RESUMO
BACKGROUND: Vitamin C has potential protective effects through antioxidant and anti-inflammatory properties. However, the effect of vitamin C supplementation on microvascular function and peripheral tissue perfusion in human sepsis remains unknown. We aimed to determine vitamin C effect on microvascular endothelial dysfunction and peripheral tissue perfusion in septic shock patients. METHODS: Patients with septic shock were prospectively included after initial resuscitation. Bedside peripheral tissue perfusion and skin microvascular reactivity in response to acetylcholine iontophoresis in the forearm area were measured before and 1 h after intravenous vitamin C supplementation (40 mg/kg). Norepinephrine dose was not modified during the studied period. RESULTS: We included 30 patients with septic shock. SOFA score was 11 [8-14], SAPS II was 66 [54-79], and in-hospital mortality was 33%. Half of these patients had vitamin C deficiency at inclusion. Vitamin C supplementation strongly improved microvascular reactivity (AUC 2263 [430-4246] vs 5362 [1744-10585] UI, p = 0.0004). In addition, vitamin C supplementation improved mottling score (p = 0.06), finger-tip (p = 0.0003) and knee capillary refill time (3.7 [2.6-5.5] vs 2.9 [1.9-4.7] s, p < 0.0001), as well as and central-to-periphery temperature gradient (6.1 [4.9-7.4] vs 4.6 [3.4-7.0] °C, p < 0.0001). The beneficial effects of vitamin C were observed both in patients with or without vitamin C deficiency. CONCLUSION: In septic shock patients being resuscitated, vitamin C supplementation improved peripheral tissue perfusion and microvascular reactivity whatever plasma levels of vitamin C. ClinicalTrials.gov Identifier: NCT04778605 registered 26 January 2021.
Assuntos
Choque Séptico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Humanos , Microcirculação , Perfusão , Ressuscitação , Choque Séptico/tratamento farmacológicoRESUMO
BACKGROUND: A dysregulated immune response is emerging as a key feature of critical illness in COVID-19. Neutrophils are key components of early innate immunity that, if not tightly regulated, contribute to uncontrolled systemic inflammation. We sought to decipher the role of neutrophil phenotypes, functions, and homeostasis in COVID-19 disease severity and outcome. METHODS: By using flow cytometry, this longitudinal study compares peripheral whole-blood neutrophils from 90 COVID-19 ICU patients with those of 22 SARS-CoV-2-negative patients hospitalized for severe community-acquired pneumonia (CAP) and 38 healthy controls. We also assessed correlations between these phenotypic and functional indicators and markers of endothelial damage as well as disease severity. RESULTS: At ICU admission, the circulating neutrophils of the COVID-19 patients showed continuous basal hyperactivation not seen in CAP patients, associated with higher circulating levels of soluble E- and P-selectin, which reflect platelet and endothelial activation. Furthermore, COVID-19 patients had expanded aged-angiogenic and reverse transmigrated neutrophil subsets-both involved in endothelial dysfunction and vascular inflammation. Simultaneously, COVID-19 patients had significantly lower levels of neutrophil oxidative burst in response to bacterial formyl peptide. Moreover patients dying of COVID-19 had significantly higher expansion of aged-angiogenic neutrophil subset and greater impairment of oxidative burst response than survivors. CONCLUSIONS: These data suggest that neutrophil exhaustion may be involved in the pathogenesis of severe COVID-19 and identify angiogenic neutrophils as a potentially harmful subset involved in fatal outcome.
