Jaimin Patel

Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial)

IntroductionSeveral observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis.MethodsA single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization.Results100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238).ConclusionsAcute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings.Trial RegistrationInternational Standard Randomized Control Trial Registry ISRCTN64637517.

Vitamin D deficiency in human and murine sepsis

Objectives: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and ICU mortality but causality of these associations has not been demonstrated. To determine whether sepsis and severe sepsis are associated with vitamin D deficiency and to determine whether vitamin D deficiency influences the severity of sepsis. Design, Setting, and Patients: Sixty-one patients with sepsis and severe sepsis from two large U.K. hospitals and 20 healthy controls were recruited. Murine models of cecal ligation and puncture and intratracheal lipopolysaccharide were undertaken in normal and vitamin D deficient mice to address the issue of causality. Measurements and Main Results: Patients with severe sepsis had significantly lower concentrations of 25-hydroxyvitamin D3 than patients with either mild sepsis or age-matched healthy controls (15.7 vs 49.5 vs 66.5 nmol/L; p = 0.0001). 25-hydroxyvitamin D3 concentrations were significantly lower in patients who had positive microbiologic culture than those who were culture negative (p = 0.0023) as well as those who died within 30 days of hospital admission (p = 0.025). Vitamin D deficiency in murine sepsis was associated with increased peritoneal (p = 0.037), systemic (p = 0.019), and bronchoalveolar lavage (p = 0.011) quantitative bacterial culture. This was associated with reduced local expression of the cathelicidin-related antimicrobial peptide as well as evidence of defective macrophage phagocytosis (p = 0.029). In the intratracheal lipopolysaccharide model, 1,500 IU of intraperitoneal cholecalciferol treatment 6 hours postinjury reduced alveolar inflammation, cellular damage, and hypoxia. Conclusions: Vitamin D deficiency is common in severe sepsis. This appears to contribute to the development of the condition in clinically relevant murine models and approaches to correct vitamin D deficiency in patients with sepsis should be developed.

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

Rationale: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. Objectives: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. Methods: The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community‐acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double‐blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. Measurements and Main Results: In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high‐dose (80‐mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double‐blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. Conclusions: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011‐002082‐38).

Statins for sepsis: distinguishing signal from the noise when designing clinical trials.

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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 angiotensin-converting 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 patients 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.

A complete audit cycle to assess adherence to a lung protective ventilation strategy

There is clear evidence for the use of a protective ventilation protocol in patients with acute respiratory distress syndrome (ARDS). There is evidence to suggest that protective ventilation is beneficial in patients at risk of ARDS. A protective ventilation strategy was implemented on our intensive care unit in critical care patients who required mechanical ventilation for over 48 h, with and at risk for ARDS. A complete audit cycle was performed over 13 months to assess compliance with a safe ventilation protocol in intensive care. The ARDS network mechanical ventilation protocol was used as the standard for our protective ventilation strategy. This recommends ventilation with a tidal volume (Vt) of 6 ml/kg of ideal body weight (IBW) and plateau airway pressure of ≤30 cm H2O. The initial audit failed to meet this standard with Vts of 9.5 ml/kg of IBW. Following the implementation of a ventilation strategy and an educational program, we demonstrate a significant improvement in practice with Vts of 6.6 ml/kg of IBW in the re-audit. This highlights the importance of simple interventions and continuous education in maintaining high standards of care.

Pre-emptive or early adjuvant simvastatin therapy in elderly patients with infection and sepsis

Abstract Background The incidence, severity, morbidity, and mortality associated with sepsis increases with age, and statin treatment improves outcomes during infection. We characterised the effect of age and acute infection on key neutrophil functions, assessed whether physiologically relevant doses of simvastatin altered neutrophil functions, and, if benefits were seen, when statins could be used during septic infection. Methods Neutrophils extracted from the whole blood of healthy volunteers and patients with a lower respiratory tract infection (LRTI), pneumonia, or sepsis were assessed for migratory accuracy, phagocytosis, and production of neutrophil extracellular traps (NET) before and after in-vitro treatment with simvastatin. In addition, neutrophil function was assessed in healthy elderly volunteers, who were receiving simvastatin (80 mg/day for 2 weeks) or placebo as part of a crossover, double-blind, randomised controlled trial. Here we present data for neutrophil migration. Findings Neutrophils from healthy volunteers (n=70, aged 21–94 years) showed preserved chemokinesis (random movement) but reduced chemotaxis (directed migration) ( r 2 =−0·48, p Interpretation Neutrophil function in elderly people is compromised in health, and deteriorates further during infective episodes in accordance with the severity of the disease. Migratory accuracy can be improved with short-term in-vitro simvastatin therapy in health and mild infection but not in sepsis. Our data suggest that statin therapy might be a preventive or an early adjuvant intervention rather than a treatment in established sepsis. We are testing in a clinical trial whether simvastatin 80 mg for 7 days modifies neutrophil responses in elderly patients with pneumonia and sepsis. Funding British Journal of Anaesthesia, Royal College of Anaesthetists.

