Fang Gao Smith

Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

Summary Background In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. Methods We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FIO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. Findings We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03–2·08). Interpretation Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended. Funding UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.

Critical illness-induced dysglycaemia: diabetes and beyond

Type 2 diabetes has reached epidemic proportions in many parts of the world. The disease is projected to continue to increase and double within the foreseeable future. Dysglycaemia develops in the form of hyperglycaemia, hypoglycaemia and marked glucose variability in critically ill adults whether they are known to have premorbid diabetes or not. Patients with such glucose dysregulation have increased morbidity and mortality. Whether this is secondary to cause and effect from dysglycaemia or is just related to critical illness remains under intense investigation. Identification of intensive care unit (ICU) patients with unrecognised diabetes remains a challenge. Further, there are few data regarding the development of type 2 diabetes in survivors after hospital discharge. This commentary introduces the concept of critical illness-induced dysglycaemia as an umbrella term that includes the spectrum of abnormal glucose homeostasis in the ICU. We outline the need for further studies in the area of glucose regulation and for follow-up of the natural history of abnormal glucose control during ICU admission and beyond.

Quick biochemical markers for assessment of quality control of intraoperative cell salvage: a prospective observational study

BackgroundIntraoperative Cell Salvage (ICS), hereby referred to ‘mechanical red cell salvage’, has been widely used in adult elective major surgeries to reduce requirement for homologous red blood cell transfusion and its associated complications. However, amount of free haemoglobin (fHb) from ICS has been shown related to incidence of renal failure. fHb is the most important indicator of quality control of cell salvaged blood, thus monitoring the fHb concentration is imperative to minimise renal injury. However, currently there has been lacking quick biochemical markers to monitor the levels of fHb during ICS. The aim of this study was to screen quick biochemical markers for evaluating the amount of fHb during use of intraoperative cell salvage.MethodsTwenty patients undergoing elective cardiovascular surgery were enrolled. Blood was collected and processed using a Fresenius continuous auto-transfusion system device. The concentration of fHb, albumin (Alb), and calcium (Ca) in three washing modes were measured, and their clearance rates were calculated. The correlations among the clearances and concentrations of fHb, albumin, and calcium were analysed.ResultsIn three washing modes, concentrations of albumin and calcium are significantly associated with amount of fHb:fHb(g/L) = 0.111Alb(g/L) –0.108, R = 0.638, p = 0.000; fHb(g/L) = 1.721Ca(mmol/L) +0.091, R = 0.514, p = 0.000. Furthermore, the clearance rates of albumin and calcium significantly predict clearance of fHb, CRfHb = 0.310CRALB + 0.686, R = 0.753, p = 0.000, CRfHb = 0.073 CR Ca + 0.913, R = 0.497, p = 0.000.ConclusionsIn clinic practice, clearance rates of albumin, or calcium can be used to evaluate the quality of salvaged blood, fHb. Bed-side measurement of calcium could offer a more feasible means for clinicians to undertake a real-time assessment of fHb.

Maresin1 stimulates alveolar fluid clearance through the alveolar epithelial sodium channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 pathway.

Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h. MaR1 markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema and lung injury. In addition, rat lung tissue protein was isolated after intervention, and we found MaR1 improved epithelial sodium channel (ENaC), Na,K-adenosine triphosphatase (ATPase) protein expression and Na,K-ATPase activity. MaR1 down-regulated Nedd4-2 protein expression though PI3k/Akt but not though PI3k/SGK1 pathway in vivo. In primary rat alveolar type II epithelial cells stimulated with LPS, MaR1-upregulated ENaC and Na,K-ATPase protein abundance in the plasma membrane. Finally, the lipoxin A4 Receptor inhibitor (BOC-2) and PI3K inhibitor (LY294002) not only blocked MaR1’s effects on cAMP/cGMP, the expression of phosphorylated Akt and Nedd4-2, but also inhibited the effect of MaR1 on AFC in vivo. In conclusion, MaR1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. Our findings reveal a novel mechanism for pulmonary edema fluid reabsorption and MaR1 may provide a new therapy for the resolution of ALI/ARDS.

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe illness characterized by uncontrolled inflammation. The resolution of inflammation is a tightly regulated event controlled by endogenous mediators, such as resolvin D1 (RvD1). Cyclooxygenase-2 (COX-2) has been reported to promote inflammation, along with PGE2, in the initiation of inflammation, as well as in prompting resolution, with PGD2 acting in the later phase of inflammation. Our previous work demonstrated that RvD1 enhanced COX-2 and PGD2 expression to resolve inflammation. In this study, we investigated mechanisms underlying the effect of RvD1 in modulating proresolving COX-2 expression. In a self-limited ARDS model, an LPS challenge induced the biphasic activation of COX-2, and RvD1 promoted COX-2 expression during the resolution phase. However, it was significantly blocked by treatment of a NF-κB inhibitor. In pulmonary fibroblasts, NF-κB p50/p50 was shown to be responsible for the proresolving activity of COX-2. Additionally, RvD1 potently promoted p50 homodimer nuclear translocation and robustly triggered DNA-binding activity, upregulating COX-2 expression via lipoxin A4 receptor/formyl peptide receptor 2. Finally, the absence of p50 in knockout mice prevented RvD1 from promoting COX-2 and PGD2 expression and resulted in excessive pulmonary inflammation. In conclusion, RvD1 expedites the resolution of inflammation through activation of lipoxin A4 receptor/formyl peptide receptor 2 receptor and NF-κB p50/p50–COX-2 signaling pathways, indicating that RvD1 might have therapeutic potential in the management of ARDS.