Assuntos
COVID-19 , Infecções Comunitárias Adquiridas , Pneumonia , Idoso , Homeostase , Humanos , Inflamação , Estudos Longitudinais , Neutrófilos/fisiologia , Pneumonia/patologia , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Cirrhosis is associated with hemodynamic and vascular disorders. However, microvascular reactivity of cirrhotic patients in the context of sepsis has poorly been investigated. DESIGN: Prospective observational study. SETTING: Medical ICU in a tertiary teaching hospital. PATIENTS: We prospectively included adult patients admitted in the ICU for septic shock with and without cirrhosis. After initial resuscitation, global hemodynamic parameters were recorded and skin microvascular reactivity to local acetylcholine iontophoresis was measured. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty patients with septic shock were included (60% male), 10 with cirrhosis and 20 without, with a median age of 61 years (54-74 yr). Cirrhotic patients were mainly classed as Child-Pugh C (80%) and all of them had ascites. Sequential Organ Failure Assessment score and ICU mortality of cirrhotic patients were higher than the noncirrhotic patients, respectively (6.5 [5.0-8.3] vs 11.5 [9.0-14.0]; p < 0.01; 15% vs 70%; p < 0.01). Peripheral tissue perfusion and global hemodynamic parameters were not different between the cirrhotic and noncirrhotic patients but arterial lactate level was three times higher in patients with cirrhosis (6.0 mmol/L [3.9-8.0 mmol/L] vs 2.0 mmol/L [0.9-3.5 mmol/L]; p < 0.01). Basal skin microvascular blood flow was not statistically different between the groups (4.94 perfusion units [3.45-8.73 perfusion units] vs 6.95 perfusion units [5.24-8.38 perfusion units]; p = 0.29). After acetylcholine simulation, skin microvascular blood flow increased more in cirrhotic patients than in noncirrhotic patients (644% [217-966%] vs 169% [73-505%], p = 0.03). Global microvascular reactivity was seven times higher in cirrhotic patients (area under the curve, 16,412 perfusion units [13,898-19,041 perfusion units] vs 2,664 perfusion units [969-4,604 perfusion units]; p < 0.001). CONCLUSIONS: We identified an exaggerated vasodilating microvascular response in cirrhotic patients with septic shock. Such a result may explain vasopressor resistance and paves the way for future therapeutic trials, targeting nitric oxide pathway specifically in this population.
Assuntos
Cirrose Hepática/fisiopatologia , Índice de Gravidade de Doença , Choque Séptico/fisiopatologia , Pele/irrigação sanguínea , Equilíbrio Ácido-Base/fisiologia , Idoso , Feminino , Humanos , Cirrose Hepática/mortalidade , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Choque Séptico/mortalidadeRESUMO
Haploidentical transplantation has extended the availability of allogeneic hematopoietic stem cell transplant (alloHCT) to almost all patients. Sequential conditioning regimens have been proposed for the treatment of hematological active disease. Whether these new transplantation procedures affect the prognosis of critically ill alloHCT recipients remains unknown. We evaluated this question in a retrospective study including consecutive alloHCT patients admitted to the intensive care unit of a tertiary academic center from 2010 to 2017. During the study period, 412 alloHCTs were performed and 110 (27%) patients-median age 55 (36-64) years-were admitted to ICU in a median time of 58.5 (14-245) days after alloHCT. Twenty-nine (26%) patients had received a haploidentical graft and 34 (31%) a sequential conditioning. Median SOFA score was 9 (6-11). Invasive mechanical ventilation (MV) was required in 61 (55%) patients. Fifty-six (51%) patients died in the hospital. Independent factors associated with in-hospital mortality were as follows: MV (OR=8.44 [95% CI 3.30-23.19], p<0.001), delta SOFA between day 3 and day 1 (OR=1.60 [95% CI 1.31-2.05], p<0.0001), and sequential conditioning (OR=3.7 [95% CI 1.14-12.92], p=0.033). Sequential conditioning was also independently associated with decreased overall survival (HR=1.86 [95% CI 1.05-3.31], p=0.03). Other independent factors associated with reduced overall survival were HCT-specific comorbidity index ≥2 (HR=1.76 [95% CI 1.10-2.84], p=0.02), acute GVHD grade ≥2 (HR=1.88 [95% CI 1.14-3.10], p=0.01), MV (HR=2.37 [95% CI 1.38-4.07, p=0.002), and vasopressors (HR=2.21 [95% CI 1.38-3.54], p=0.001). Haploidentical transplantation did not affect outcome. Larger multicenter studies are warranted to confirm these results.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Comorbidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Histocompatibilidade , Mortalidade Hospitalar , Humanos , Imunossupressores/uso terapêutico , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Modelos de Riscos Proporcionais , Respiração Artificial , Estudos Retrospectivos , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
