados con estas. Las resinas secuestradoras de ácidos biliares son una alternativa interesante, pese a que la evidencia que avala su uso no ha sido evaluada cuidadosamente. Métodos: Se realizó una búsqueda de la literatura en MEDLINE, Embase y en la Biblioteca Cochrane hasta junio de 2013, acerca de artículos publicados en inglés y español, identificando experimentos clínicos aleatorizados y estudios de cohortes que evaluaran el impacto de las resinas secuestradoras de ácidos biliares en mortalidad, eventos cardiovasculares, niveles de lípidos séricos y efectos adversos. Se presenta la información de forma descriptiva. Resultados: Se identificaron cuatro experimentos clínicos aleatorizados y un estudio de cohortes, que incluían 6.833 pacientes. Solo uno de los estudios evaluó el impacto en la mortalidad cardiovascular, evidenciando que no hay diferencia estadísticamente significativa en comparación con placebo (RR de 0,76; IC 95% 0,5:1,15), aunque se observó una reducción del 16% en la incidencia de infarto agudo de miocardio (RR 0,84; IC 95% 0,67:1,00). Tres estudios evaluaron cambios en las fracciones lipídicas, los cuales mostraron disminución moderada en los niveles de colesterol LDL, sin percibir diferencias clínicamente significativas en los niveles de colesterol HDL y triglicéridos. Conclusión: La evidencia que respalda el uso de resinas secuestradoras de ácidos biliares es limitada y no avala su empleo como terapia de primera línea en pacientes con dislipidemia; no obstante, son una alternativa en pacientes con efectos adversos o intolerancia al manejo con estatinas.

Background: Recent international guidelines have proposed statins as the corner stone of dyslipidemia management in adults. However it is not clear if they are best option for patients with statin related intolerance or what their adverse effects are. The bile acid sequestrants are an interesting alternative, however its evidence has not been carefully evaluated. Methods: A search was conducted on MEDLINE, Embase and Cochrane library databases for articles published up to June 2013, limited to Spanish and English language. Randomized clinical trials (RCT) and cohort studies evaluating the impact of bile acid sequestrants on mortality, cardiovascular outcomes, seric lipids and adverse effects were selected. Information was presented in a descriptive way. Results: Four RCT and one cohort study with aggregate data on 6833 people were included. Just one study evaluated cardiovascular mortality showing no statistically significant difference when compared with placebo, (RR 0.76; 95% CI 0.5:1.15), however there was a 16% reduction on acute myocardial infarction incidence. (RR 0.84; 95% IC 0.67: 1.00). Three studies evaluated seric lipids changes showing a moderate reduction in LDL levels without clinical significant differences on HDL and triglyceride levels. Conclusions: The evidence supporting bile acid sequestrants use is lacking and not conclusive to recommend its use as first-line therapy in dyslipidemic patients; however, these are an alternative option for patients with statin-related intolerance or adverse effects.

Guía de práctica clínica para la prevención, detección temprana, diagnóstico, tratamiento y seguimiento de las dislipidemias: evaluación del riesgo cardiovascular / Clinical practice guidelines for the prevention, early detection, diagnosis, treatment and follow up of dyslipidemia: cardiovascular risk assessment

Objetivo: El tratamiento de la dislipidemia debe ser acorde con el riesgo individual de cada paciente. Existen múltiples ecuaciones de predicción de riesgo cardiovascular, sin embargo, es necesario determinar cuál es la más adecuada para ser utilizada en la población colombiana. Métodos: La alianza CINETS, comisionada por el Ministerio de la Protección Social y Colciencias, revisó la evidencia disponible con respecto a qué métodos de evaluación de riesgo cardiovascular son válidos en la población colombiana. Se generaron recomendaciones utilizando la metodología GRADE. Población: Población adulta con diagnóstico de dislipidemia o en riesgo de desarrollarla. Recomendaciones: En la población de prevención primaria o sin enfermedad cardiovascular clínicamente manifiesta se recomienda utilizar la escala de Framingham recalibrada para Colombia para clasificar el riesgo (Recomendación fuerte a favor de la intervención). Existen personas con condiciones que por sí mismas implican un riesgo mayor y ameritan manejo farmacológico directo.

Aim: The treatment of dyslipidemia must be related with patient's individual risk. There are multiple functions for predicting cardiovascular risk; however, it is necessary to determine the most appropriate for being used in Colombian population. Methods: The CINETS alliance, endorsed by the Colombian Social Protection Ministry and Colciencias, reviewed the evidence available about the validity of cardiovascular risk evaluation methods in Colombian Population. Recommendations were generated using GRADE methodology. Population: General adult population with or at risk of dyslipidemia. Recommendations In primary prevention population, or without clinically evident cardiovascular disease, Framingham risk function recalibrated for Colombia must be used to calculate cardiovascular risk (Strong recommendation). In patients with an especial condition increasing cardiovascular risk, direct pharmacologic treatment must be used.

