RESUMEN
Massive intraoperative bleeding is a major and potentially life-threatening complication during surgical procedures. The lethal triade of hemorrhagic shock with metabolic acidosis, hypothermia and coagulopathy enhances bleeding tendency. Avoiding this vitious circle requires a well-structured and standardized procedure. Primary goals include the maintenance of adequate tissue oxygenation, restauration of proper coagulatory function, normothermia and homeostasis of acid-base and electrolyte balance. In the present article, these therapeutic goals and their pathophysiological background are illustrated with a clinical case example.
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Pérdida de Sangre Quirúrgica/prevención & control , Sustitutos Sanguíneos/administración & dosificación , Transfusión Sanguínea/métodos , Monitoreo Intraoperatorio/métodos , Transfusión de Sangre Autóloga , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2(-/-) AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2(-/-) mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs.
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Complemento C1q/metabolismo , Modelos Animales de Enfermedad , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Glicoproteínas de Membrana/metabolismo , Neumonía Neumocócica/inmunología , Receptores Inmunológicos/metabolismo , Mucosa Respiratoria/inmunología , Animales , Apoptosis , Línea Celular Transformada , Células Cultivadas , Complemento C1q/genética , Citocinas/metabolismo , Femenino , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , PPAR gamma/metabolismo , Fagocitosis , Neumonía Neumocócica/metabolismo , Neumonía Neumocócica/patología , Receptores Inmunológicos/genética , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Análisis de SupervivenciaRESUMEN
During inflammation, neutrophils are rapidly mobilized from the bone marrow storage pool into peripheral blood (PB) to enter lesional sites, where most rapidly undergo apoptosis. Monocytes constitute a second wave of inflammatory immigrates, giving rise to long-lived macrophages and dendritic cell subsets. According to descriptive immunophenotypic and cell culture studies, neutrophils may directly "transdifferentiate" into monocytes/macrophages. We provide mechanistic data in human and murine models supporting the existence of this cellular pathway. First, the inflammatory signal-induced MKK6-p38MAPK cascade activates a monocyte differentiation program in human granulocyte colony-stimulating factor-dependent neutrophils. Second, adoptively transferred neutrophils isolated from G-CSF-pretreated mice rapidly acquired monocyte characteristics in response to inflammatory signals in vivo. Consistently, inflammatory signals led to the recruitment of osteoclast progenitor cell potential from ex vivo-isolated G-CSF-mobilized human blood neutrophils. Monocytic cell differentiation potential was retained in left-shifted band-stage neutrophils but lost in neutrophils from steady-state PB. MKK6-p38MAPK signaling in HL60 model cells led to diminishment of the transcription factor C/EBPα, which enabled the induction of a monocytic cell differentiation program. Gene profiling confirmed lineage conversion from band-stage neutrophils to monocytic cells. Therefore, inflammatory signals relayed by the MKK6-p38MAPK cascade induce monocytic cell differentiation from band-stage neutrophils.
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Diferenciación Celular/inmunología , Inflamación/inmunología , MAP Quinasa Quinasa 6/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Animales , Western Blotting , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/inmunología , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Células HL-60 , Humanos , Inflamación/genética , Inflamación/metabolismo , Interleucina-1beta/farmacología , MAP Quinasa Quinasa 6/genética , MAP Quinasa Quinasa 6/metabolismo , Ratones Endogámicos C57BL , Monocitos/metabolismo , Neutrófilos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/inmunología , Osteoblastos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Transcriptoma/efectos de los fármacos , Transcriptoma/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVE: Mortality on medical intensive care units (ICU) is approximately 25%. It is associated with age, severity of illness, and comorbidities. Preexisting depression is a risk factor for worse outcome in many diseases. The impact of depression on outcome of ICU patients has not been investigated. We assessed a possible association between mortality and preexisting depressive mood at the time of ICU admission. The primary end point was 28-day mortality. METHODS: This single-center cohort study was conducted in a tertiary medical ICU. Two hundred patients were evaluated for preexisting depressive mood at ICU admission, determined by Hospital Anxiety and Depression Scale (HADS) score ≥8 in the depression dimension in patients with appropriate cognitive function. Patients with insufficient cognitive function were assessed using observer rating by next of kin by Hammond scale (cutoff ≥4) and/or a modified version of the Hospital Anxiety and Depression Scale for observer rating (cutoff ≥10). RESULTS: In total, 66 (33%) of 200 patients were classified with preexisting depressive mood. Forty-nine (24.5%) of 200 patients had died by day 28. Of these, 23 (47%) had preexisting depressive mood as compared with 43 of 151 (29%) 28-day survivors (p = .017). Multiple logistic regression analysis revealed that preexisting depressive mood at the time of ICU admission is an independent risk factor for 28-day (odds ratio = 2.2, 95% confidence interval = 1.08-4.5, p = .030) and in-hospital mortality (median time till death = 20.5 [2-186] days, odds ratio = 2.58, 95% confidence interval = 1.31-5.1, p = .006). CONCLUSION: Preexisting depressive mood might be an independent risk factor for 28-day mortality in medical ICU patients. This could have diagnostic and therapeutic implications for critically ill patients.