BACKGROUND: Little is known on the outcome and risk factors for mortality of patients admitted in Intensive Care units (ICUs) for Acute cholangitis (AC). METHODS: Retrospective multicenter study included adults admitted in eleven intensive care units for a proven AC from 2005 to 2018. Risk factors for in-hospital mortality were identified using multivariate analysis. RESULTS: Overall, 382 patients were included, in-hospital mortality was 29%. SOFA score at admission was 8 [5-11]. Biliary obstruction was mainly related to gallstone (53%) and cancer (22%). Median total bilirubin and PCT were respectively 83 µmol/L [50-147] and 19.1 µg/L [5.3-54.8]. Sixty-three percent of patients (n = 252) had positive blood culture, mainly Gram-negative bacilli (86%) and 14% produced extended spectrum beta lactamase bacteria. At ICU admission, persisting obstruction was frequent (79%) and biliary decompression was performed using therapeutic endoscopic retrograde cholangiopancreatography (76%) and percutaneous transhepatic biliary drainage (21%). Adjusted mortality significantly decreased overtime, adjusted OR for mortality per year was 0.72 [0.54-0.96] (p = 0.02). In a multivariate analysis, factors at admission associated with in-hospital mortality were: SOFA score (OR 1.14 [95% CI 1.05-1.24] by point, p = 0.001), lactate (OR 1.21 [95% CI 1.08-1.36], by 1 mmol/L, p < 0.001), total serum bilirubin (OR 1.26 [95% CI 1.12-1.41], by 50 µmol/L, p < 0.001), obstruction non-related to gallstones (p < 0.05) and AC complications (OR 2.74 [95% CI 1.45-5.17], p = 0.002). Time between ICU admission and biliary decompression > 48 h was associated with in-hospital mortality (adjusted OR 2.73 [95% CI 1.30-6.22], p = 0.02). CONCLUSIONS: In this large retrospective multicenter study, we found that AC-associated mortality significantly decreased overtime. Severity of organ failure, cause of obstruction and local complications of AC are risk factors for mortality, as well as delayed biliary drainage > 48 h.
Assuntos
Colangite/microbiologia , Colangite/fisiopatologia , Mortalidade/tendências , Idoso , Idoso de 80 Anos ou mais , Colangite/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Escores de Disfunção Orgânica , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Mottling score, a tissue perfusion parameter, is correlated with outcome in septic shock patients. However, its predictive value on mortality according to prognostic covariates such as vasopressor dose and other tissue perfusion parameters remains unknown. METHODS: Mottling score and tissue perfusion parameters were recorded at ICU admission (H0), H-6, H 12, and H-24 and used to assess the predictive value of mottling score on 14-day mortality in a development cohort. Results were then validated in an independent cohort of septic shock patients in Brazil. RESULTS: Overall, 259 patients with sepsis or septic shock were included, 14-day mortality was 37%. Factors associated with death were mottling score (OR 2.26 [95% CI, 1.72-2.97]), arterial lactate level (OR 1.29 [1.11-1.5]), and urine output < 0.5 ml/Kg/h (OR 3.03 [1.37-6.69]). The C statistic for the model was 0.90 in the development cohort and 0.76 in the validation cohort. The predictive value of mottling score was not affected by vasopressor doses (p for interaction = 0.33): OR for mottling score ranged from 2.34 [1.10-3.15] in patients without vasopressor to 3.84 [1.98-7.43] in patients infused with high doses of vasopressor (> 0.8 µg/kg/min). There was no difference in the effect of mottling score on mortality according to mean arterial pressure, heart rate, cardiac index, and urine output, but we found a significant interaction between arterial lactate level and mottling score (p = 0.04). The predictive value of the mottling score remains significant when using the recent SEPSIS-3 definition of septic shock. Finally, a decrease of mottling score during resuscitation was significantly associated with better outcome after adjustment on SOFA score (p = 0.001). CONCLUSIONS: Our results support the high prognostic value of mottling score for 14-day mortality in septic patients, whatever vasopressor dosage and other perfusion parameters. Mottling score variations during resuscitation are also predictive of mortality.
