Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Effect of early mobilisation on long-term cognitive impairment in critical illness in the USA: a randomised controlled trial.

BACKGROUND: Patients who have received mechanical ventilation can have prolonged cognitive impairment for which there is no known treatment. We aimed to establish whether early mobilisation could reduce the rates of cognitive impairment and other aspects of disability 1 year after critical illness. METHODS: In this single-centre, parallel, randomised controlled trial, patients admitted to the adult medical-surgical intensive-care unit (ICU), at the University of Chicago (IL, USA), were recruited. Inclusion criteria were adult patients (aged ≥18 years) who were functionally independent and mechanically ventilated at baseline and within the first 96 h of mechanical ventilation, and expected to continue for at least 24 h. Patients were randomly assigned (1:1) via computer-generated permuted balanced block randomisation to early physical and occupational therapy (early mobilisation) or usual care. An investigator designated each assignment in consecutively numbered, sealed, opaque envelopes; they had no further involvement in the trial. Only the assessors were masked to group assignment. The primary outcome was cognitive impairment 1 year after hospital discharge, measured with a Montreal Cognitive Assessment. Patients were assessed for cognitive impairment, neuromuscular weakness, institution-free days, functional independence, and quality of life at hospital discharge and 1 year. Analysis was by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01777035, and is now completed. FINDINGS: Between Aug 11, 2011, and Oct 24, 2019, 1222 patients were screened, 200 were enrolled (usual care n=100, intervention n=100), and one patient withdrew from the study in each group; thus 99 patients in each group were included in the intention-to-treat analysis (113 [57%] men and 85 [43%] women). 65 (88%) of 74 in the usual care group and 62 (89%) of 70 in the intervention group underwent testing for cognitive impairment at 1 year. The rate of cognitive impairment at 1 year with early mobilisation was 24% (24 of 99 patients) compared with 43% (43 of 99) with usual care (absolute difference -19·2%, 95% CI -32·1 to -6·3%; p=0·0043). Cognitive impairment was lower at hospital discharge in the intervention group (53 [54%] 99 patients vs 68 [69%] 99 patients; -15·2%, -28·6 to -1·7; p=0·029). At 1 year, the intervention group had fewer ICU-acquired weaknesses (none [0%] of 99 patients vs 14 [14%] of 99 patients; -14·1%; -21·0 to -7·3; p=0·0001) and higher physical component scores on quality-of-life testing than did the usual care group (median 52·4 [IQR 45·3-56·8] vs median 41·1 [31·8-49·4]; p<0·0001). There was no difference in the rates of functional independence (64 [65%] of 99 patients vs 61 [62%] of 99 patients; 3%, -10·4 to 16·5%; p=0·66) or mental component scores (median 55·9 [50·2-58·9] vs median 55·2 [49·5-59·7]; p=0·98) between the intervention and usual care groups at 1 year. Seven adverse events (haemodynamic changes [n=3], arterial catheter removal [n=1], rectal tube dislodgement [n=1], and respiratory distress [n=2]) were reported in six (6%) of 99 patients in the intervention group and in none of the patients in the usual care group (p=0·029). INTERPRETATION: Early mobilisation might be the first known intervention to improve long-term cognitive impairment in ICU survivors after mechanical ventilation. These findings clearly emphasise the importance of avoiding delays in initiating mobilisation. However, the increased adverse events in the intervention group warrants further investigation to replicate these findings. FUNDING: None.

Management of Persistent Air Leaks.

Alveolar-pleural fistulas causing persistent air leaks (PALs) are associated with prolonged hospital stays and high morbidity. Prior guidelines recommend surgical repair as the gold standard for treatment, albeit it is a solution with limited success. In patients who have recently undergone thoracic surgery or in whom surgery would be contraindicated based on the severity of illness, there has been a lack of treatment options. This review describes a brief history of treatment guidelines for PALs. In the past 20 years, newer and less invasive treatment options have been developed. Aside from supportive care, the literature includes anecdotal successful reports using fibrin sealants, ethanol injection, metal coils, and Watanabe spigots. More recently, larger studies have demonstrated success with chemical pleurodesis, autologous blood patch pleurodesis, and endobronchial valves. This manuscript describes these treatment options in detail, including postprocedural adverse events. Further research, including randomized controlled trials with comparison of these options, are needed, as is long-term follow-up for these interventions.

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma.

RATIONALE: Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy shows promising outcomes, little is known about its effects on airway inflammation. OBJECTIVES: We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty. METHODS: Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of α-SMA in endobronchial biopsies. MEASUREMENTS AND MAIN RESULTS: α-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-ß1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty. CONCLUSIONS: Clinical improvement and reduction in α-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.

Diastereoselective oxidative carbon-carbon bond formation via silyl bis-enol ethers.

Diisopropylsilyl bis-enol ethers are shown to be powerful intermediates for the diastereoselective dimerization and cross-coupling of cyclic ketones. The trends observed for the oxidative coupling of a range of different dialkylsilyl bis-enol ethers derived from cyclohexanone are rationalized by invoking a stereochemical model based on a Thorpe-Ingold effect.