The impact of body mass index on mortality in patients with acute kidney injury: a systematic review protocol

BackgroundAcute kidney injury (AKI) refers to a broad spectrum of kidney damage and is attributed a high morbidity and mortality rate at all degrees of severity. Obesity increases the risk for developing AKI. However, some studies have shown that obesity at onset of AKI is paradoxically associated with greater survival. The aim of this review is to explore the relationship between body mass index and survival in patients with AKI.MethodsAn electronic search will be conducted using MEDLINE, EMBASE, CINAHL and CENTRAL using predefined search strategies. The cited and citing references of selected key studies will also be searched for relevant articles. Risk of bias will be assessed using a modified Quality in Prognosis Studies (QUIPS) tool. The primary outcome will be an exploration of the association between BMI and mortality in patients presenting with AKI. Two authors will independently select, data extract, and risk of bias assess articles. Any discrepancies will be resolved by consensus or by consulting a third author. A narrative synthesis of the findings from the included studies will be presented. Meta-analyses will be conducted where the data is available from clinically and methodologically similar studies and in the same format. Heterogeneity in such analyses, beyond that expected by chance, will be quantified using the I2 statistic. Sub-group analyses will be performed to determine the influence of gender, AKI duration, underlying aetiology, and intervening treatments, on pooled results.DiscussionBody mass index may be an important modifiable risk factor for mortality in patients presenting with AKI. The proposed systematic review will help to elucidate the association between all categories of BMI and survival in this patient group.Systematic review registrationPROSPERO CRD42017071124.

Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

Inflammation always accompanies infection during sepsis. Mitochondrial dysfunction and the role of reactive oxygen species (ROS) produced by mitochondria have been proposed in the pathogenesis of sepsis. Maresins have protective and resolving effects in experimental models of infection. In the present study, we investigated the effects of maresin 1 (MaR1) on mitochondrial function in cecal ligation and puncture (CLP)-induced sepsis and sepsis patients to identify mechanisms underlying maresin 1-mediated stimulation of ROS in mitochondria. We found that treatment with MaR1 significantly inhibited production of cytokines, decreased bacterial load in the peritoneal lavage fluid, reduced the number of neutrophils, decreased lactic acid level and upregulated cyclic AMP (cAMP) concentration, with the outcome of decreased lung injury in CLP-induced sepsis in mice. The effects of MaR1 on downregulation nitric oxide (NOX) activity, improvement CAT and SOD activity to inhibit ROS production in mitochondria was dependent on lipoxin receptor (ALX) and cAMP. Survival rates were significantly increased after the treatment of mice with MaR1. In BMDM stimulated with LPS, MaR1 inhibited the ROS production, downregulated enzyme activity, reduced mtO2 production, increased mitochondrial membrane potential, improved adenosine triphosphate (ATP) content and mitochondrial DNA (mtDNA) copy number. Finally, the effects of MaR1 on ROS production in the blood of healthy volunteers stimulated with LPS or sepsis patients were associated with ALX and cAMP. Taken together, these data suggest that treatment with MaR1 could attenuate mitochondrial dysfunction during sepsis through regulating ROS production.

Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury

Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 µg/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 × 10−3 mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 ± 1.60 vs. 15.85 ± 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS-induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K-ATPase and upregulated P-Akt via inhibiting Nedd4–2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K-ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4–2 signaling pathway.Respiratory distress: Clearing fluid on the lungsTreatment that involves boosting levels of a signaling molecule could help reduce fluid on the lungs in acute respiratory distress syndrome (ARDS). This condition usually affects critically ill patients with illnesses such as pneumonia or sepsis, and leads to severe inflammation and flooding of the lungs with fluid. This prevents microscopic air sacs called aveoli from processing oxygen and carbon dioxide effectively. At present there is no effective management for the condition. Now, Sheng-Wei Jin at Wenzhou Medical University, China, and co-workers have shown that boosting levels of a signaling molecule called protectin DX can help with aveolar fluid clearance in rats. They found that protectin DX activates sodium channels within the aveoli, helping clear fluid, and also acts as an anti-inflammatory and pro-resolving mediator to protect lung tissues from further injury.