In vitro and in vivo effects of salbutamol on neutrophil function in acute lung injury

Background: Intravenous salbutamol (albuterol) reduces lung water in patients with the acute respiratory distress syndrome (ARDS). Experimental data show that it also reduces pulmonary neutrophil accumulation or activation and inflammation in ARDS. Aim: To investigate the effects of salbutamol on neutrophil function. Methods: The in vitro effects of salbutamol on neutrophil function were determined. Blood and bronchoalveolar lavage (BAL) fluid were collected from 35 patients with acute lung injury (ALI)/ARDS, 14 patients at risk from ARDS and 7 ventilated controls at baseline and after 4 days’ treatment with placebo or salbutamol (ALI/ARDS group). Alveolar–capillary permeability was measured in vivo by thermodilution (PiCCO). Neutrophil activation, adhesion molecule expression and inflammatory cytokines were measured. Results: In vitro, physiological concentrations of salbutamol had no effect on neutrophil chemotaxis, viability or apoptosis. Patients with ALI/ARDS showed increased neutrophil activation and adhesion molecule expression compared with at risk-patients and ventilated controls. There were associations between alveolar– capillary permeability and BAL myeloperoxidase (r = 0.4, p = 0.038) and BAL interleukin 8 (r = 0.38, p = 0.033). In patients with ALI/ARDS, salbutamol increased numbers of circulating neutrophils but had no effect on alveolar neutrophils. Conclusion: At the onset of ALI/ARDS, there is increased neutrophil recruitment and activation. Physiological concentrations of salbutamol did not alter neutrophil chemotaxis, viability or apoptosis in vitro. In vivo, salbutamol increased circulating neutrophils, but had no effect on alveolar neutrophils or on neutrophil activation. These data suggest that the beneficial effects of salbutamol in reducing lung water are unrelated to modulation of neutrophil-dependent inflammatory pathways

Outcomes following oesophagectomy in patients with oesophageal cancer: a secondary analysis of the ICNARC Case Mix Programme Database

Introduction: This report describes the case mix and outcomes of patients with oesophageal cancer admitted to adult critical care units following elective oesophageal surgery in England, Wales and Northern Ireland. Methods: Admissions to critical care following elective oesophageal surgery for malignancy were identified using data from the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme Database. Information on admissions between December 1995 and September 2007 were extracted and the association between in-hospital mortality and patient characteristics on admission to critical care was assessed using multiple logistic regression analysis. The performance of three prognostic models (Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II and the ICNARC physiology score) was also evaluated. Results: Between 1995 and 2007, there were 7227 admissions to 181 critical care units following oesophageal surgery for malignancy. Overall mortality in critical care was 4.4% and in-hospital mortality was 11%, although both declined steadily over time. Eight hundred and seventy-three (12.2%) patients were readmitted to critical care, most commonly for respiratory complications (49%) and surgical complications (25%). Readmitted patients had a critical care unit mortality of 24.7% and in-hospital mortality of 33.9%. Overall in-hospital mortality was associated with patient age, and various physiological measurements on admission to critical care (partial pressure of arterial oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio, lowest arterial pH, mechanical ventilation, serum albumin, urea and creatinine). The three prognostic models evaluated performed poorly in measures of discrimination, calibration and goodness of fit. Conclusions: Surgery for oesophageal malignancy continues to be associated with significant morbidity and mortality. Age and organ dysfunction in the early postoperative period are associated with an increased risk of death. Postoperative serum albumin is confirmed as an additional prognostic factor. More work is required to determine how this knowledge may improve clinical management

Sepsis induces a dysregulated neutrophil phenotype that is associated with increased mortality

Background. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods. This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA) using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman’s rho. Results. Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p=0.002). PMA NETosis from patients with septic shock was reduced further (p<0.001) compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p<0.001), and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p=0.002) and 90-day mortality (p=0.014) in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions. Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced immunosuppression. For the first time, we demonstrate that reduced ex vivo NETosis is associated with poorer outcomes from sepsis

Basic life support providers’ assessment of centre of the chest and inter-nipple line for hand position and their underlying anatomical structures

INTRODUCTION Effective chest compression is an integral part of good quality cardiopulmonary resuscitation. There remains uncertainty over the optimal method for identifying the correct hand position for chest compression. The aim of this study was to identify the relationship between basic life support (BLS) providers assessment of the inter-nipple line (INL) versus the centre of the chest (CoC) and to identify the anatomical structures underneath these land marks. METHOD Thirty consecutive patients having elective CT scans of the thorax were recruited and photographs of the patient fully clothed were taken in the supine position. 30 healthcare students trained in BLS were asked to mark the ‘point between the nipples’ and the ‘centre of the chest’ on each photograph in a random sequence. Corresponding points were marked on the CT images and the underlying anatomical structures were identified. RESULTS Hand positions using CoC landmark were significantly higher and were more variable than INL landmark (Measurement represented as ratio of sternal length: mean CoC 0.709, 95% CI 0.677, 0.740 vs mean INL 0.803 95% CI 0.772, 0.835; p<0.0001). Structures underneath CoC and INL hand positions were significantly different; CoC compressing predominantly the aortic arch and ascending aorta and INL compressing the left ventricle and left ventricular outflow (p<0.001). Hand positions were not significantly affected by gender of patients. CONCLUSION Both the centre of the chest landmark and inter-nipple line identify positions on the lower third of the sternum. The centre of the chest technique identifies a point that is consistently higher and more variable than the inter-nipple line. Structures compressed under both landmarks were different although the implications of this are unknown

Case Report Icatibant in the Treatment of Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema

We describe the case of a 75-year-old woman who presented with massive tongue and lip swelling secondary to angiotensinconverting enzyme inhibitor-induced angioedema. An awake fibre-optic intubation was performed because of impending airway obstruction. As there was no improvement in symptoms after 72 hours, the selective bradykinin B2 receptor antagonist icatibant (Firazyr) was administered and the patient&apos;s trachea was successfully extubated 36 hours later. To our knowledge this is the first documented case of icatibant being used for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema in the United Kingdom and represents a novel therapeutic option in its management

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

BACKGROUND: Intraoperative 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. METHODS: Twenty 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. RESULTS: In 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, CR(fHb) = 0.310CR(ALB) + 0.686, R = 0.753, p = 0.000, CR(fHb) = 0.073 CR (Ca) + 0.913, R = 0.497, p = 0.000. CONCLUSIONS: In 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

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Background: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI