Rca Dancer

P265 Concurrent statin and macrolide use during pneumonia treatment improves survival to hospital discharge and beyond

Background Pneumonia is a leading cause of hospital admission. With mortality exceeding 18% (BTS CAP Audit 2013) the search for strategies to reduce this continues. Statins are receiving increasing attention for a potential role in improving survival from acute bacterial infections. MHRA guidance recommends that statins should be paused during treatment with a macrolide due to risk of myopathy and rhabdomyolysis. We undertook a retrospective study to determine the frequency of concurrent statin and macrolide administration in patients diagnosed with pneumonia and whether concurrent use of a statin and macrolide antibiotic to treat pneumonia improved survival compared to stopping statin treatment, and whether concurrent use was safe and tolerable. 165 patient episodes were identified by searching for patients who were coded as having pneumonia and were prescribed a statin and macrolide. Data was collected on statin, dose, severity of pneumonia including intensive care admission, comorbidities, survival, renal and liver function. Results 62% of the cohort continued a statin throughout pneumonia treatment. In the continued statin group survival to hospital discharge was 79% versus 64% in the group in whom the statin was paused (p = 0.034). Severity of pneumonia (CURB score) was similar for both groups. Statin users were less likely to be admitted to intensive care (28% vs 46%, p = 0.0219). Charlson comorbidity index score was similar for the statin (6.4, IQR = 5–8) and non-statin (6.1, IQR = 5–8) groups. There was no increased risk of acute liver, kidney injury or myopathy in the continued statin group. Conclusion Continued statin use during treatment for pneumonia with a macrolide antibiotic is safe and may improve survival compared to stopping statin use. Current guidance on concurrent use of statins and macrolides should be reviewed. Abstract P265 Figure 1

T2 Vitamin D supplementation reduces perioperative systemic and alveolar inflammation in patients undergoing oesophagectomy: Results of the Vindaloo Trial

Vitamin D deficiency is associated with increased risk of ARDS post-oesophagectomy. We recruited patients to a double-blind, randomised controlled trial of high dose Vitamin D supplementation 3–14 days pre-oesophagectomy. 79 patients were randomised to receive placebo or 300,000 IU oral Vitamin D liquid 3–14 days prior to oesophagectomy. Blood samples were collected pre-dose, post-dose (pre-op) and post-op and analysed for 25-OH and 1,25-dOH Vitamin D, inflammatory cells and cytokines. Broncho-alveolar lavage fluid was collected at the end of the operation. PICCO biomarkers of alveolar capillary damage (EVLWI and PVPI) were measured pre- and post-op. Pre-operative supplementation with Vitamin D was well tolerated with no SUSARs and significantly increased circulating 25-OH and 1,25-OH Vitamin D (p < 0.0001). This was associated with reduced systemic inflammation (IL-6 (p = 0.02) and IL-8 (p = 0.002)) and an increase in circulatory Treg (p = 0.027). Changes in PICCO biomarkers were lower in supplemented patients suggesting lower perioperative alveolar oedema (EVLWI p = 0.05, PVPI p = 0.04). This did not result in a significant difference in oxygenation at 24 h. Post-op, systemic and alveolar alarmin (IL-1B, IL-6, IL-8) response was similar in treated and untreated patients but the systemic release of IL-1ra (p = 0.046), sTNFR-1 (p = 0.05) and s-TNFR-2 (p = 0.02) were elevated in treated patients. There was also evidence of decreased alveolar macrophage efferocytosis in patients with Vitamin D deficiency (p = 0.003). Clinical diagnoses of ARDS were significantly lower in this cohort than in previous cohorts, but the study was not powered to detect that outcome. Mortality post-operative was not significantly different at 30 or 90 days but there is a significant difference after 300 days of follow-up (placebo 33% mortality, Vitamin D 8% mortality p = 0.033). In conclusion, vitamin D supplementation was a safe, well tolerated pre-operative intervention that reduced systemic inflammation and biomarkers of alveolar oedema. With evidence of enhanced anti-inflammatory mechanism that may have influenced longer term post-operative survival, Vitamin D deficiency should be identified and treated in patients at risk of ARDS.