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Enfermedad Crítica/mortalidad , Depresión/mortalidad , Antidepresivos/uso terapéutico , Estudios de Cohortes , Enfermedad Crítica/psicología , Depresión/complicaciones , Depresión/tratamiento farmacológico , Femenino , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Factores de RiesgoRESUMEN
BACKGROUND: Patients undergoing open heart surgery with cardiopulmonary bypass (CPB) often develop a systemic immune reaction, characterized by an increase of proinflammatory and anti-inflammatory mediators. We previously demonstrated that continued mechanical ventilation during CPB reduces this response. We hypothesized that this strategy may also impact on matrix metalloproteinase (MMP) release. MATERIAL AND METHODS: Thirty consecutive patients undergoing coronary artery bypass grafting with CPB were randomized into a ventilated (VG) (n = 15) and a standard non-ventilated group (NVG) (n = 15). Blood was collected at the beginning, at the end of surgery, and on the five consecutive days. MMPs, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), and lipocalin 2 (LCN2) were measured by enzyme-linked immunosorbent assay. Parameters of transpulmonary oxygen transport were assessed at different time points. RESULTS: MMP-8, MMP-9, and LCN2 were significantly lower at the end of surgery in VG compared with those in NVG patients (MMP-8 [ng/mL]: 7.1 [3.5] versus 12.5 [7.7], P = 0.02; MMP-9 [ng/mL]: 108 [42] versus 171 [98], P = 0.029; LCN2 [ng/mL]: 109 [42] versus 171 [98], P = 0.03). TIMP-1 concentrations were lower on postoperative day one, (TIMP-1 [ng/mL]: 174 [55] versus 273 [104], P = 0.003), whereas MMP-3 levels were lower on postoperative days four and five (MMP-3 [ng/mL]: 44 [17] versus 67 [35], P = 0.026). The arterial partial pressure of oxygen/fraction of inspired oxygen ratio was significantly higher in VG patients throughout the postoperative observation period, which did not affect the length of postoperative ventilatory support. CONCLUSIONS: Continued mechanical ventilation during CPB reduces serum levels of MMPs, their inhibitor TIMP-1 and LCN2, which preserves MMP-9 activity. The present study suggests that continued mechanical ventilation improves postoperative oxygenation and could potentially prevent aggravation of lung injury after CPB.