Assuntos
Microcirculação/fisiologia , Sepse/tratamento farmacológico , Índice de Gravidade de Doença , Vasoconstritores/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Brasil , Feminino , Hidratação/métodos , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Prognóstico , Sepse/mortalidade , Resultado do Tratamento , Vasoconstritores/uso terapêuticoRESUMO
BACKGROUND: Red blood cell (RBC) transfusion is a common treatment for hospitalized patients. However, the effects of RBC transfusion on microvascular function remain controversial. METHODS: In a medical ICU in a tertiary teaching hospital, we prospectively included anemic patients requiring RBC transfusion. Skin microvascular reactivity was measured before and 30 min after RBC transfusion. Plasma was collected to analyze intravascular hemolysis and draw the lipidomic and cytokine profiles. RESULTS: In a cohort of 59 patients, the median age was 66 [55-81] years and SAPS II was 38 [24-48]. After RBC transfusion, endothelium-dependent microvascular reactivity improved in 35 (59%) patients, but worsened in 24 others (41%). Comparing clinical and biological markers revealed that baseline blood leucokyte counts distinguished improving from worsening patients (10.3 [5.7; 19.7] vs. 4.6 [2.1; 7.3] × 109/L; p = 0.001) and correlated with variations of microvascular reactivity (r = 0.36, p = 0.005). Blood platelet count was also higher in improving patients (200 [97; 280] vs 160 [40; 199] × 103/mL, p = 0.03) but did not correlate with variations of microvascular reactivity. We observed no intravascular hemolysis (HbCO, heme, bilirubin, LDH), but recorded a significant increase in RBC microparticle levels specific to improving patients after transfusion (292 [108; 531] vs. 53 [34; 99] MP/µL; p = 0.03). The improvement in microvascular dilation was positively correlated with RBC microparticle levels (R = 0.83, p < 0.001) and conversion of arachidonic acid into vasodilating eicosanoids. CONCLUSIONS: Patients displaying an improved microvascular reactivity after RBC transfusion had high blood leukocyte counts, increased RBC microparticle formation, and enhanced metabolism of arachidonic acid into vasodilating lipids. Our data suggested a contribution of recipient leukocytes to the vascular impact of RBC transfusion.
Assuntos
Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/normas , Microvasos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Transfusão de Eritrócitos/métodos , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Escore Fisiológico Agudo SimplificadoRESUMO
BACKGROUND: Corticosteroids have become standard of care for COVID-19 but their effect on the systemic immune-inflammatory response has been little investigated. METHODS: Multicenter prospective cohort, including critically ill COVID-19 patients between March and November 2020. C-reactive protein (CRP), lymphocyte count and fibrinogen levels were collected upon hospital admission before initiation of steroid treatment and at ICU admission, three days and seven days later, along with interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha (TNF-α) plasma levels. RESULTS: A hundred and fifty patients were included, 47 received corticosteroids, 103 did not. Median age was 62 [53-70], and 96 (65%) patients were mechanically ventilated. Propensity score matching rendered 45 well-balanced pairs of treated and non-treated patients, particularly on pre-treatment CRP levels. Using a mixed model, CRP (P=0.019), fibrinogen (P=0.003) and lymphocyte counts (P=0.006) remained lower in treated patients over ICU stay. Conversely, there was no significant difference over the ICU stay for Il-6 (P=0.146) and IL-10 (0.301), while TNF- α levels were higher in the treated group (P=0.013). Among corticosteroid-treated patients, CRP (P=0.012), fibrinogen (P=0.041) and lymphocyte count (P=0.004) over time were associated with outcome, whereas plasma cytokine levels were not. CONCLUSIONS: Steroid treatment was associated with an early and sustained decrease in the downstream IL-6-dependent inflammatory signature but an increase in TNF-α levels. In corticosteroid-treated patients, CRP and lymphocyte count were associated with outcome, conversely to plasma cytokine levels. Further research on using these biomarker's kinetics to individualize immunomodulatory treatments is warranted.