S98 Vitamin D deficiency increases bacterial load in a murine model of sepsis-induced lung injury

Introduction We have previously shown that patients with Acute Lung Injury (ALI) are severely vitamin D deficient. Several studies have reported a high prevalence of vitamin D deficiency in critically ill patients with sepsis, associated with increased morbidity and mortality but whether this is cause or effect is unknown. Bacteraemic sepsis is more common in the winter months when vitamin D levels are lowest. The purpose of this study was to investigate the local and systemic effects of vitamin D deficiency in a murine model of sepsis-induced lung injury where we can predictably time the initiating insult. Methods We fed 8 wild-type C57Bl/6 mice a diet completely devoid of vitamin D for 6 weeks to induce severe vitamin D deficiency (9 nmol/l) and compared to 7 mice fed a vitamin D sufficient diet (42 nmol/l). Caecal ligation and puncture (CLP) was used to establish sepsis. Animals were culled 16h after CLP and blood, peritoneal lavage fluid (PLF) and bronchoalveloar lavage fluid (BALF) were collected. Cell infiltrates were assessed by flow cytometry. Fluid protein levels were measured and tissue protein permeability index (PPI) was calculated as the ratio between fluid and serum protein. Bacterial load was evaluated as colony-forming units (CFU) after 24h incubation on appropriate media. Results Vitamin D deficient mice had increased bacterial load in BALF, blood and PLF compared to dietary sufficient mice. BALF protein permeability index was higher in deficient compared to sufficient mice but there was no difference in cell numbers recruited to the lung. PLF protein permeability index was also increased in the deficient group compared to sufficient mice with an associated significant increase in neutrophils recruited to the peritoneum. (See Table 1) Abstract S98 Table 1. Differences between dietary deficient and sufficient mice post CLP induced sepsis. Data is expressed as median values. Sufficient (n = 7) Deficient (n = 8) p-value Bacteria (CFU x103) BALFBloodPLF 0.510.288.22 2.5166.1336.6 0.0380.0190.005 PPI (x1000) BALFPLF 1.8227.2 3.3046.9 0.00030.05 Neutrophil Number BALFPLF (x106) 64.12.11 27.94.60 0.1830.04 Conclusion Vitamin D deficiency significantly increases the bacterial load both systemically, locally and within the lung in a murine model of peritonitis. This is associated with an increase in tissue permeability locally and within the lung. These data support pre-existing vitamin D deficiency as a determinant of the severity of bacteraemic sepsis and may account for some of the seasonal variations observed in the incidence of sepsis.

S15 Changes in perioperative ards with time: a comparison of two trials

Introduction and objective The BALTI-Prevention Trial1 translational sub-study (recruitment completed in 2011) and VINDALOO Trial2 (recruitment completed in 2015) both used oesophagectomy as a model for investigation of the pharmacological prevention of ARDS. The VINDALOO trial showed a lower ARDS incidence independent of the agents evaluated. Our objective was to characterise this difference. Methods Databases from both trials were available and additional information was obtained retrospectively from hospital records. Analysis was performed using appropriate statistical tests. Results There was a substantially higher ARDS incidence in BALTI-P compared to VINDALOO (RR 1.17 (1.08–1.28)) (Figure 1). There were more never (21 versus 7) and fewer current (12 versus 25) smokers in the VINDALOO group (p = 0.003). Perioperative risk scores did not differ between groups (P-POSSUM mortality p = 0.98, P-POSSUM morbidity p = 0.87, O-POSSUM p = 0.58), nor did use of neoadjuvant chemotherapy (p = 1.0). The incidence of serious complications (Clavien-Dindo score of four or more), was not different between the two groups (RR 1.15 (0.94–1.40)). Univariate analysis of the combined groups showed risk factors for ARDS not using regional anaesthesia (OR 3.2 (1.0–9.8) p = 0.038) and current smoking (OR 3.0 (1.1–8.3) p = 0.038). Abstract S15 Figure 1 ARDS incidence was higher in the BALTI-Prevention compared to the VINDALOO trial (p = 0.004) Conclusion Smoking is an environmental risk factor for ARDS and changing patterns in smoking behaviour appear important in these perioperative cohorts. Other studies have demonstrated that aggregates of small but important changes in care can cumulatively make a significant difference to risk of nosocomial ARDS and our data suggests that this may have resulted in a reduction in perioperative ARDS in this group. Our study has demonstrated that ARDS incidence post oesophagectomy has fallen. In future, trials utilising oesophagectomy as a model of ARDS should consider selection of a defined higher-risk sub-set of patients. References Perkins G, et al. The beta agonist lung injury trial prevention. A randomised controlled trial. Am J Respir Crit Care Med 2014;189(6):674–683. Parekh D, et al. Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial. Trials 2013;14(100). doi:10.1186/1745-6215-1114-1100.

P147 Current smokers face increased risk of Acute Lung Injury post oesophagectomy compared to former smokers- implications for therapy and trial design?

