BackgroundExcessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔPocc) could be used as a highly feasible non-invasive technique to screen for these conditions.MethodsRespiratory muscle pressure (Pmus), dynamic transpulmonary driving pressure (ΔPL,dyn, the difference between peak and end-expiratory transpulmonary pressure), and ΔPocc were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔPL,dyn and Pmus from ΔPocc was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China).ResultsFifty-two daily recordings were collected in 16 patients. In this sample, Pmus and ΔPL were frequently excessively high: Pmus exceeded 10 cm H2O on 84% of study days and ΔPL,dyn exceeded 15 cm H2O on 53% of study days. ΔPocc measurements accurately detected Pmus > 10 cm H2O (AUROC 0.92, 95% CI 0.83–0.97) and ΔPL,dyn > 15 cm H2O (AUROC 0.93, 95% CI 0.86–0.99). In the external validation cohort (n = 12), estimating Pmus and ΔPL,dyn from ΔPocc measurements detected excessively high Pmus and ΔPL,dyn with similar accuracy (AUROC ≥ 0.94).ConclusionsMeasuring ΔPocc enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.

IntroductionBased on the hypothesis that failure of weaning from mechanical ventilation is caused by respiratory demand exceeding the capacity of the respiratory muscles, we evaluated whether extubation failure could be characterized by increased respiratory drive and impaired efficiency to generate inspiratory pressure and ventilation.MethodsAirway pressure, flow, volume, breathing frequency, and diaphragm electrical activity were measured in a heterogeneous group of patients deemed ready for a spontaneous breathing trial. Efficiency to convert neuromuscular activity into inspiratory pressure was calculated as the ratio of negative airway pressure and diaphragm electrical activity during an inspiratory occlusion. Efficiency to convert neuromuscular activity into volume was calculated as the ratio of the tidal volume to diaphragm electrical activity. All variables were obtained during a 30-minute spontaneous breathing trial on continuous positive airway pressure (CPAP) of 5 cm H2O and compared between patients for whom extubation succeeded with those for whom either the spontaneous breathing trial failed or for those who passed, but then the extubation failed.ResultsOf 52 patients enrolled in the study, 35 (67.3%) were successfully extubated, and 17 (32.7%) were not. Patients for whom it failed had higher diaphragm electrical activity (48%; P < 0.001) and a lower efficiency to convert neuromuscular activity into inspiratory pressure and tidal volume (40% (P < 0.001) and 53% (P < 0.001)), respectively. Neuroventilatory efficiency demonstrated the greatest predictability for weaning success.ConclusionsThis study shows that a mixed group of critically ill patients for whom weaning fails have increased neural respiratory drive and impaired ability to convert neuromuscular activity into tidal ventilation, in part because of diaphragm weakness.Trial RegistrationClinicaltrials.gov identifier NCT01065428. ©2012 Liu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

BackgroundMesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF) and to induce the differentiation of dendritic cells (DCs) into tolerogenic dendritic cells (DCregs) and participate in the immune response. However, whether MSCs induce the production of DCregs by secreting HGF to alleviate early ALI remains unclear. We observed that the protective effect of mouse bone marrow-derived MSCs against lipopolysaccharide (LPS)-induced ALI was achieved by inducing mature DCs (mDCs) to differentiate into DCregs, and its mechanism is related to the activation of the HGF/Akt pathway.MethodsMSCs or MSCs with overexpression or knockdown of HGF were cocultured with DCs derived from mouse bone marrow using a Transwell system for 3 days. Moreover, we used MSCs or MSCs with overexpression or knockdown of HGF to treat LPS-induced ALI mice for 24 h. Flow cytometry was performed to measure the phagocytosis, accumulation, and maturation of DCs, as well as proliferation of T cells. Lung injury was estimated by lung wet weight to body weight ratio (LWW/BW) and histopathological analysis. Furthermore, we used the Akt inhibitor MK-2206 in a coculture system to elucidate the role of the HGF/Akt pathway in regulating the differentiation of DCs into regulatory DCs and relieving lung injury in early ALI mice.ResultsImmature DCs (imDCs) were induced to mature after 24 h of LPS (50 ng/ml) stimulation. MSCs or HGF induced the differentiation of mDCs into regulatory DCs characterized by low expression of MHCII, CD86, and CD40 molecules, strong phagocytic function, and the ability to inhibit T cell proliferation. The effect of MSCs on DCregs was enhanced with the increase in HGF secretion and was weakened with the decrease in HGF secretion. DCregs induced by recombinant HGF were attenuated by the Akt inhibitor MK-2206. Lung DC aggregation and mDC ratio increased in LPS-induced ALI mice, while treatment with MSCs decreased lung DC aggregation and maturation and alleviated lung pathological injury. High expression of the HGF gene enhanced the above effect of MSCs, while decreased expression of HGF weakened the above effect of MSCs.ConclusionsMSCs alleviate early ALI via paracrine HGF by inducing mDCs to differentiate into regulatory DCs. Furthermore, the mechanism of HGF-induced differentiation of mDCs into DCregs is related to the activation of the Akt pathway.