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Puente Cardiopulmonar , Lipocalinas/sangre , Metaloproteinasas de la Matriz/sangre , Proteínas Proto-Oncogénicas/sangre , Respiración Artificial , Inhibidor Tisular de Metaloproteinasa-1/sangre , Proteínas de Fase Aguda , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Lipocalina 2 , Masculino , Persona de Mediana Edad , Oxígeno/sangreRESUMEN
INTRODUCTION: Early initiation of appropriate antimicrobial treatment is a cornerstone in managing pneumonia. Because microbiologic processing may not be available around the clock, optimal storage of specimens is essential for accurate microbiologic identification of pathogenetic bacteria. The aim of our study was to determine the accuracy of two commonly used storage approaches for delayed processing of bronchoalveolar lavage in critically ill patients with suspected pneumonia. METHODS: This study included 132 patients with clinically suspected pneumonia at two medical intensive care units of a tertiary care hospital. Bronchoalveolar lavage samples were obtained and divided into three aliquots: one was used for immediate culture, and two, for delayed culture (DC) after storage for 24 hours at 4°C (DC4) and -80°C (DC-80), respectively. RESULTS: Of 259 bronchoalveolar lavage samples, 84 (32.4%) were positive after immediate culture with 115 relevant culture counts (≥104 colony-forming units/ml). Reduced (<104 colony-forming units/ml) or no growth of four and 57 of these isolates was observed in DC4 and DC-80, respectively. The difference between mean bias of immediate culture and DC4 (-0.035; limits of agreement, -0.977 to 0.906) and immediate culture and DC-80 (-1.832; limits of agreement, -4.914 to 1.267) was -1.788 ± 1.682 (P < 0.0001). Sensitivity and negative predictive value were 96.5% and 97.8% for DC4 and 50.4% and 75.4% for DC-80, respectively; the differences were statistically significant (P < 0.0001). CONCLUSIONS: Bronchoalveolar lavage samples can be processed for culture when stored up to 24 hours at 4°C without loss of diagnostic accuracy. Delayed culturing after storage at -80°C may not be reliable, in particular with regard to Gram-negative bacteria.
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Líquido del Lavado Bronquioalveolar/microbiología , Unidades de Cuidados Intensivos , Neumonía Bacteriana/diagnóstico , Neumonía Asociada al Ventilador/diagnóstico , Manejo de Especímenes/normas , Anciano , Carga Bacteriana , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Manejo de Especímenes/métodos , Temperatura , Factores de TiempoRESUMEN
INTRODUCTION: Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting. METHODS: In this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM). RESULTS: A total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint. CONCLUSIONS: Early treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01867645.
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Inmunoglobulina M/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Insuficiencia Multiorgánica/complicaciones , Enfermedades Musculares/tratamiento farmacológico , Polineuropatías/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Adulto , Anciano , Austria , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/etiología , Placebos , Polineuropatías/etiología , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Phosphatidylinositol 3-kinase has been described as an essential signaling component involved in the chemotactic cell influx that is required to eliminate pathogens. At the same time, PI3K was reported to modulate the immune response, thus limiting the magnitude of acute inflammation. The precise role of the PI3K pathway and its endogenous antagonist phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during clinically relevant bacterial infections is still poorly understood. Utilizing mice lacking myeloid cell-specific PTEN, we studied the impact of PTEN on the immune response to Streptococcus pneumoniae. Survival analysis disclosed that PTEN-deficient mice displayed less severe signs of disease and prolonged survival. The inflammatory response to S. pneumoniae was greatly reduced in macrophages in vitro and in vivo. Unexpectedly, neutrophil influx to the lungs was significantly impaired in animals lacking myeloid-cell PTEN, whereas the additional observation of improved phagocytosis by alveolar macrophages lacking PTEN ultimately resulted in unaltered lung CFUs following bacterial infection. Together, the absence of myeloid cell-associated PTEN and consecutively enhanced PI3K activity dampened pulmonary inflammation, reduced neutrophil influx, and augmented phagocytic properties of macrophages, which ultimately resulted in decreased tissue injury and improved survival during murine pneumococcal pneumonia.
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Actividad Bactericida de la Sangre/inmunología , Mediadores de Inflamación/fisiología , Células Mieloides/enzimología , Fosfohidrolasa PTEN/fisiología , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/microbiología , Animales , Línea Celular Tumoral , Recuento de Colonia Microbiana , Regulación hacia Abajo/inmunología , Interleucina-10/fisiología , Macrófagos Alveolares/enzimología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/patología , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/biosíntesis , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neumonía Neumocócica/enzimología , Neumonía Neumocócica/patología , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pneumoniae/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Regulación hacia Arriba/inmunologíaRESUMEN
RATIONALE: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far. OBJECTIVES: To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. METHODS: The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated. MEASUREMENTS AND MAIN RESULTS: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. CONCLUSIONS: The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.
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Lesión Pulmonar Aguda/prevención & control , Productos de Degradación de Fibrina-Fibrinógeno/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Neumonía Bacteriana/prevención & control , Infecciones por Pseudomonas/prevención & control , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/complicaciones , Animales , Modelos Animales de Enfermedad , Ácido Clorhídrico , Inflamación/prevención & control , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/microbiología , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.