Introduction Patients undergoing oesophagectomy have ~25% risk of developing post-operative Acute Lung Injury (ALI). A recent meta-analysis showed that smoking cessation prior to an operation reduces the risk of respiratory complications [1]. We hypothesised that current smokers would have an increased risk of ALI post-oesophagectomy compared with former smokers. Methods We analysed data from 14 current smokers and 37 former smokers recruited to the translational sub-study of the BALTI prevention trial. Extravascular Lung Water Index (EVLWI) and Pulmonary Vascular Permeability Index (PVPI) were measured using PICCO. Plasma and Bronchoalveolar lavage fluid (BALF) cytokine levels were measured by ELISA. Results Current smokers were significantly younger and had a lower BMI than former smokers. Current smokers were more likely to develop post-operative ALI which required ventilation but there was no difference in the rate of respiratory infection. PVPI was significantly higher immediately post op and on day 1 post op and EVLWI was significantly higher on day 1 post op in current smokers (see table). Plasma levels of FAS ligand were significantly lower in current smokers pre-op, post-op and on day 1 post-op. Pre-op plasma levels of sICAM1 were significantly higher in current smokers but there was no difference in post-op levels. Plasma levels of IL-17 were lower pre-op, post-op and on day 1, although only the post-op difference reached significance. In BAL, levels of VEGF were significantly lower and levels of IL1ra and TNFR1 were significantly higher in current smokers (see table). Conclusion Current smokers have a higher risk of Acute Lung Injury following oesophagectomy than former smokers. This finding is supported by higher post-operative levels of extravascular lung water and pulmonary vascular permeability and differences in both plasma and BAL cytokines in current smokers. Our data highlights the importance of encouraging patients to stop smoking prior to major surgery as well as the need to control for smoking history in trials aiming to ameliorate lung injury in this patient group. References Wong, J. et al. Short-term preoperative smoking cessation and postoperative complications: a systematic review and meta-analysis. Can J Anaesth, 2012. 59(3): 268–79 Abstract P147 Table 1. Differences between current smokers and former smokers undergoing oesophagectomy. Data is expressed as median values except where specified. Current Smokers (n = 14) Former Smokers (n = 37) P-value Age (Years) 48 65 <0.001 BMI (kg/m2) 22 26 0.002 Developed ALI - n (%) 6 (43) 6 (16) 0.045 Developed respiratory infection - n (%) 5 (35) 12 (32) 0.824 EVLWI (ml/kg) Pre-op 8.3 7.8 0.520 Post-op 11.0 9.3 0.191 Day 1 9.8 7.9 0.040 PVPI Pre-op 2.13 1.74 0.151 Post-op 2.43 1.97 0.050 Day 1 2.09 1.69 0.008 Fas Ligand(pg/ml) Pre-op 21.85 36.78 0.001 Post-op 17.62 30.73 0.001 Day 1 9.05 18.38 <0.001 sICAM-1 (ng/ml) Pre-op 103.52 56.95 0.005 Post-op 51.38 43.01 0.199 Day 1 100.38 88.00 0.226 IL-17A (pg/ml) Pre-op 8.42 55.66 0.088 Post-op 2.64 36.84 0.043 Day 1 8.26 83.57 0.084 VEGF (pg/ml) BAL 94.05 153.40 0.016 IL1ra (pg/ml) BAL 50.99 9.83 0.007 sTNFR1 (pg/ml) BAL 270.5 168.5 0.042

S57 The Role of Vitamin D Deficiency in Regulating the Severity and Duration of Murine Lung Injury

Introduction Vitamin D has been shown to modulate both the innate and adaptive immune responses. Patients deficient have increased susceptibility to both infection and autoimmunity. Our research suggests patients with, or at risk of developing acute lung injury (ALI), are severely Vitamin D deficient/insufficient. As there are no licenced treatments for ALI, novel therapies need to be developed, therefore we investigated the effect of Vitamin D deficiency in a murine model of ALI to understand the mechanistic drivers of its action. Methods Using a diet completely devoid of Vitamin D, we established near complete Vitamin D deficiency in otherwise wild type C57Bl/6 mice. We combined this with intra-tracheal instillations of LPS (50µg), and analysed the inflammatory response within the lungs of these mice compared to those fed on a Vitamin D sufficient diet. In addition, systemic Vitamin D supplementation was assessed by intra-peritoneal injection of cholecalciferol 48hrs prior to LPS instillation. Cell infiltrates, expression of several inflammatory markers within bronchial lavage fluid (BALF), as well as tissue permeability were examined to evaluate the immune response and resulting lung damage. Results Dietary Vitamin D deficient mice (n=12) had elevated BALF protein concentration (p=0.0369) and red blood cell (RBC) extravasation (p=0.084) 48hrs post IT-LPS, suggestive of increased alveolar epithelial damage. BALF levels of VEGF (p=0.0023) and CXCL1/KC (p=0.0121) were significantly increased 48hrs post-LPS, indicating an increase in the inflammatory response in deficient mice. Moreover, inflammation was prolonged with both the total number of cells recruited into the BALF (p=0.0479), and the number of apoptotic neutrophils (p=0.034) significantly higher at 96hrs post LPS in Vitamin D deficient mice. Furthermore, wild type mice with normal Vitamin D levels pre-treated with cholecalciferol had reduced BALF cellular inflammation (p=0.0093), with a lower BALF protein concentration (p=0.076) and RBC accumulation in BALF (p=0.0274) 48hrs post-LPS. Conclusion Our data indicate that Vitamin D deficiency significantly augments both the severity and duration of murine lung injury and that exogenous Vitamin D reduces lung responses to LPS even in mice with normal Vitamin D levels. These data support the use of Vitamin D to both prevent and potentially treat established ALI.

