Yingzi Huang

Neuroventilatory efficiency and extubation readiness in critically ill 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.

Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice

IntroductionMesenchymal stem cells (MSCs) have potential for re-epithelization and recovery in acute respiratory distress syndrome (ARDS). In a previous in vitro study, the results showed that the canonical Wnt/β-catenin pathway promoted the differentiation of MSCs into type II alveolar epithelial cells, conferred resistance to oxidative stress, and promoted their migration, suggesting that the Wnt/β-catenin pathway might be one of the key mechanisms underling the therapeutic effect of mouse MSCs in ARDS.MethodsMouse MSCs stable transfected with β-catenin or green fluorescent protein control were transplanted intratracheally into the ARDS mice induced by lipopolysaccharide. Lung tissue injury and repair assessment were examined using haematoxylin and eosin staining, lung injury scoring, Masson’s trichrome staining and fibrosis scoring. Homing and differentiation of mouse MSCs were assayed by labelling and tracing MSCs using NIR815 dye, immunofluorescent staining, and Western immunoblot analysis. The inflammation and permeability were evaluated by detecting the cytokine and protein measurements in bronchoalveolar lavage fluid using enzyme-linked immunosorbent assay.ResultsIn this study, β-catenin-overexpressing MSC engraftment led to more significant effects than the GFP controls, including the retention of the MSCs in the lung, differentiation into type II alveolar epithelial cells, improvement in alveolar epithelial permeability, and the pathologic impairment of the lung tissue.ConclusionThese results suggest that the activation of canonical Wnt/β-catenin pathway by mouse MSCs by overexpressing β-catenin could further improve the protection of mouse MSCs against epithelial impair and the therapeutic effects of mouse MSCs in ARDS mice.

Stable Genetic Alterations of β-Catenin and ROR2 Regulate the Wnt Pathway, Affect the Fate of MSCs

The Wnt pathways have been shown to be critical for the fate of mesenchymal stem cells (MSCs) in vitro, but their roles in MSCs in vivo remain poorly characterized due to the lack of stable alterations in their signaling. In the present study, we constructed long‐term and stable mMSCs lines with activated and inactivated β‐catenin (the key molecule of the canonical Wnt signaling pathway) or ROR2 (the key molecule of the noncanonical Wnt5a/ROR2 signaling pathway) modifications with lentiviral vectors. We found that the transduction efficiencies mediated by the lentiviral vectors were 92.61–97.04% and were maintained over 20 passages of mMSCs. Transfection by lentiviral vectors not only regulated the mRNA and protein expression of β‐catenin or ROR2 but also regulated nuclear β‐catenin accumulation or the Wnt5a/JNK and Wnt5a/PKC pathways belonging to the canonical Wnt and noncanonical Wnt5a/ROR2 pathways, respectively. β‐Catenin or ROR2 gene overexpression promoted mMSC proliferation, migration and differentiation into osteoblasts, while inhibiting the adipogenic differentiation of mMSCs. In contrast, inactivation of the β‐catenin or ROR2 genes resulted in the opposite effects. Therefore, these results confirm that lentiviral vector transduction can facilitate sustained and efficient gene modification of the Wnt pathway in mMSCs. This study provides a method to investigate the effects of the Wnt pathway on the fate of mMSCs in vivo and for the further improvement of MSC‐based therapies. J. Cell. Physiol. 229: 791–800, 2014.

Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials

IntroductionThe aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis.MethodsWe searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software.ResultsA total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I2 = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09).ConclusionsIn this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.

Pulmonary acute respiratory distress syndrome: positive end-expiratory pressure titration needs stress index

