Comparing lung aeration and respiratory effort using two different spontaneous breathing trial: T-piece vs pressure support ventilation.

OBJECTIVE: To assess the changes in lung aeration and respiratory effort generated by two different spontaneous breathing trial (SBT): T-piece (T-T) vs pressure support ventilation (PSV). DESIGN: Prospective, interventionist and randomized study. SETTING: Intensive Care Unit (ICU) of Hospital del Mar. PARTICIPANTS: Forty-three ventilated patients for at least 24 h and considered eligible for an SBT were included in the study between October 2017 and March 2020. INTERVENTIONS: 30-min SBT with T-piece (T-T group, 20 patients) or 8-cmH2O PSV and 5-cmH2O positive end expiratory pressure (PSV group, 23 patients). MAIN VARIABLES OF INTEREST: Demographics, clinical data, physiological variables, lung aeration evaluated with electrical impedance tomography (EIT) and lung ultrasound (LUS), and respiratory effort using diaphragmatic ultrasonography (DU) were collected at different timepoints: basal (BSL), end of SBT (EoSBT) and one hour after extubation (OTE). RESULTS: There were a loss of aeration measured with EIT and LUS in the different study timepoints, without statistical differences from BSL to OTE, between T-T and PSV [LUS: 3 (1, 5.5) AU vs 2 (1, 3) AU; p = 0.088; EELI: -2516.41 (-5871.88, 1090.46) AU vs -1992.4 (-3458.76, -5.07) AU; p = 0.918]. Percentage of variation between BSL and OTE, was greater when LUS was used compared to EIT (68.1% vs 4.9%, p ≤ 0.001). Diaphragmatic excursion trend to decrease coinciding with a loss of aeration during extubation. CONCLUSION: T-T and PSV as different SBT strategies in ventilated patients do not show differences in aeration loss, nor estimated respiratory effort or tidal volume measured by EIT, LUS and DU.

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

Circulating microRNA profiling is altered in the acute respiratory distress syndrome related to SARS-CoV-2 infection.

One of the hallmarks of SARS-CoV-2 infection is an induced immune dysregulation, in some cases resulting in cytokine storm syndrome and acute respiratory distress syndrome (ARDS). Several physiological parameters are altered as a result of infection and cytokine storm. Among them, microRNAs (miRNAs) might reflect this poor condition since they play a significant role in immune cellular performance including inflammatory responses. Circulating miRNAs in patients who underwent ARDS and needed mechanical ventilation (MV+; n = 15) were analyzed by next generation sequencing in comparison with patients who had COVID-19 poor symptoms but without intensive care unit requirement (MV-; n = 13). A comprehensive in silico analysis by integration with public gene expression dataset and pathway enrichment was performed. Whole miRNA sequencing identified 170 differentially expressed miRNAs between patient groups. After the validation step by qPCR in an independent sample set (MV+ = 10 vs. MV- = 10), the miR-369-3p was found significantly decreased in MV+ patients (Fold change - 2.7). After integrating with gene expression results from COVID-19 patients, the most significant GO enriched pathways were acute inflammatory response, regulation of transmembrane receptor protein Ser/Thr, fat cell differentiation, and regulation of biomineralization and ossification. In conclusion, miR-369-3p was altered in patients with mechanical ventilation requirement in comparison with COVID-19 patients without this requirement. This miRNA is involved in inflammatory response which it can be considered as a prognosis factor for ARDS in COVID-19 patients.

Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients.

The clinical evolution of COVID-19 pneumonia is poorly understood. Identifying the metabolic pathways that are altered early with viral infection and their association with disease severity is crucial to understand COVID-19 pathophysiology, and guide clinical decisions. This study aimed at assessing the critical metabolic pathways altered with disease severity in hospitalized COVID-19 patients. Forty-nine hospitalized patients with COVID-19 pneumonia were enrolled in a prospective, observational, single-center study in Barcelona, Spain. Demographic, clinical, and analytical data at admission were registered. Plasma samples were collected within the first 48 h following hospitalization. Patients were stratified based on the severity of their evolution as moderate (N = 13), severe (N = 10), or critical (N = 26). A panel of 221 biomarkers was measured by targeted metabolomics in order to evaluate metabolic changes associated with subsequent disease severity. Our results show that obesity, respiratory rate, blood pressure, and oxygen saturation, as well as some analytical parameters and radiological findings, were all associated with disease severity. Additionally, ceramide metabolism, tryptophan degradation, and reductions in several metabolic reactions involving nicotinamide adenine nucleotide (NAD) at inclusion were significantly associated with respiratory severity and correlated with inflammation. In summary, assessment of the metabolomic profile of COVID-19 patients could assist in disease severity stratification and even in guiding clinical decisions.

Successfully non-surgical management of flail chest as first manifestation of multiple myeloma: A case report.