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IntroductionProne positioning (PP) has been reported to improve the survival of patients with severe acute respiratory distress syndrome (ARDS). However, it is uncertain whether the beneficial effects of PP are associated with positive end-expiratory pressure (PEEP) levels and long durations of PP. In this meta-analysis, we aimed to evaluate whether the effects of PP on mortality could be affected by PEEP level and PP duration and to identify which patients might benefit the most from PP.MethodsPublications describing randomized controlled trials (RCTs) in which investigators have compared prone and supine ventilation were retrieved by searching the following electronic databases: PubMed/MEDLINE, the Cochrane Library, the Web of Science and Elsevier Science (inception to May 2013). Two investigators independently selected RCTs and assessed their quality. The data extracted from the RCTs were combined in a cumulative meta-analysis and analyzed using methods recommended by the Cochrane Collaboration.ResultsA total of nine RCTs with an aggregate of 2,242 patients were included. All of the studies received scores of up to three points using the methods recommended by Jadad et al. One trial did not conceal allocation. This meta-analysis revealed that, compared with supine positioning, PP decreased the 28- to 30-day mortality of ARDS patients with a ratio of partial pressure of arterial oxygen/fraction of inspired oxygen ≤100 mmHg (n = 508, risk ratio (RR) = 0.71, 95 confidence interval (CI) = 0.57 to 0.89; P = 0.003). PP was shown to reduce both 60-day mortality (n = 518, RR = 0.82, 95% CI = 0.68 to 0.99; P = 0.04) and 90-day mortality (n = 516, RR = 0.57, 95% CI = 0.43 to 0.75; P < 0.0001) in ARDS patients ventilated with PEEP ≥10 cmH2O. Moreover, PP reduced 28- to 30-day mortality when the PP duration was >12 h/day (n = 1,067, RR = 0.73, 95% CI = 0.54 to 0.99; P = 0.04).ConclusionsPP reduced mortality among patients with severe ARDS and patients receiving relatively high PEEP levels. Moreover, long-term PP improved the survival of ARDS patients.