BACKGROUND The heterogeneity of lung injury in pulmonary acute respiratory distress syndrome (ARDS) may have contributed to the greater response of hyperinflated area with positive end-expiratory pressure (PEEP). PEEP titrated by stress index can reduce the risk of alveolar hyperinflation in patients with pulmonary ARDS. The authors sought to investigate the effects of PEEP titrated by stress index on lung recruitment and protection after recruitment maneuver (RM) in pulmonary ARDS patients. MATERIALS AND METHODS Thirty patients with pulmonary ARDS were enrolled. After RM, PEEP was randomly set according to stress index, oxygenation, static pulmonary compliance (Cst), or lower inflection point (LIP) + 2 cmH2O strategies. Recruitment volume, gas exchange, respiratory mechanics, and hemodynamic parameters were collected. RESULTS PEEP titrated by stress index (15.1 ± 1.8 cmH2O) was similar to the levels titrated by oxygenation (14.5 ± 2.9 cmH2O), higher than that titrated by Cst (11.3 ± 2.5 cmH2O) and LIP (12.9 ± 1.6 cmH2O) (P < 0.05). Compared with baseline, PaO2/FiO2 and recruitment volume were significantly improved after PEEP titration with the four strategies (P < 0.05). PaO2/FiO2 and recruitment volume were similar when using PEEP titrated by stress index and oxygenation but higher than that titrated by Cst and LIP. Compared with baseline, lung compliance increased significantly when PEEP determined by Cst, but there was no difference of Cst in these four strategies. There was no influence of PEEP titration with the four strategies on hemodynamic parameters. CONCLUSIONS PEEP titration by stress index might be more beneficial for pulmonary ARDS patients after RM.

The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND:Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care. METHODS:We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS:Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74–1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57–0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect. CONCLUSIONS:In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.

MSCs modified with ACE2 restore endothelial function following LPS challenge by inhibiting the activation of RAS.

Angiotensin (Ang) II plays an important role in the process of endothelial dysfunction in acute lung injury (ALI) and is degraded by angiotensin‐converting enzyme2 (ACE2). However, treatments that target ACE2 to injured endothelium and promote endothelial repair of ALI are lacking. Mesenchymal stem cells (MSCs) are capable of homing to the injured site and delivering a protective gene. Our study aimed to evaluate the effects of genetically modified MSCs, which overexpress the ACE2 protein in a sustained manner via a lentiviral vector, on Ang II production in endothelium and in vitro repair of lipopolysaccharide (LPS)‐induced endothelial injury. We found that the efficiency of lentiviral vector transduction of MSCs was as high as 97.8% and was well maintained over 30 passages. MSCs modified with ACE2 showed a sustained high expression of ACE2 mRNA and protein. The modified MSCs secreted soluble ACE2 protein into the culture medium, which reduced the concentration of Ang II and increased the production of Ang 1–7. MSCs modified with ACE2 were more effective at restoring endothelial function than were unmodified MSCs, as shown by the enhanced survival of endothelial cells; the downregulated production of inflammatory mediators, including ICAM‐1, VCAM‐1, TNF‐α, and IL‐6; reduced paracellular permeability; and increased expression of VE‐cadherin. These data demonstrate that MSCs modified to overexpress the ACE2 gene can produce biologically active ACE2 protein over a sustained period of time and have an enhanced ability to promote endothelial repair after LPS challenge. These results encourage further testing of the beneficial effects of ACE2‐modified MSCs in an ALI animal model. J. Cell. Physiol. 230: 691–701, 2015.

Therapeutic Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Models of Pulmonary and Extrapulmonary Acute Lung Injury.

Bone marrow-derived mesenchymal stem cells (MSCs) offer a promising therapy for acute lung injury (ALI). However, whether the same MSC treatments possess similar potential for different ALI models is not fully clear. The present study evaluated the distribution and therapeutic effects of intravenous MSC administration for the treatment of intratracheal lipopolysaccharide (LPS)-induced intrapulmonary ALI and intravenous LPS/zymosan-induced extrapulmonary ALI, matched with lung injury severity, at 30 min and 1, 3, and 7 days. We found that MSC transplantation attenuated lung injury and inhibited lung inflammation in both ALI models. The benefits of MSCs were more significant in the intrapulmonary ALI mice. In vivo and ex vivo fluorescence imaging showed that MSCs primarily homed into the lung. However, more MSCs were recruited into the lungs of the intrapulmonary ALI mice than those of the extrapulmonary ALI mice over the time course. A few MSCs were also detected in the liver and spleen at days 3 and 7. In addition, the two ALI models showed different extrapulmonary organ dysfunction. A lower percentage of cell apoptosis and SDF-1α levels was found in the liver and spleen of the intrapulmonary ALI mice than in those of the extrapulmonary ALI mice. These results suggested that the two ALI models were accompanied with different degrees of extrapulmonary organ damage, which resulted in differences in the trafficking and accumulation of MSCs to the injured lung and consequently accounted for different therapeutic effects of MSCs for lung repair in the two ALI models. These data suggest that intravenous administration of MSCs has a greater potential for the treatment of intrapulmonary ALI than extrapulmonary ALI matched with lung injury severity; these differences were due to more recruitment of MSCs in the lungs of intrapulmonary ALI mice than those of extrapulmonary ALI mice. This finding may contribute to the clinical use of MSCs for the treatment of ALI.