S96 Simvastatin as an adjuvant therapy for infection and sepsis–in-vitro and in-vivo studies suggest pre-emptive / early therapy in the elderly

Ageing is associated with increased episodes of sepsis and poorer outcomes. Statins are associated with improved outcomes during infection. We aimed to characterise the impact of age and acute severe infection on key neutrophil functions, assess whether physiologically relevant doses of simvastatin altered neutrophil functions and if benefits were seen, when during a septic episode statins could be utilised. Methods Neutrophils from healthy volunteers and patients with lower respiratory tract infections (LRTI), pneumonia and sepsis were assessed for migratory accuracy, phagocytosis and neutrophil extracellular trap production before and after in-vitro treatment with simvastatin. Healthy elderly volunteers received 80mg simvastatin or placebo in a cross over double-blind randomised controlled trial and neutrophil functions were assessed. Data presented is for migration. Results Neutrophils from healthy subjects (n = 70, aged 21–94) demonstrated preserved neutrophil movement) (R2 = -0.48, p < 0.0001) towards chemoattractants (data shown for IL-8). Neutrophil chemotaxis decreased after 60yrs (comparing <35 to >65yrs: mean difference (MD)1.25μm/min, p = 0.02). There was a progressive decrease in neutrophil chemotaxis in old patients with a LRTI, pneumonia and severe sepsis (MD compared to healthy control; LRTI (n = 10), 0.7μm/min, p = 0.04; pneumonia (n = 5), MD1.1μm/min, p = 0.02; sepsis (n = 22) MD1.6μm/min, p = 0.01) with “septic neutrophils” unable to mount targeted chemotaxis. Improvements to baseline were seen following recovery. In-vitro treatment of neutrophils from healthy older people with simvastatin (1µM) restored “old” neutrophil chemotaxis to that of “young” cells. Simvastatin also restored neutrophil migration from old patients with LRTI and pneumonia to baseline but not in patients with sepsis. Two weeks of oral simvastatin 80mg once daily therapy in healthy old volunteers (Age>65,n = 20) increased the accuracy of neutrophil migration (MD1.68μm/min, p = 0.02) replicating benchwork. Conclusions “Elderly” neutrophil function is compromised in health, and deteriorates during infective episodes, in accordance with the severity of the insult. Migratory accuracy can be improved with simvastatin therapy however neutrophil function in sepsis patients cannot be modulated during short term in-vitro therapy. Our data suggest statin therapy might be a preventative or an early adjuvant intervention rather than a treatment in established sepsis. We are testing whether simvastatin 80mg for seven days modifies neutrophil responses in elderly patients with pneumonia and sepsis (SNOOPI Trial). Abstract S96 Figure 1. Simavastatin 80mg once daily for 14 days improves directional migration (chemostaxis) of neutrophils from healthy elderly volunteers towards IL-8. *Student’s t-Test

Statin therapy in patients with community-acquired pneumonia.

ABSTRACT Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated. We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking. These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections.

S16 Simvastatin improves neutrophil migration in elderly patients with septic pneumonia and reduces 6-month mortality and re-admissions: results of the snoopi trial

Introduction and objectives Community acquired pneumonia is a leading infectious cause of death in the elderly and the commonest source of sepsis. Neutrophil functions decline with age, and deteriorate further in sepsis.1 Restoring neutrophil function may improve sepsis outcomes. Recent in-vitro and in-vivo studies suggest simvastatin improves aspects of neutrophil function.2 Adjuvant statin therapy in severely critically ill patients has failed to improve outcomes and may be associated with increased morbidity,4,5 however our ASEPSIS study suggested that early intervention with statins may reduce the progression of sepsis in a ward-based cohort of milder sepsis patients.6 In light of this, we investigated whether oral treatment with simvastatin improved neutrophil function and clinical outcomes in elderly patients with septic pneumonia. Methods ‘SNOOPI’ was a phase-4, randomised controlled trial comparing 7-days of 80mg simvastatin with placebo in patients aged 55 years or over admitted to hospital with septic pneumonia.3 The primary outcome was changes in neutrophil extracellular trap (NETs) formation by day3/4 compared with baseline. Secondary outcomes included neutrophil migration, safety and tolerability, length of stay, readmissions and mortality. Results 61 patients were recruited acute admissions unit at the Queen Elizabeth Hospital Birmingham between 2013 and 2015, with 31 patients randomised to simvastatin and 30 to placebo. Groups were well matched for baseline characteristics, pneumonia and sepsis severity, co-morbidities and biochemical and haematological parameters. There was no significant difference in the primary end-point of change in NETS at day3/4. Directional neutrophil migration (chemotaxis) was significantly improved in patients who received simvastatin at day 3/4 (0.35 ± 0.16 μm/min vs. −0.15 ± 0.17 μm/min; p = 0.033). Simvastatin was well tolerated with no SUSARS, even with the co-prescription of macrolides. At 6-months, patients in the simvastatin group were less likely to have been admitted to hospital or died compared to those in the placebo group (OR: 0.44; 95% CI: 0.21–0.91; p = 0.02) (Figure 1). Conclusions The current study suggests that early intervention with statins in septic pneumonia patients may improve patient outcomes. We propose that one of the mechanistic drivers may be the restoration of sepsis-associated dysregulated neutrophil function. Further larger studies are warranted to confirm whether early intervention with statins in patients with sepsis confer an overall survival benefit. References Alves-Filho JC, Spiller F, Cunha FQ. Neutrophil paralysis in sepsis. Shock 2010;34(Suppl 1):15–21. Sapey E, Greenwood H, Walton G, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 2014;123(2):239–248. Greenwood H, Patel J, Mahida R, et al. Simvastatin to modify neutrophil function in older patients with septic pneumonia (SNOOPI): study protocol for a randomised placebo-controlled trial. Trials 2014;15:332. McAuley DF, Laffey JG, O’Kane CM, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med 2014;371:1695–1703. The National Heart L, Blood Institute ACTN. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014;370:2191–2200. Patel JM, Snaith C, Thickett DR, et al. Randomised double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Critical Care 2012;16(6):R231. Abstract S16 Figure 1 Kaplan-Meier Curve showing the time (in-days)to either death or re-admission to hospital in patients’ allocated to simvastatin or placebo