Expression of Exhaustion Markers on CD8+ T-Cell Patterns Predict Outcomes in Septic Patients Admitted to the ICU.

RATIONALE: There is an unmet need to improve the description of the state of T-cell exhaustion in patients with sepsis, its reproducibility and correlation with the outcomes before including immunotherapy (like recombinant interleukin-7 or immune checkpoint inhibitors) in the therapeutic armamentarium against sepsis. DESIGN: Observational prospective study. SETTING: Two ICUs in a teaching hospital (France). PATIENTS: Eighty patients with sepsis admitted to the ICU. INTERVENTIONS: Quantification of CD4+ and CD8+ T-cell exhaustion at days 1 and 3. Quantification of the exhaustion markers (programmed death [PD]-1, 2B4, and cluster of differentiation [CD] 160) on T cells, the number of CD4+ regulatory T cells (CD3+ CD4+ CD25hi CD127Lo cells), and the phorbol myristate acetate/ionomycin/ionomycin-induced cytokines production (tumor necrosis factor-α, interleukin-2, and interferon-γ). MEASUREMENTS AND MAIN RESULTS: Using unsupervised clustering analysis, patients could be split in three clusters according to their dominant pattern expression of exhaustion markers on CD8+ T cells (i.e., 2B4lowPD-1lowCD160low, 2B4hiPD-1hiCD160low, and 2B4hiPD-1lowCD160hi) regardless of their underlying morbidities. Only 2B4hiPD-1hiCD160low CD8+ T cells had cytokine production defect, whereas 2B4hi PD-1lowCD160hi pattern correlated with cytokine overproduction. Patients with a predominant "highly activated" 2B4hiPD-1lowCD160hi pattern did not develop secondary bacterial infections. By multivariate analysis, Simplified Acute Physiology Score 2 gravity score at day 1 (p = 0.003) and patterns of exhaustion markers on CD8+ T cells (p = 0.03) were associated with the risk of death. Neither the level of CD4+ regulatory T cells nor the CD4+ exhaustion patterns were associated with the outcomes. CONCLUSIONS: Easy-to-use multicolor flow cytometry assessing 2B4, PD-1, and CD160 expression on CD8+ T cells at day 1 identifies septic patients with poor outcome and discriminates patient subsets in who immunomodulatory drugs should be tested.

Diagnostic and management of life-threatening Adult-Onset Still Disease: a French nationwide multicenter study and systematic literature review.

BACKGROUND: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome. METHODS: A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review. RESULTS: Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively. CONCLUSIONS: AOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.

Beat-by-beat assessment of cardiac afterload using descending aortic velocity-pressure loop during general anesthesia: a pilot study.

INTRODUCTION: Continuous cardiac afterload evaluation could represent a useful tool during general anesthesia (GA) to titrate vasopressor effect. Using beat to beat descending aortic pressure(P)/flow velocity(U) loop obtained from esophageal Doppler and femoral pressure signals might allow to track afterload changes. Methods We defined three angles characterizing the PU loop (alpha, beta and Global After-Load Angle (GALA)). Augmentation index (AIx) and total arterial compliance (Ctot) were measured via radial tonometry. Peripheral Vascular Resistances (PVR) were also calculated. Twenty patients were recruited and classified into low and high cardiovascular (CV) risk group. Vasopressors were administered, when baseline mean arterial pressure (MAP) fell by 20%. Results We studied 118 pairs of pre/post bolus measurements. At baseline, patients in the lower CV risk group had higher cardiac output (6.1 ± 1.7 vs 4.2 ± 0.6 L min; p = 0.005), higher Ctot (2.7 ± 1.0 vs 2.0 ± 0.4 ml/mmHg, p = 0.033), lower AIx and PVR (13 ± 10 vs 32 ± 11% and 1011 ± 318 vs 1390 ± 327 dyn s/cm5; p < 0.001 and p = 0.016, respectively) and lower GALA (41 ± 15 vs 68 ± 6°; p < 0.001). GALA was the only PU Loop parameter associated with Ctot, AIx and PVR. After vasopressors, MAP increase was associated with a decrease in Ctot, an increase in AIx and PVR and an increase in alpha, beta and GALA (p < 0.001 for all). Changes in GALA and Ctot after vasopressors were strongly associated (p = 0.004). Conclusions PU Loop assessment from routine invasive hemodynamic optimization management during GA and especially GALA parameter could monitor cardiac afterload continuously in anesthetized patients, and may help clinicians to titrate vasopressor therapy.