Antimicrobial stewardship of Chinese ministry of health reduces multidrug-resistant organism isolates in critically ill patients: a pre-post study from a single center

BackgroundChina’s Ministry of Health (MOH) has established a policy about the antimicrobial stewardship. To date, the effects of this policy on multidrug-resistant organism (MDRO) in critically ill patients are unknown.MethodsA pre-post study was conducted on intensive care unit (ICU) patients from June 2010 to May 2011 and from June 2012 to May 2013. Bacterial cultures were conducted at ICU admission and discharge. In June 2011, our hospital started to administer the antimicrobial stewardship program of Chinese MOH. We collected the data on antimicrobial consumption during the 3-year period in all hospital and individual department every month, and analyzed the correlation between the proportion of critically patients colonized or infected with MDRO and antimicrobial consumption.ResultsA total of 978 patients were involved in the present study. With the intervention, the monthly mean Defined Daily Dose (DDD) per 100 occupied bed-days throughout the hospital decreased from 96 ± 7 to 65 ± 6 (p < 0.001), and the proportion of patients colonized or infected with MDRO decreased from 36 to 13% at the time of ICU admission and declined from 48 to 29% at the time of ICU discharge (both p < 0.001). There was a significant positive relationship between the proportion of all critically ill patients colonized or infected with MDRO at ICU admission and the DDD of the entire hospital (R2 = 0.7858, p < 0.001).ConclusionThe antimicrobial stewardship program of Chinese MOH reduced the consumption of antibiotics. Moreover, the proportion of patients colonized or infected with MDRO decreased along with reduced consumption of antibiotics.Trial registrationRetrospectively registered: NCT02128399; Date of registration: 22 APR 2014; Detail information web link: https://clinicaltrials.gov/ct2/show/NCT02128399?term=NCT02128399&rank=1

Propofol increases preload dependency in septic shock patients

BACKGROUND Predicting fluid responsiveness is crucial for fluid administration in septic shock patients. Midazolam and propofol decrease vascular tone and venous return, which may influence preload dependency. However, little is known about the effects of these two sedatives on preload dependency in septic shock patients. We evaluated the effects of sedation with propofol or midazolam on preload dependency in septic shock patients who have been fluid resuscitated. METHODS Forty-three septic shock patients who were undergoing early goal-directed therapy resuscitated within 24 h were enrolled. The patients were randomly divided into the midazolam group and the propofol group. An initial passive leg-raising test (PLR1) was performed to evaluate passive leg raising test (PLR) responsiveness. Then, the patients were infused with midazolam or propofol. After increasing the doses of the sedatives to titrate to a Ramsay 4 score, a second passive leg raising test (PLR2) was conducted to evaluate PLR responsiveness. The primary end-point was the preload dependency before and after sedation with midazolam or propofol. RESULTS In the midazolam-PLR1-negative patients, there was no difference between the changes in the cardiac index induced by PLR1 (PLR1-Δ cardiac function index [CI]) and the changes in the cardiac index induced by PLR2 (PLR2-Δ CI) (+1.4% ± 7.4% versus +1.7% ± 6.4%, P > 0.05). However, in the propofol-PLR1-negative patients, there was a significant increase in the PLR-Δ CI after sedation to a Ramsay 4 score compared with a Ramsay 3 score (+7.3% ± 4.8% versus +3.2% ± 4.7%, P = 0.008). There were no differences between PLR1-Δ CI and PLR2-Δ CI within the midazolam-PLR1-positive patients or within the propofol-PLR1-positive patients. CONCLUSIONS In titrating the sedation level from a Ramsay 3 score to a Ramsay 4 score, propofol but not midazolam increased preload dependency in septic shock patients with fluid nonresponsiveness.