Assuntos
COVID-19 , Interleucina-6 , Humanos , Pessoa de Meia-Idade , Interleucina-10 , Fator de Necrose Tumoral alfa , Estudos Prospectivos , Estado Terminal/terapia , Citocinas , Proteína C-Reativa , Corticosteroides , Fibrinogênio , EsteroidesRESUMO
OBJECTIVES: Mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely in the absence of tissue hypoperfusion, but the consequences on fluid balance and kidney function remain unknown. DESIGN: During a 1-year period, we retrospectively collected data of consecutive septic patients admitted for sepsis with a mean arterial pressure (MAP) less than 65 mm Hg despite fluid resuscitation. SETTING: Medical 18-bed ICU in a tertiary teaching hospital. PATIENTS: Septic patients with a MAP less than 65 mm Hg despite initial resuscitation. INTERVENTIONS: In our ICU, MAP between 55 and 65 mm Hg was tolerated in the absence of peripheral hypoperfusion (permissive hypotension) or corrected using norepinephrine (septic shock group) when peripheral tissue hypoperfusion was present. MEASUREMENTS AND MAIN RESULTS: Ninety-four consecutive septic patients were included, 15 in the permissive hypotension group and 79 in the septic shock group. Median age was 66 years (57-77 yr) and 42% were women. The main sources of infection were respiratory (45%) and abdominal (18%). Severity was more important in septic shock group with higher Sequential Organ Failure Assessment score (7 [5-10] vs. 4 [1-6]; p < 0.0001), more frequent organ support therapy and ultimately higher mortality (38 vs. 0%; p < 0.01). The total volume of crystalloids infused before ICU admission was not different between groups (1930 ± 250 vs. 1850 ± 150 mL; p = 0.40). Within the 6 first hours of ICU stay, patients in the permissive hypotension group received less fluids (530 ± 170 vs. 1100 ± 110 mL; p = 0.03) and had higher urinary output (1.4 mL [0.88-2.34 mL] vs. 0.47 mL/kg/hr [0.08-1.25 mL/kg/hr]; p < 0.001). In addition, kidney injury evaluated using KDIGO score was lower in the permissive hypotension group at 48 hours (0 hr [0-1 hr] vs. 1 hr [0-2 hr]; p < 0.05). CONCLUSIONS: In septic patients without clinical peripheral hypoperfusion, mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely without vasopressor infusion and was not associated with excessive fluid administration or kidney damage.
RESUMO
Background: Cardiopulmonary bypass (CPB) during cardiac surgery leads to deleterious systemic inflammation. We hypothesized that TREM-1, a myeloid receptor shed after activation, drives systemic inflammation during CPB. Methods: Prospective observational bi-centric study. Blood analysis (flow cytometry and ELISA) before and at H2 and H24 after CPB. Inclusion of adult patients who underwent elective cardiac surgery with CPB. Results: TREM-1 expression on neutrophils decreased between H0 and H2 while soluble (s)TREM-1 plasma levels increased. sTREM-1 levels increased at H2 and at H24 (p < 0.001). IL-6, IL-8, G-CSF and TNF-α, but not IL-1ß, significantly increased at H2 compared to H0 (p < 0.001), but dropped at H24. Principal component analysis showed a close relationship between sTREM-1 and IL-8. Three patterns of patients were identified: Profile 1 with high baseline sTREM-1 levels and high increase and profile 2/3 with low/moderate baseline sTREM-1 levels and no/moderate increase overtime. Profile 1 patients developed more severe organ failure after CPB, with higher norepinephrine dose, higher SOFA score and more frequently acute kidney injury at both H24 and H48. Acute atrial fibrillation was also more frequent in profile 1 patients at H24 (80% vs. 19.4%, p = 0.001). After adjustment on age and duration of CPB, H0, H2 and H24 sTREM-1 levels remained associated with prolonged ICU and hospital length of stay. Conclusions: Baseline sTREM-1 levels as well as early kinetics after cardiac surgery identified patients at high risk of post-operative complications and prolonged length of stay.