BACKGROUND: Multiple myeloma is a malignant neoplasm of the bone marrow characterized by neoplastic proliferation of monoclonal plasma cells with a high relationship with destructive bone disease. We present a case of a patient diagnosed with multiple myeloma and sternal fracture in association with multiple bilateral rib fractures and thoracic kyphosis, who developed a severe acute respiratory failure, thus complicating the initial presentation of multiple myeloma. We discuss the therapeutic implications of this uncommon presentation. CASE SUMMARY: A 56-year-old man presented to Hematological Department after he had been experiencing worsening back pain over the last five months, with easy fatigability and progressive weight loss. He had no history of previous trauma. The chemical blood tests were compatible with a diagnosis of multiple myeloma. A radiographic bone survey of all major bones revealed, in addition to multiple bilateral rib fractures, a sternal fracture and compression fracture at T9, T10, T11 and L1 vertebrae. Subcutaneous fat biopsy was positive for amyloid. We started treatment with bortezomib and dexamethasone. After 24 h of treatment, he presented dyspnea secondary to flail chest. He required urgent intubation and ventilatory support being transferred to intensive care unit for further management. The patient remained connected to mechanical ventilation (positive pressure) as treatment which stabilized the thorax. A second cycle of bortezomib plus dexamethasone was started and analgesia was optimized. The condition of the patient improved, as evidenced by callus formation on successive computed tomography scans. The patient was taken off the ventilator one month later, and he was extubated successfully, being able to breathe unaided without paradoxical motion. CONCLUSION: This case highlights the importance of combination between bortezomib and dexamethasone to induce remission of multiple myeloma and the initiation of positive airway pressure with mechanical ventilation to stabilize chest wall to solve the respiratory failure. This combined approach allowed to obtain a quick and complete resolution of the clinical situation.

Linezolid Dosing in Patients With Liver Cirrhosis: Standard Dosing Risk Toxicity.

BACKGROUND: Limited data regarding altered linezolid pharmacokinetics in patients with liver cirrhosis are available. The objective of this study was to evaluate the pharmacokinetics, efficacy and safety of linezolid in cirrhotic patients. METHODS: A case-control 1:1 study of patients undergoing linezolid therapeutic drug monitoring was conducted between January 2015 and June 2017. Cases with liver cirrhosis were matched with controls by age, body weight, comorbidities, renal function, and intensive care unit (ICU) admission. RESULTS: Fifty-two patients were included, 26 in each group. Patients with Child-Pugh Scores A, B, and C were 1 (3.8%), 13 (50.0%), and 12 (46.2%), respectively. Cases had higher median linezolid trough plasma concentrations than controls [20.6 (17.4) versus 2.7 (11.3); P < 0.001)] and more frequently achieved an optimal pharmacodynamic index [26 (100%) versus 16 (61.5%); P = 0.002]. In addition, potentially toxic concentrations and treatment discontinuation due to overexposure and hematological toxicity were also more frequently seen in cirrhotic patients. Overall clinical cure rate was high (67.4%), and in-hospital mortality was 28.8%. No differences in clinical outcomes were observed between both groups. CONCLUSIONS: Linezolid showed a high clinical cure rate. Nevertheless, plasma concentrations and treatment discontinuation due to hematological toxicity were higher in cirrhotic patients. Liver cirrhosis may influence linezolid pharmacokinetics and question the use of standard doses. Therapeutic drug monitoring of linezolid would be valuable in these patients.

Aeration changes induced by high flow nasal cannula are more homogeneous than those generated by non-invasive ventilation in healthy subjects.

BACKGROUND: Non-invasive mechanical ventilation (NIV) is a standard respiratory support technique used in intensive care units. High-Flow Nasal Cannula (HFNC) has emerged as an alternative, but further evidence is needed. The lung aeration and diaphragm changes achieved with these two strategies in healthy subjects have not been compared to date. METHODS: Twenty healthy subjects were recruited. Ten were ventilated with NIV and ten underwent HFNC. Lung impedance and diaphragmatic ultrasound measurements were performed before and after 30 min of respiratory support. The Mar-index was defined as the ratio of the diaphragm excursion-time index to the respiratory rate. RESULTS: Both groups showed significant decreases in respiratory rate (NIV: 14.4 (4.1) vs 10.4 (1.6), p = 0.009; HFNC: 13.6 (4.3) vs 7.9 (1.5) bpm, p = 0.002) and significant increases in the end-expiratory lung impedance (EELI) (NIV: 66,348(10,761) vs. 73,697 (6858), p = 0.005; HFNC: 66,252 (9793) vs 69,869 (9135), p = 0.012). NIV subjects showed a significant increase in non-dependent silent spaces (4.13 (2.25) vs 5.81 (1.49)%, p = 0.037) while the increase was more homogeneous with HFNC. The variation in EELI tended to be higher in NIV than in HFNC (8137.08 (6152.04) vs 3616.94 (3623.03), p = 0.077). The Mar-index was higher in HFNC group (13.15 vs 5.27 cm-sec2/bpm, p = 0.02). CONCLUSIONS: NIV and HFNC increased EELI in healthy subjects, suggesting an increase in the functional residual capacity. The EELI increase may be higher in NIV, but HFNC produced a more homogeneous change in lung ventilation. HFNC group has a higher MAR-index that could reflect a different ventilatory system adaptation.