Alternativas terapéuticas al manejo farmacológico con estatinas en adultos con dislipidemia. Revisión sistemática de la literatura y recomendaciones generales / Therapeutic alternatives to pharmacological management with statin drugs in adults with dyslipidemia. Systematic literature review and general recommendations

Objetivo: Evaluar el impacto sobre la incidencia y recurrencia de eventos cardiovasculares y cerebrovasculares (prevención primaria y secundaria), los niveles de las fracciones lipídicas y la incidencia de efectos secundarios en personas con hipercolesterolemia intolerantes al tratamiento con las estatinas. Métodos: Se elaboró una guía de práctica clínica siguiendo los lineamientos de la guía metodológica del Ministerio de Salud y Protección Social para recolectar de forma sistemática la evidencia científica y formular las recomendaciones utilizando la metodología GRADE. Población Población adulta, con diagnóstico de dislipidemia, o en riesgo de desarrollarla, intolerantes al manejo con las estatinas. Recomendaciones: Se formulan recomendaciones a favor del uso de diferentes medicamentos (los fibratos, la niacina, los ácidos omega 3, las resinas secuestradoras de ácidos biliares, el ezetimibe), según su efectividad hipolipemiante y reducción de eventos cardiovasculares, como propuesta adaptada al contexto social colombiano.

Objective To evaluate the impact on the incidence and recurrence of cardiovascular and cerebrovascular events (primary and secondary prevention), the levels of lipid fractions and the incidence of side effects in people with hypercholesterolemia intolerant to statin therapy. Methods: A clinical practice guideline was developed following the guidelines of the methodological guidance of the Ministry of Health and Social Protection to systematically collect the evidence and make recommendations using the GRADE methodology. Population: Adult population, diagnosed with dyslipidemia or at risk of developing, intolerant to management with statin drugs. Recommendations: Recommendations for the use of different medications (fibrates, niacin, omega 3 acids, bile acid binding resins, ezetimibe) are formulated according to their lipid-lowering effectiveness and reduction of cardiovascular events, a proposal adapted to the Colombian social context.

Guía de práctica clínica para la prevención, detección temprana, diagnóstico, tratamiento y seguimiento de las dislipidemias: tratamiento farmacológico con estatinas / Clinical practice guidelines for prevention, early detection, diagnose, treatment and follow-up of dyslipidemias: farmacological treatment with statins

Objetivo: Evaluar el impacto del tratamiento con estatinas sobre la incidencia y la recurrencia de los eventos cardiovasculares y los cerebrovasculares (prevención primaria y secundaria), los niveles de las fracciones lipídicas y la incidencia de efectos secundarios (el cáncer y la diabetes mellitus) en personas con hipercolesterolemia. Métodos: Se elaboró una guía de práctica clínica siguiendo los lineamientos de la guía metodológica del Ministerio de Salud y Protección Social para recolectar de forma sistemática la evidencia científica y formular las recomendaciones utilizando la metodología GRADE. Resultados: Se evidenció un efecto benéfico del tratamiento farmacológico con estatinas tanto en población de prevención primaria como en prevención secundaria, logrando reducciones clínica y estadísticamente significativas en la mortalidad y en los eventos cardiovasculares y cerebrovasculares. Adicionalmente, el tratamiento intensivo con estatinas mostró mayor reducción en los eventos cardiovasculares y cerebrovasculares ateroscleróticos al compararlo con el tratamiento de intensidad moderada. No se encontraron diferencias significativas en el riesgo de desarrollar cáncer al comparar estatinas frente a placebo pero sí se encontró un incremento de nueve por ciento en el riesgo de presentar diabetes mellitus asociado al tratamiento con estatinas. Conclusiones: Se formulan recomendaciones a favor del uso de estatinas como primera línea de tratamiento de hipercolesterolemia, y se establecen criterios para definir la intensidad de la terapia (alta o moderada respuesta) según el riesgo cardiovascular a 10 años, el nivel de colesterol LDL (cLDL), la edad y los antecedentes personales y los familiares.

Objective: To evaluate the impact of statin therapy on the incidence and recurrence of cardiovascular and cerebrovascular events (primary and secondary prevention), the levels of lipid fractions and the incidence of side effects (cancer and diabetes mellitus) in people with hypercholesterolemia. Methods: A clinical practice guideline was developed following the guidelines of the methodological guidance of the Ministry of Health and Social Protection to systematically collect the evidence and make recommendations using the GRADE methodology. Results: A beneficial effect of pharmacological treatment with statins in both primary prevention and secondary prevention was evident, achieving clinically and statistically significant reductions in mortality and cardiovascular and cerebrovascular events. Additionally, intensive statin therapy showed greater reduction in atherosclerotic cardiovascular and cerebrovascular events as compared to the treatment of moderate intensity. No significant differences in the risk of developing cancer by comparing statins versus placebo were found, but a 9% increase in the risk of diabetes mellitus associated with statin therapy was found. Conclusions: Recommendations for the use of statins as first-line treatment of hypercholesterolemia are formulated, and criteria to define the intensity of therapy (high or moderate response) as cardiovascular risk at 10 years, level of LDL (LDLc), age and personal and family history were established.