RESUMO
BACKGROUND: Several studies have reported an increased risk of thrombotic events in COVID-19 patients, but the pathophysiology of this procoagulant phenotype remains poorly understood. We hypothesized that corticosteroids may attenuate this procoagulant state through their anti-inflammatory effects. The aim of this study was to evaluate the impact of dexamethasone (DXM) on the coagulation profile of severely ill COVID-19 patients. METHODS: We conducted a retrospective, observational before/after bi-centric cohort study among ICU patients hospitalized for severe COVID-19 and receiving therapeutic anticoagulation by unfractionated heparin (UFH). Before and after the standardized use of DXM, we compared inflammatory and coagulation profiles, as well as the kinetics of heparin requirement, adjusted for weight and anti-Xa activity. RESULTS: Eighty-six patients were included, 35 in the no-DXM group, and 51 in the DXM group. At admission, CRP and fibrinogen levels were not different between groups, neither were UFH infusion rates. At day 3 after ICU admission, CRP (178±94 mg/L vs. 99±68 mg/L, P<0.001) and fibrinogen (7.2±1.4 g/L vs. 6.1±1.4 g/L, P=0.001) significantly decreased in the DXM group, but not in the no-DXM group. Over time, UFH infusion rates were lower in the DXM group (P<0.001) without any significant difference in plasma anti-Xa activity. CRP variations correlated with heparin dose variations between Day 0 and Day 3 (r=0.39, P=0.009). Finally, the incidence of venous thromboembolic events during in-ICU stay was significantly reduced in the DXM group (4 vs. 43%, P<0.0001). CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone use was associated with a decrease in both pro-inflammatory and procoagulant profile.
Assuntos
Corticosteroides , COVID-19 , Heparina , Humanos , Corticosteroides/uso terapêutico , Anticoagulantes/uso terapêutico , Estudos de Coortes , Estudos Controlados Antes e Depois , Estado Terminal , Dexametasona/uso terapêutico , Fibrinogênio , Heparina/uso terapêutico , Estudos RetrospectivosRESUMO
Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1ß production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
Assuntos
Aterosclerose , Humanos , Animais , Camundongos , Aterosclerose/metabolismo , Autofagia/genética , Apolipoproteínas E/genética , Lipídeos , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a challenging diagnosis and is associated with extremely high mortality in critically ill patients, particularly due to delayed diagnosis and when complicated by intestinal necrosis. Plasma citrulline and intestinal-fatty acid binding protein (I-FABP) have been proposed as potential biomarkers, but have never been studied prospectively in this setting. We aimed to investigate diagnostic features, the accuracy of plasma citrulline and I-FABP to diagnose NOMI and intestinal necrosis as well as prognosis. METHODS: We conducted a prospective observational study in 3 tertiary ICU centers in consecutive patients with NOMI suspicion defined by at least two inclusion criteria among: new-onset or worsening circulatory failure, gastrointestinal dysfunction, biological signs and CT-scan signs of mesenteric ischemia. Diagnosis features and outcomes were compared according to NOMI, intestinal necrosis or ruled out diagnosis using stringent classification criteria. RESULTS: Diagnosis of NOMI was suspected in 61 patients and confirmed for 33 patients, with intestinal necrosis occurring in 27 patients. Clinical digestive signs, routine laboratory results and CT signs of mesenteric ischemia did not discriminate intestinal necrosis from ischemia without necrosis. Plasma I-FABP was significantly increased in presence of intestinal necrosis (AUC 0.83 [0.70-0.96]). A threshold of 3114 pg/mL showed a sensitivity of 70% [50-86], specificity of 85% [55-98], a negative predictive value of 58% [36-93] and a positive predictive value 90% [67-96] for intestinal necrosis diagnosis. When intestinal necrosis was present, surgical resection was significantly associated with ICU survival (38.5%), whereas no patient survived without necrosis resection (HR = 0.31 [0.12-0.75], p = 0.01). CONCLUSION: In critically ill patients with NOMI, intestinal necrosis was associated with extremely high mortality, and increased survival when necrosis resection was performed. Elevated plasma I-FABP was associated with the diagnosis of intestinal necrosis. Further studies are needed to investigate plasma I-FABP and citrulline performance in less severe forms of NOMI.
