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.

Cerebral Venous Thrombosis and Subdural Collection in a Comatose Patient: Do Not Forget Intracranial Hypotension. A Case Report.

BACKGROUND: The typical sign of intracranial hypotension (IH) is postural headache. However, IH can be associated with a large diversity of clinical or radiological signs leading to difficult diagnosis especially in case of coma. The association of cerebral venous thrombosis (CVT) and subdural hemorrhage is rare but should suggest the diagnosis of IH. METHODS: Case report. CASE DESCRIPTION: We report here a case of comatose patient due to spontaneous IH complicated by CVT and subdural hemorrhage. The correct diagnosis was delayed due to many confounding factors. IH was suspected after subdural hemorrhage recurrence and confirmed by magnetic resonance imaging (MRI). After 2 epidural patches with colloid, favorable outcome was observed. DISCUSSION: The most common presentation of IH is postural orthostatic headaches. In the present case report, the major clinical signs were worsening of consciousness and coma, which are a rare presentation. Diagnosis of IH is based on the association of clinical history, evocative symptomatology, and cerebral imaging. CVT occurs in 1-2% of IH cases and the association between IH, CVT, and subdural hemorrhage is rare. MRI is probably the key imaging examination. In the present case, epidural patch was performed after confounding factors for coma had been treated. Benefit of anticoagulation had to be balanced in this case with potential hemorrhagic complications, especially within the brain. CONCLUSION: Association of CVT and subdural hemorrhage should lead to suspect IH. Brain imaging can help and find specific signs of IH.

Functional and Structural Integrity of Frontoparietal Connectivity in Traumatic and Anoxic Coma.

OBJECTIVES: Recovery from coma might critically depend on the structural and functional integrity of frontoparietal networks. We aimed to measure this integrity in traumatic brain injury and anoxo-ischemic (cardiac arrest) coma patients by using an original multimodal MRI protocol. DESIGN: Prospective cohort study. SETTING: Three Intensive Critical Care Units affiliated to the University in Toulouse (France). PATIENTS: We longitudinally recruited 43 coma patients (Glasgow Coma Scale at the admission < 8; 29 cardiac arrest and 14 traumatic brain injury) and 34 age-matched healthy volunteers. Exclusion criteria were disorders of consciousness lasting more than 30 days and focal brain damage within the explored brain regions. Patient assessments were conducted at least 2 days (5 ± 2 d) after complete withdrawal of sedation. All patients were followed up (Coma Recovery Scale-Revised) 3 months after acute brain injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional and structural MRI data were recorded, and the analysis was targeted on the posteromedial cortex, the medial prefrontal cortex, and the cingulum. Univariate analyses and machine learning techniques were used to assess diagnostic and predictive values. Coma patients displayed significantly lower medial prefrontal cortex-posteromedial cortex functional connectivity (area under the curve, 0.94; 95% CI, 0.93-0.95). Cardiac arrest patients showed specific structural disturbances within posteromedial cortex. Significant cingulum architectural disturbances were observed in traumatic brain injury patients. The machine learning medial prefrontal cortex-posteromedial cortex multimodal classifier had a significant predictive value (area under the curve, 0.96; 95% CI, 0.95-0.97), best combination of subregions that discriminates a binary outcome based on Coma Recovery Scale-Revised). CONCLUSIONS: This exploratory study suggests that frontoparietal functional disconnections are specifically observed in coma and their structural counterpart provides information about brain injury mechanisms. Multimodal MRI biomarkers of frontoparietal disconnection predict 3-month outcome in our sample. These findings suggest that fronto-parietal disconnection might be particularly relevant for coma outcome prediction and could inspire innovative precision medicine approaches.

Pharmacotherapy of sodium disorders in neurocritical care.

PURPOSE OF REVIEW: To describe the pathophysiology and pharmacotherapy of dysnatremia in neurocritical care patients. RECENT FINDINGS: Sodium disorders may affect approximately half of the neurocritical care patients and are associated with worse neurological outcome and increased risk of death. Pharmacotherapy of sodium disorders in neurocritical care patients may be challenging and is guided by a careful investigation of water and sodium balance. SUMMARY: In case of hyponatremia, because of excessive loss of sodium, fluid challenge with isotonic solution, associated with salt intake is the first-line therapy, completed with mineralocorticoids if needed. In case of hyponatremia because of SIADH, fluid restriction is the first-line therapy followed by urea if necessary. Hypernatremia should always be treated with hypotonic solutions according to the free water deficit, associated in case of DI with desmopressin. The correction speed should take into consideration the symptoms associated with dysnatremia and the rapidity of the onset.

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.