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Animales Recién Nacidos/inmunología , Homeostasis/inmunología , Inmunidad Innata/inmunología , Interleucina-13/inmunología , Pulmón/inmunología , Animales , Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos C57BL , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
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.
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Endotoxinas/toxicidad , Inmunoglobulina M/farmacología , Sepsis/inducido químicamente , Sepsis/tratamiento farmacológico , Anciano , Biomarcadores/metabolismo , Estudios de Cohortes , Femenino , Humanos , Inmunoglobulina M/uso terapéutico , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Sepsis/metabolismoRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTEN(MyKO)), after induction of BIPF, exhibit increased TGF-ß1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTEN(MyKO) mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTEN(MyKO) mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.
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Citocinas/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Mediadores de Inflamación/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Animales , Bleomicina , Western Blotting , Colágeno/genética , Colágeno/metabolismo , Activación Enzimática , Femenino , Expresión Génica , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética , Macrófagos/clasificación , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/metabolismo , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta1/metabolismoAsunto(s)
Fibrilación Atrial/mortalidad , Hiperglucemia/mortalidad , Infarto del Miocardio/mortalidad , Estrés Fisiológico/fisiología , Fibrilación Atrial/etiología , Mortalidad Hospitalaria , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/etiología , Insulina/uso terapéutico , Factores de RiesgoRESUMEN
Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.
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Proteínas de Fase Aguda/inmunología , Lipocalinas/inmunología , Macrófagos Alveolares/inmunología , Proteínas Oncogénicas/inmunología , Neumonía Neumocócica/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas de Fase Aguda/deficiencia , Proteínas de Fase Aguda/genética , Adulto , Anciano , Animales , Femenino , Humanos , Tolerancia Inmunológica , Interleucina-10/biosíntesis , Lipocalina 2 , Lipocalinas/genética , Pulmón/inmunología , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteínas Oncogénicas/deficiencia , Proteínas Oncogénicas/genética , Neumonía Neumocócica/etiología , Quimera por Trasplante/inmunologíaRESUMEN
OBJECTIVE: The aim of the study was to determine if health-related quality of life of long-term survivors changes 24 months after intensive care treatment compared to the quality of life before admission. METHODS: From 281 patients treated at the ICU in 2001, 132 survivors were contacted by phone on average 24 months after discharge. Fernandez questionnaire was used to assess preadmission quality of life prospectively and postdischarge quality of life, retrospectively. In addition, age, sex, admission diagnosis, ICU length of stay, presence of organ failure, and necessity of mechanical ventilation were determined. RESULTS: In the 101 ICU survivors who responded to the questionnaire, the total score of quality of life did not change significantly over time (5.48 ± 5.3 before admission vs. 5.6 ± 5.8 at follow-up; p = 0.9). Similarly, the performance of normal daily activities did not alter (3.0 ± 3.5 vs. 3.39 ± 3.6; p = 0,3). In contrast, the ability to perform basic physiological activities worsened significantly (0.39 ± 0.76 vs. 0.76 ± 1.52; p = 0.037), whereas the emotional state improved significantly after intensive care treatment (2.08 ± 1.78 vs. 1.46 ± 1.56, p = 0.003). In a stepwise multiple regression analysis the total score of quality of life before admission was the only variable which influenced the quality of life 2 years after ICU-stay. CONCLUSIONS: In the interviewed population the total score of health-related quality of life did not change after intensive care treatment. Surprisingly, emotional state improved significantly although physical performance decreased. Quality of life after ICU discharge was predominantly influenced by preadmission quality of life. However, these results are not reflective of all ICU survivors.