RESUMO
BACKGROUND: SARS-CoV-2 pneumonia is responsible for unprecedented numbers of acute respiratory failure requiring invasive mechanical ventilation (IMV). This work aimed to assess whether adding face-mask noninvasive ventilation (NIV) to high-flow nasal oxygen (HFNO) was associated with a reduced need for endotracheal intubation. METHODS: This retrospective cohort study was conducted from July 2020 to January 2021 in two tertiary care intensive care units (ICUs) in Paris, France. Patients admitted for laboratory confirmed SARS-CoV-2 infection with acute hypoxemic respiratory failure requiring HFNO with or without NIV were included. The primary outcome was the rate of endotracheal intubation. Secondary outcomes included day-28 mortality, day-28 respiratory support and IMV free days, ICU and hospital length-of-stay. Sensitivity analyses with both propensity score matching and overlap weighting were used. RESULTS: One hundred twenty-eight patients were included, 88 (69%) received HFNO alone and 40 (31%) received additional NIV. Additional NIV was associated with a reduced rate of endotracheal intubation in multivariate analysis (53 [60%] vs. 15 [38%], HR=0.46 [95% CI: 0.23-0.95], P=0.04). Sensitivity analyses by propensity score matching (HR=0.45 [95% CI: 0.24-0.84], P=0.01) and overlap weighting (HR=0.52 [95% CI: 0.28-0.94], P=0.03) were consistent. Day-28 mortality was 25 (28%) in the HFNO group and 8 (20%) in the NIV group (HR=0.75 [95% CI: 0.15-3.82], P=0.72). NIV was associated with higher IMV free days (20 [0-28] vs. 28 [14-28], P=0.015). All sensitivity analyses were consistent regarding secondary outcomes. CONCLUSIONS: Need for endotracheal intubation was lower in critically-ill SARS-CoV-2 patients receiving face-mask noninvasive mechanical ventilation in addition to high-flow oxygen therapy.
Assuntos
COVID-19 , Ventilação não Invasiva , Insuficiência Respiratória , COVID-19/terapia , Estudos de Coortes , Estado Terminal/terapia , Humanos , Unidades de Terapia Intensiva , Intubação Intratraqueal , Oxigênio , Pontuação de Propensão , Respiração Artificial , Insuficiência Respiratória/terapia , Estudos Retrospectivos , SARS-CoV-2RESUMO
Little is known about the immuno-inflammatory response to Tocilizumab and its association with outcome in critically-ill SARS-CoV2 pneumonia. In this multicenter retrospective cohort of SARS-CoV-2 patients admitted to three intensive care units between March and April 2020, we matched on gender and SAPS II 21 Tocilizumab-treated patients to 42 non-treated patients. Need for mechanical ventilation was 76% versus 79%. IL-6, C-reactive protein, and fibrinogen had been collected within the first days of admission (T1), 3 d (T2) and 7 d (T3) later. Tocilizumab-treated patients had persistently higher IL-6 plasma levels and persistently lower C-Reactive protein and fibrinogen levels. Among Tocilizumab-treated patients, baseline levels of inflammatory biomarkers were not different according to outcome. Conversely, C-reactive protein and fibrinogen decrease was delayed in non-survivors. C-Reactive protein decreased at T1 in survivors (45 [30-98] vs 170 [69-204] mg/l, P < 0.001) but only at T2 in non-survivors (37 [13-74] vs 277 [235-288], P = 0.03). Fibrinogen decreased at T2 in survivors (4.11 [3.58-4.69] vs 614 [5.61-7.85] g/l, P = 0.005) but not in non-survivors (4.79 [4.12-7.58] vs 7.24 [6.22-9.24] g/l, P = 0.125). Tocilizumab treatment was thus associated with a persistent both increase in plasma IL-6, and decrease in C-reactive protein and fibrinogen. Among Tocilizumab-treated patients, the decrease in inflammatory biomarkers was delayed in non-survivors.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , COVID-19/mortalidade , Inflamação/tratamento farmacológico , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Coortes , Estado Terminal , Feminino , Fibrinogênio/análise , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Estudos Retrospectivos , Resultado do TratamentoRESUMO
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Camundongos , Animais , Dissecção Aórtica/patologia , Fenótipo , Mutação , Macrófagos/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/complicaçõesRESUMO
Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6Chi monocytes available for initial melanoma development, in an IL-1ß-dependent manner. Descendants of circulating myeloid cells, which accumulate in the tumor microenvironment of mice under HFHCD, heighten pro-angiogenic and immunosuppressive activities locally. Limiting myeloid cell accumulation or targeting VEGF-A production by myeloid cells decrease HFHCD-induced tumor growth acceleration. Reverting the HFHCD to a chow diet at the time of tumor implantation protects against tumor growth. Together, these data shed light on cross-disease communication between cardiovascular pathologies and cancer.