Background Non-invasive respiratory strategies (NIRS) including high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) have become widely used in patients with COVID-19 who develop acute respiratory failure. However, use of these therapies, if ineffective, might delay initiation of invasive mechanical ventilation (IMV) in some patients. We aimed to determine early predictors of NIRS failure and develop a simple nomogram and online calculator that can identify patients at risk of NIRS failure. MethodsWe did a retrospective, multicentre observational study in 23 hospitals designated for patients with COVID-19 in China. Adult patients (≥18 years) with severe acute respiratory syndrome coronavirus 2 infection and acute respiratory failure receiving NIRS were enrolled. A training cohort of 652 patients (21 hospitals) was used to identify early predictors of NIRS failure, defined as subsequent need for IMV or death within 28 days after intensive care unit admission. A nomogram was developed by multivariable logistic regression and concordance statistics (C-statistics) computed. C-statistics were validated internally by cross-validation in the training cohort, and externally in a validation cohort of 107 patients (two hospitals). Findings Patients were enrolled between Jan 1 and Feb 29, 2020. NIV failed in 211 (74%) of 286 patients and HFNC in 204 (56%) of 366 patients in the training cohort. NIV failed in 48 (81%) of 59 patients and HFNC in 26 (54%) of 48 patients in the external validation cohort. Age, number of comorbidities, respiratory rate-oxygenation index (ratio of pulse oximetry oxygen saturation/fraction of inspired oxygen to respiratory rate), Glasgow coma scale score, and use of vasopressors on the first day of NIRS in the training cohort were independent risk factors for NIRS failure. Based on the training dataset, the nomogram had a C-statistic of 0•80 (95% CI 0•74-0•85) for predicting NIV failure, and a C-statistic of 0•85 (0•82-0•89) for predicting HFNC failure. C-statistic values were stable in both internal validation (NIV group mean 0•79 [SD 0•10], HFNC group mean 0•85 [0•07]) and external validation (NIV group value 0•88 [95% CI 0•72-0•96], HFNC group value 0•86 [0•72-0•93]). Interpretation We have developed a nomogram and online calculator that can be used to identify patients with COVID-19 who are at risk of NIRS failure. These patients might benefit from early triage and more intensive monitoring.

Background Difficult weaning frequently develops in ventilated patients and is associated with poor outcome. In neurally adjusted ventilatory assist, the ventilator is controlled by diaphragm electrical activity, which has been shown to improve patient–ventilator interaction. The objective of this study was to compare neurally adjusted ventilatory assist and pressure support ventilation in patients difficult to wean from mechanical ventilation. Methods In this nonblinded randomized clinical trial, difficult-to-wean patients (n = 99) were randomly assigned to neurally adjusted ventilatory assist or pressure support ventilation mode. The primary outcome was the duration of weaning. Secondary outcomes included the proportion of successful weaning, patient–ventilator asynchrony, ventilator-free days, and mortality. Weaning duration was calculated as 28 days for patients under mechanical ventilation at day 28 or deceased before day 28 without successful weaning. Results Weaning duration in all patients was statistically significant shorter in the neurally adjusted ventilatory assist group (n = 47) compared with the pressure support ventilation group (n = 52; 3.0 [1.2 to 8.0] days vs. 7.4 [2.0 to 28.0], mean difference: −5.5 [95% CI, −9.2 to −1.4], P = 0.039). Post hoc sensitivity analysis also showed that the neurally adjusted ventilatory assist group had shorter weaning duration (hazard ratio, 0.58; 95% CI, 0.34 to 0.98). The proportion of patients with successful weaning from invasive mechanical ventilation was higher in neurally adjusted ventilatory assist (33 of 47 patients, 70%) compared with pressure support ventilation (25 of 52 patients, 48%; respiratory rate for neurally adjusted ventilatory assist: 1.46 [95% CI, 1.04 to 2.05], P = 0.026). The number of ventilator-free days at days 14 and 28 was statistically significantly higher in neurally adjusted ventilatory assist compared with pressure support ventilation. Neurally adjusted ventilatory assist improved patient ventilator interaction. Mortality and length of stay in the intensive care unit and in the hospital were similar among groups. Conclusions In patients difficult to wean, neurally adjusted ventilatory assist decreased the duration of weaning and increased ventilator-free days. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

IntroductionThe effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients.MethodsThis is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging.ResultsNineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure (from 11 ± 4 to 13 ± 4 mmHg, P = 0.002), cardiac output (from 5.4 ± 1.4 to 6.4 ± 2.1 l/minute, P = 0.001), and central venous oxygen saturation (from 81 ± 7 to 83 ± 7%, P = 0.001). There were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mm2, P = 0.009), proportion of small perfused vessels (from 85 ± 18 to 92 ± 14%, P = 0.002), and small microvascular flow index (from 2.45 ± 0.61 to 2.80 ± 0.68, P = 0.009) when compared with a mean arterial pressure of 65 mmHg.ConclusionsIncreasing mean arterial pressure from 65 mmHg to normal levels is associated with improved microcirculation in hypertensive septic shock patients.Trial registrationClinicaltrials.gov: NCT01443494; registered 28 September 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0866-0) contains supplementary material, which is available to authorized users.