S49 Is the development of acute lung injury influenced by increased levels of IL17 as a result of Treg/TH17 imbalance?

Introduction Vitamin D is known to have profound effects on the immune system. We have shown that vitamin D is lower in patients with Acute Lung Injury (ALI) than in healthy or at risk controls and that in patients at risk of ALI post oesophagectomy, low vitamin D levels are associated with increased post-operative systemic inflammatory response and alveolar epithelial dysfunction. Studies have shown that when T cells are exposed to vitamin D, expression of IL17 decreases and regulatory capacity increases. We hypothesised that vitamin D deficiency may play a role in development of Acute Lung Injury (ALI) via changes in the balance between regulatory T cells (Treg) and pro-inflammatory Th17 cells. Methods Plasma levels of 25-OH Vitamin D (Tandem mass spectrometry) and 1,25-OH Vitamin D (ELISA)were measured in samples from patients with ALI. Normal T cells were exposed to BAL from patients with ALI with or without addition of exogenous vitamin D and determined frequencies of Treg and Th17 cells using flow cytometry. Results All samples tested had insufficient plasma levels of 25-OH vitamin D (<75 nmol/l, median 14.1 nmol/l). 1,25 vitamin D levels ranged from <20 to 176 pmol/l (reference range 43–144 pmol/l). 1,25 vitamin D levels were significantly related to both ITU survival (p=0.04) and survival at 90 days (p=0.04). Our initial findings suggest that BAL taken on day 0 of ARDS upregulated IL17 expression in normal T cells. This finding was blocked by exogenous 1,25-OH Vitamin D. By contrast, BAL taken on day 4 upregulated FoxP3 and CD25 expression, suggesting an increase in regulatory T cell activity. Discussion These results suggest that in early ARDS an imbalance in T cells favouring expression of IL-17 may play a role in the inflammatory response to injury, and this may be attenuated by adequate vitamin D levels. Later in the course of the disease, Treg cells may predominate and play a role in resolution.

S105 Does vitamin D deficiency increase risk of acute lung injury post oesophagectomy

Introduction Vitamin D has profound effects on the immune system and its deficiency has been implicated in increased risk of diseases such as tuberculosis and pneumonia. We have shown vitamin D levels to be lower in patients with Acute Lung Injury than in healthy or at risk controls. We hypothesised that vitamin D deficiency may be a risk factor for developing Acute Lung Injury (ALI) following transthoracic oesophagectomy. Methods 25-OH vitamin D (tandem mass spectrometry) and 1.25-OH vitamin D (ELISA) were measured in plasma samples taken from patients prior to oesophagectomy. IL-6, RAGE and HMGB-1 were measured by ELISA. Extravascular Lung Water (EVLW) measurements were recorded using a PiCCO catheter. Results All patients undergoing oesophagectomy had insufficient levels of 25-OH vitamin D (<75 nmol/l, median 25.5 nmol/l). 1.25-OH vitamin D levels ranged from 26 to 182 pmol/l (reference range 43–144 pmol/l). Patients who developed ALI more than 72 h post-op had lower levels of 25-Vitamin D (p=0.032). Very low levels of 25-OH vitamin D (<15 nmol/l) were significantly associated with elevated post-operative systemic inflammatory response (as demonstrated by higher plasma levels of IL-6 (p=0.006) and HMGB-1 (p=0.04)) with evidence of increased epithelial damage (elevated RAGE (p=0.03)). Levels of 25 vitamin D3<15 nmol/l were associated with greater post-operative increases in extra vascular lung water (p=0.03). Patients with severe vitamin d deficiency (<20 nmol/l) had a 40% risk of developing post-operative ALI compared to 15% in those with less severe deficiency (p=0.03). Discussion These results suggest that very low 25 vitamin D levels in oesophagectomy patients are associated with an elevated post-operative systemic inflammatory response, increased alveolar epithelial dysfunction and an increased risk of developing lung injury. These data support the rationale for clinical trials of vitamin D replacement as a preventative therapy for acute lung injury.