Assuntos
Dislipidemias , Monócitos , Animais , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Dislipidemias/patologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/patologia , Células Mieloides/patologia , Microambiente TumoralRESUMO
Experimental studies have provided strong evidence that chronic inflammation triggered by the sub-endothelial accumulation of cholesterol-rich lipoproteins in arteries is essential in the initiation and progression of atherosclerosis. Recent clinical trials highlighting the efficacy of anti-inflammatory therapies in coronary patients have confirmed that this is also true in humans Monocytes/macrophages are central cells in the atherosclerotic process, but adaptive immunity, through B and T lymphocytes, as well as dendritic cells, also modulates the progression of the disease. Analysis of the role of different T cell subpopulations in murine models of atherosclerosis identified effector Th1 cells as proatherogenic, whereas regulatory T cells (Tregs) have been shown to protect against atherosclerosis. For these reasons, better understanding of how Tregs influence the atherosclerotic process is believed to provide novel Treg-targeted therapies to combat atherosclerosis. This review article summarizes current knowledge about the role of Tregs in atherosclerosis and discusses ways to enhance their function as novel immunomodulatory therapeutic approaches against cardiovascular disease.
Assuntos
Aterosclerose/imunologia , Aterosclerose/terapia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Tolerância Imunológica , Imunidade Celular , Ativação Linfocitária/imunologiaRESUMO
BACKGROUND: SARS coronavirus 2 (SARS-CoV-2) is responsible for high morbidity and mortality worldwide, mostly due to the exacerbated inflammatory response observed in critically ill patients. However, little is known about the kinetics of the systemic immune response and its association with survival in SARS-CoV-2+ patients admitted in ICU. We aimed to compare the immuno-inflammatory features according to organ failure severity and in-ICU mortality. METHODS: Six-week multicentre study (N = 3) including SARS-CoV-2+ patients admitted in ICU. Analysis of plasma biomarkers at days 0 and 3-4 according to organ failure worsening (increase in SOFA score) and 60-day mortality. RESULTS: 101 patients were included. Patients had severe respiratory diseases with PaO2/FiO2 of 155 [111-251] mmHg), SAPS II of 37 [31-45] and SOFA score of 4 [3-7]. Eighty-three patients (83%) required endotracheal intubation/mechanical ventilation and among them, 64% were treated with prone position. IL-1ß was barely detectable. Baseline IL-6 levels positively correlated with organ failure severity. Baseline IL-6 and CRP levels were significantly higher in patients in the worsening group than in the non-worsening group (278 [70-622] vs. 71 [29-153] pg/mL, P < 0.01; and 178 [100-295] vs. 100 [37-213] mg/L, P < 0.05, respectively). Baseline IL-6 and CRP levels were significantly higher in non-survivors compared to survivors but fibrinogen levels and lymphocyte counts were not different between groups. After adjustment on SOFA score and time from symptom onset to first dosage, IL-6 and CRP remained significantly associated with mortality. IL-6 changes between Day 0 and Day 3-4 were not different according to the outcome. A contrario, kinetics of CRP and lymphocyte count were different between survivors and non-survivors. CONCLUSIONS: In SARS-CoV-2+ patients admitted in ICU, a systemic pro-inflammatory signature was associated with clinical worsening and 60-day mortality.
RESUMO
The mechanical obstruction of cerebrospinal fluid (CSF) flow can lead to very high hyperproteinorachia. In myeloma, tumoral clivus obstruction can cause such high proteinorachia, associated with paraprotein detection in the CSF in absence of intrathecal synthesis.