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Cuidados Críticos/psicología , Cuidados Críticos/estadística & datos numéricos , Depresión/epidemiología , Depresión/psicología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Calidad de Vida/psicología , Austria/epidemiología , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , SobrevivientesRESUMEN
OBJECTIVE To evaluate the impact of real-time continuous glucose monitoring (CGM) on glycemic control and risk of hypoglycemia in critically ill patients. RESEARCH DESIGN AND METHODS A total 124 patients receiving mechanical ventilation were randomly assigned to the real-time CGM group (n = 63; glucose values given every 5 min) or to the control group (n = 61; selective arterial glucose measurements according to an algorithm; simultaneously blinded CGM) for 72 h. Insulin infusion rates were guided according to the same algorithm in both groups. The primary end point was percentage of time at a glucose level <110 mg/dl. Secondary end points were mean glucose levels and rate of severe hypoglycemia (<40 mg/dl). RESULTS Percentage of time at a glucose level <110 mg/dl (59.0 +/- 20 vs. 55.0 +/- 18% in the control group, P = 0.245) and the mean glucose level (106 +/- 18 vs. 111 +/- 10 mg/dl in the control group, P = 0.076) could not be improved using real-time CGM. The rate of severe hypoglycemia was lower in the real-time CGM group (1.6 vs. 11.5% in the control group, P = 0.031). CGM reduced the absolute risk of severe hypoglycemia by 9.9% (95% CI 1.2-18.6) with a number needed to treat of 10.1 (95% CI 5.4-83.3). CONCLUSIONS In critically ill patients, real-time CGM reduces hypoglycemic events but does not improve glycemic control compared with intensive insulin therapy guided by an algorithm.
Asunto(s)
Glucemia/análisis , Sistemas de Computación , Enfermedad Crítica/terapia , Monitoreo Fisiológico/métodos , Adulto , Anciano , Algoritmos , Glucemia/metabolismo , Femenino , Humanos , Hipoglucemia/etiología , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/instrumentación , Respiración Artificial , RiesgoRESUMEN
OBJECTIVE: To evaluate the impact of circulatory shock requiring norepinephrine therapy on the accuracy and reliability of a subcutaneous continuous glucose monitoring system (CGMS) in critically ill patients. DESIGN AND SETTING: A prospective, validation study of a medical intensive care unit at a university hospital was carried out. METHODS: Continuous glucose monitoring was performed subcutaneously in 50 consecutive patients on intensive insulin therapy (IIT), who were assessed according to the a priori strata of circulatory shock requiring norepinephrine therapy or not. RESULTS: A total of 736 pairs of sensor glucose (SG)/blood glucose (BG) values were analysed (502 without and 234 with norepinephrine therapy). For all values, repeated measures Bland-Altman analysis showed a mean difference of 0.08 mmol/l (limits of agreement: -1.26 and 1.43 mmol/l). Circulatory shock requiring norepinephrine therapy did not influence the relation of arterial BG with SG in a multivariable random effects linear regression analysis. The covariates norepinephrine dose, body mass index (BMI), glucose level and severity of illness also had no influence. Insulin titration grid analysis showed that 98.6% of the data points were in the acceptable treatment zone. No data were in the life-threatening zone. CONCLUSIONS: Circulatory shock requiring norepinephrine therapy, as well as other covariates, had no influence on the accuracy and reliability of the CGMS in critically ill patients.
Asunto(s)
Glucemia/análisis , Sistemas de Infusión de Insulina , Norepinefrina/uso terapéutico , Choque/tratamiento farmacológico , Vasoconstrictores/uso terapéutico , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Choque/fisiopatologíaRESUMEN
PURPOSE: Hypoxic hepatitis (HH) is a frequent cause of acute hepatocellular damage at the intensive care unit. Although mortality is reported to be high, risk factors for mortality in this population are unknown. METHODS: One-hundred and seventeen consecutive patients with HH were studied prospectively at three medical intensive care units of a university hospital. RESULTS: The main causes of hypoxic hepatitis were low cardiac output and septic shock, and most patients (74%) had more than one underlying factor. Peak aspartate transaminase (P = 0.02), lactate dehydrogenase (P = 0.03), INR (P < 0.001) and lactate (P < 0.01) were higher in non-survivors. Prolonged duration of HH caused higher overall mortality rate (P = 0.03). INR > 2 (P = 0.02), septic shock (P = 0.01) and SOFA score >10 (P = 0.04) were risk factors of mortality in the regression model. CONCLUSIONS: Hypoxic hepatitis is the consequence of multiorgan injury. Outcome is influenced by the severity of liver impairment and the etiology and severity of the basic disease.