Combined Thoracic Ultrasound Assessment during a Successful Weaning Trial Predicts Postextubation Distress.

BACKGROUND: Recent studies suggest that isolated sonographic assessment of the respiratory, cardiac, or neuromuscular functions in mechanically ventilated patients may assist in identifying patients at risk of postextubation distress. The aim of the present study was to prospectively investigate the value of an integrated thoracic ultrasound evaluation, encompassing bedside respiratory, cardiac, and diaphragm sonographic data in predicting postextubation distress. METHODS: Longitudinal ultrasound data from 136 patients who were extubated after passing a trial of pressure support ventilation were measured immediately after the start and at the end of this trial. In case of postextubation distress (31 of 136 patients), an additional combined ultrasound assessment was performed while the patient was still in acute respiratory failure. We applied machine-learning methods to improve the accuracy of the related predictive assessments. RESULTS: Overall, integrated thoracic ultrasound models accurately predict postextubation distress when applied to thoracic ultrasound data immediately recorded before the start and at the end of the trial of pressure support ventilation (learning sample area under the curve: start, 0.921; end, 0.951; test sample area under the curve: start, 0.972; end, 0.920). Among integrated thoracic ultrasound data, the recognition of lung interstitial edema and the increased telediastolic left ventricular pressure were the most relevant predictive factors. In addition, the use of thoracic ultrasound appeared to be highly accurate in identifying the causes of postextubation distress. CONCLUSIONS: The decision to attempt extubation could be significantly assisted by an integrative, dynamic, and fully bedside ultrasonographic assessment of cardiac, lung, and diaphragm functions.

Severe varicella-zoster virus pneumonia: a multicenter cohort study.

BACKGROUND: Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP). METHODS: This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015. RESULTS: One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections. CONCLUSIONS: Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.

Oxalate nephropathy following vitamin C intake within intensive care unit
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OBJECTIVE: To report a case of acute oxalate nephropathy related to vitamin C intake within the intensive care unit (ICU). DESIGN: Case report. SETTING: ICU and nephrology department of a French university hospital. PATIENT: A 57-year-old woman with septic shock related to Legionella pneumophila pneumonia complicated by acute respiratory distress syndrome and acute kidney injury who required renal replacement therapy for 75 days. MEASUREMENTS AND MAIN RESULTS: A renal biopsy was performed on day 72 because of persistent anuria and because the patient showed characteristic features of severe acute oxalate nephropathy. The only cause identified was vitamin C intake received during hospitalization within the ICU (~ 30 g over 2.5 months). At month 6 after ICU admission, estimated glomerular filtration rate was 24 mL/min/1.73m2. CONCLUSION: Compelling evidence obtained from in-vitro and animal studies suggest that vitamin C, a circulating antioxidant, may be a valuable adjunctive therapy in critically-ill patients. Data from humans are more conflicting. Oxalate, a well-known metabolite of vitamin C, is excreted by the kidneys and can exert a toxic effect on epithelial cells and causes direct tubular damage, and/or it can crystallize within the tubular lumen. This case highlights an under-recognized secondary adverse event from vitamin C given to critically-ill patients. The use of high-dose vitamin C should be prescribed with caution in this population.
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Predicting preload responsiveness using simultaneous recordings of inferior and superior vena cavae diameters.