Lactato y déficit de bases en trauma: valor pronóstico / Lactate and base deficit in trauma: Prognostic value

Objetivos: Presentación de un caso clínico y revisión no sistemática de la literatura sobre lactato y déficit de bases en trauma, su fisiopatología y su valor pronóstico. Material y método: Con autorización del comité de ética de nuestra institución, se presenta el caso de un paciente politraumatizado sometido a cirugía vascular mayor y ortopédica, su manejo en la UCI y su desenlace. La búsqueda bibliográfica se realizó en Pub Med, Scielo y Bireme. Resultados: El lactato y el déficit de bases son herramientas clínicas de seguimiento muy temprano en trauma para detectar metabolismo anaeróbico. Igualmente evaluary modificar la estrategia de reanimación. Este modelo es aplicable a cirugía cardiovascular. Conclusiones: En trauma y cirugía cardiovascular, el lactato y el déficit de bases constituyen biomarcadores que se deben cuantificar de manera muy temprana y seriada, constituyendo un factor predictivo independiente de mortalidad dentro de las primeras 48 h en los pacientes con trauma. Igualmente, el déficit de base permite una estratificación temprana de los pacientes que se presentan en estado de choque y determinar con alta probabilidad su necesidad de hemoderivados o transfusión masiva. Se requieren más estudios relacionados con los pacientes normotensos.

Objectives:Clinical case discussion and non-systematic literature review on lactate and base-deficit in trauma, its pathophysiology and prognostic value.Materials and method: The case of a polytraumatized patient that underwent major vascu-larand orthopedic surgery, ICU management and outcomes is discussed with the approval ofthe Ethics Committee of our Institution. The literature search included Pub Med, Scielo andBireme.Results:Lactate and base deficit are early follow-up clinical tools in trauma for identifyin-ganaerobic metabolism, in addition to evaluating and changing the resuscitation strategy. This model is applicable to cardiovascular surgery. Conclusions:Both in trauma and cardiovascular surgery, lactate and base deficit are biomark-ers that need to be quantified very early and in a serial manner. They are inde-pendentpredictive factors for mortality in trauma patients in the first 48 h. Similarly, the base deficit allows for an early staging of patients in shock and for estab-lishing with a high probability the need forblood by-products or mass transfusion.Further studies are required for normotensive patients.

Nefrotoxicidad inducida por medicamentos / Drug-induced nephrotoxicity

La presente revisión incluye la descripción de los diferentes tipos de nefrotoxicidad inducida por medicamentos de acuerdo a su clasificación histopatológica, mecanismo de generación, presentación clínica y medicamentos más frecuentemente implicados. Para esta revisión fue realizada una búsqueda sistemática en el Index Medicus de artículos relacionados publicados a partir de 1999, los cuales fueron seleccionados de acuerdo a su pertinencia. La nefrotoxicidad inducida por medicamentos es un hallazgo de gran importancia clínica, debido a su alta frecuencia y potencial severidad, así como al desconocimiento de medidas preventivas en muchos casos. Las principales alteraciones renales producidas por medicamentos se pueden clasificar histopatológicamente, según la función renal alterada. De este modo, se encuentra la necrosis tubular aguda, la nefritis intersticial, la lesión glomerular y las alteraciones vasculares, que a su vez incluyen la microangiopatía trombótica, la aterosclerosis y la vasculitis. Finalmente, se hace una revisión de algunos medicamentos de uso habitual con alto potencial de nefrotoxicidad, haciendo énfasis en las recomendaciones de uso clínico dirigidas a optimizar la seguridad renal de estos productos...

This review includes a description of the different types of drug-induced nephrotoxicity (DIN) according to histopathologic classification, generation mechanism, clinical presentation and drugs most frequently involved. For this review, a systematic search was conducted in the Index Medicus for articles published since 1999, which were selected according to their relevance. The DIN is a finding of major clinical importance due to their high frequency and potential severity, and the lack of preventive measures in many cases. The main renal impairments caused by drugs can be classifi ed histopathologically according to altered renal function. Thus, there is the acute tubular necrosis, interstitial nephritis, glomerular injury and vascular changes that in turn include thrombotic microangiopathy, atherosclerosis and vasculitis. Finally, some commonly used drugs with high potential for nephrotoxicity are reviewed, with emphasis on recommendations for clinical use to optimize the renal safety of these products...