INTRODUCTION: Echocardiographic indices based on respiratory variations of superior and inferior vena cavae diameters (ΔSVC and ΔIVC, respectively) have been proposed as predictors of fluid responsiveness in mechanically ventilated patients, but they have never been compared simultaneously in the same patient sample. The aim of this study was to compare the predictive value of these echocardiographic indices when concomitantly recorded in mechanically ventilated septic patients. METHODS: Septic shock patients requiring hemodynamic monitoring were prospectively enrolled over a 1-year period in a mixed medical surgical ICU of a university teaching hospital (Toulouse, France). All patients were mechanically ventilated. Predictive indices were obtained by transesophageal and transthoracic echocardiography and were calculated as follows: (Dmax - Dmin)/Dmax for ΔSVC and (Dmax - Dmin)/Dmin for ΔIVC, where Dmax and Dmin are the maximal and minimal diameters of SVC and IVC. Measurements were performed at baseline and after a 7-ml/kg volume expansion using a plasma expander. Patients were separated into responders (increase in cardiac index ≥15%) and nonresponders (increase in cardiac index <15%). RESULTS: Among 44 included patients, 26 (59%) patients were responders (R). ΔSVC was significantly more accurate than ΔIVC in predicting fluid responsiveness. The areas under the receiver operating characteristic curves for ΔSVC and ΔIVC regarding assessment of fluid responsiveness were significantly different (0.74 (95% confidence interval (CI): 0.59 to 0.88) and 0.43 (95% CI: 0.25 to 0.61), respectively (P = 0.012)). No significant correlation between ΔSVC and ΔIVC was found (r = 0.005, P = 0.98). The best threshold values for discriminating R from NR was 29% for ΔSVC, with 54% sensitivity and 89% specificity, and 21% for ΔIVC, with 38% sensitivity and 61% specificity. CONCLUSIONS: ΔSVC was better than ΔIVC in predicting fluid responsiveness in our cohort. It is worth noting that the sensitivity and specificity values of ΔSVC and ΔIVC for predicting fluid responsiveness were lower than those reported in the literature, highlighting the limits of using these indices in a heterogeneous sample of medical and surgical septic patients.

Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach.

INTRODUCTION: Pulse pressure variation (PPV) has been shown to predict fluid responsiveness in ventilated intensive care unit (ICU) patients. The present study was aimed at assessing the diagnostic accuracy of PPV for prediction of fluid responsiveness by using the grey zone approach in a large population. METHODS: The study pooled data of 556 patients from nine French ICUs. Hemodynamic (PPV, central venous pressure (CVP) and cardiac output) and ventilator variables were recorded. Responders were defined as patients increasing their stroke volume more than or equal to 15% after fluid challenge. The receiver operating characteristic (ROC) curve and grey zone were defined for PPV. The grey zone was evaluated according to the risk of fluid infusion in hypoxemic patients. RESULTS: Fluid challenge led to increased stroke volume more than or equal to 15% in 267 patients (48%). The areas under the ROC curve of PPV and CVP were 0.73 (95% confidence interval (CI): 0.68 to 0.77) and 0.64 (95% CI 0.59 to 0.70), respectively (P<0.001). A grey zone of 4 to 17% (62% of patients) was found for PPV. A tidal volume more than or equal to 8 ml.kg(-1) and a driving pressure (plateau pressure - PEEP) more than 20 cmH2O significantly improved the area under the ROC curve for PPV. When taking into account the risk of fluid infusion, the grey zone for PPV was 2 to 13%. CONCLUSIONS: In ventilated ICU patients, PPV values between 4 and 17%, encountered in 62% patients exhibiting validity prerequisites, did not predict fluid responsiveness.

The depth of neuromuscular blockade is not related to chest wall elastance and respiratory mechanics in moderate to severe acute respiratory distress syndrome patients. A prospective cohort study.

BACKGROUND: Data concerning the depth of neuromuscular blockade (NMB) required for effective relaxation of the respiratory muscles in ARDS are scarce. We hypothesised that complete versus partial NMB can modify respiratory mechanics. METHOD: Prospective study to compare the respiratory mechanics of ARDS patients according to the NMB depth. Each patient was analysed at two times: deep NMB (facial train of four count (TOFC) = 0) and intermediate NMB (TOFC >0). The primary endpoint was the comparison of chest wall elastance (ELCW) according to the NMB level. RESULTS: 33 ARDS patients were analysed. There was no statistical difference between the ELCW at TOFC = 0 compared to TOFC >0: 7 cmH2O/l [5.7-9.5] versus 7 cmH2O/l [5.3-10.8] (p = 0.36). The depth of NMB did not modify the expiratory nor inspiratory oesophageal pressure (Pesexp = 8 cmH2O [5-9.5] at TOFC = 0 versus 7 cmH2O [5-10] at TOFC >0; (p = 0.16) and Pesinsp = 10 cmH2O [8.2-13] at TOFC = 0 versus 10 cmH2O [8-13] at TOFC >0; (p = 0.12)). CONCLUSION: In ARDS, the relaxation of the respiratory muscles seems to be independent of the NMB level.