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1.  The influence of statin exposure on inflammatory markers in patients with early bacterial infection: pilot prospective cohort study 
BMC Anesthesiology  2014;14(1):106.
In the context of infection, progressive illness resulting in acute organ dysfunction is thought to be secondary to inflammatory response. Our aims were to determine risk factors for progressive illness following infection in a low-risk hospitalised cohort, including the impact of prior stain therapy.
We performed a prospective observational cohort study on two adult acute medical wards of a single tertiary academic hospital. We screened drug prescription charts of all adult acute medical admissions for inclusion criteria of inpatient administration of antibiotics for more than 24 hours for a microbiologically confirmed or clinically suspected infection. Patients were followed until admission to a high dependency unit (HDU) or intensive care unit (ICU), discharge from hospital, or to a maximum of 10 days. Outcomes were evolution of systemic inflammatory response syndrome (SIRS) criteria, white cell count and C-reactive protein measurements, and adverse clinical outcomes. We constructed multivariable models accounting for repeated within-patient measurements to determine associations between a priori selected predictors (days since admission, age, gender, Charlson score, prior statin exposure) and selected outcomes.
We enrolled 209 patients; 27.8% were statin users and the commonest infection was pneumonia (51.0%). Most (88.0%) had at least 1 SIRS criterion on admission, and 76 (37.3%) manifested additional SIRS criteria over time. Risks of admission to HDU/ICU (3.3%) and of 30-day mortality (5.7%) were low. The proportion of patients with at least 1 SIRS criterion, mean CRP, and mean WBC all decreased over time. Multivariable regression models identified days since hospital admission as the only variable associated with daily presence of SIRS criteria, WCC, or CRP (adjusted OR <1 and p < 0.0001 in all analyses). Statin exposure was not a significant predictor.
This cohort of ward patients treated for infection had a low risk of clinical deterioration, inflammatory markers improved over time, and statin exposure was not associated with any outcome. Future larger studies may identify risk factors for progression of illness in this population and plausible surrogate endpoints for evaluation in clinical trials.
PMCID: PMC4256798  PMID: 25484622
Sepsis; Biomarkers; Surrogate end-points; Progression of illness
2.  Redox State of Pentraxin 3 as a Novel Biomarker for Resolution of Inflammation and Survival in Sepsis* 
Molecular & Cellular Proteomics : MCP  2014;13(10):2545-2557.
In an endotoxaemic mouse model of sepsis, a tissue-based proteomics approach for biomarker discovery identified long pentraxin 3 (PTX3) as the lead candidate for inflamed myocardium. When the redox-sensitive oligomerization state of PTX3 was further investigated, PTX3 accumulated as an octamer as a result of disulfide-bond formation in heart, kidney, and lung—common organ dysfunctions seen in patients with sepsis. Oligomeric moieties of PTX3 were also detectable in circulation. The oligomerization state of PTX3 was quantified over the first 11 days in critically ill adult patients with sepsis. On admission day, there was no difference in the oligomerization state of PTX3 between survivors and non-survivors. From day 2 onward, the conversion of octameric to monomeric PTX3 was consistently associated with a greater survival after 28 days of follow-up. For example, by day 2 post-admission, octameric PTX3 was barely detectable in survivors, but it still constituted more than half of the total PTX3 in non-survivors (p < 0.001). Monomeric PTX3 was inversely associated with cardiac damage markers NT-proBNP and high-sensitivity troponin I and T. Relative to the conventional measurements of total PTX3 or NT-proBNP, the oligomerization of PTX3 was a superior predictor of disease outcome.
PMCID: PMC4188985  PMID: 24958171
3.  An observational cohort study to determine efficacy, adherence and outcome of the early initiation of pressure support ventilation during mechanical ventilation 
BMJ Open Respiratory Research  2014;1(1):e000028.
Timely initiation of weaning from mechanical ventilation (MV) is important. Non-validated screening criteria may delay weaning if too prescriptive. This study observed physician-led utilisation of pressure support ventilation (PSV), referenced to four reported conventional screening criteria hypothesising that these criteria would have delayed the weaning progress.
A prospective observational cohort study of adult patients receiving MV in a 30-bed university hospital intensive care unit (ICU). Logistic regression analysis identified factors associated with PSV failure. Outcome is reported according to adherence to the screening criteria.
209 patients were included (age 62.6±15.9 years, male:female 115:94, Acute Physiology and Chronic Health Evaluation (APACHE) II 16.7±6.1). Median (IQR) time to initiate PSV was 11.0 (5.0–22.0) h, and duration of weaning to extubation was 43.0 (13.0–121.5) h. PSV weaning was initiated despite significant hypoxia (partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) 35.8±15.9 kPa), moderate positive end-expiratory pressure levels (7.5±2.5 cm H2O), deep sedation (44% Richmond Agitation and Sedation Scale (RASS) ≤−3) and cardiovascular instability (48.8%). At PSV initiation, 85% of patients violated at least one screening criterion, yet 74.6% of patients remained stable for 24 h and 25.4% of patients were successfully extubated within 12 h. There was no association between individual screening criteria and PSV failure. Failure to sustain a PSV trial was associated with ventilation >7 days (RR=2.12 (1.33 to 3.38), p=0.002) and ICU mortality (RR=2.94 (1.46 to 5.94), p=0.002).
Physician-led transition to PSV and weaning was often initiated early and successfully before patients fulfilled conventional screening criteria. Failure to sustain a PSV trial could be an early indicator of prolonged MV and ICU mortality and warrants further investigation. These data support the view that current screening criteria may delay initiation of weaning.
PMCID: PMC4212705  PMID: 25478179
Assisted Ventilation; Respiratory Measurement
4.  Statin therapy in critical illness: an international survey of intensive care physicians’ opinions, attitudes and practice 
Pleotropic effects of statins on inflammation are hypothesised to attenuate the severity of and possibly prevent the occurrence of the host inflammatory response to pathogen and infection-related acute organ failure. We conducted an international survey of intensive care physicians in Australia, New Zealand (ANZ) and United Kingdom (UK). The aims of the survey were to assess the current prescribing practice patterns, attitudes towards prescribing statin therapy in critically ill patients and opinions on the need for an interventional trial of statin therapy in critically ill patients.
Survey questions were developed through an iterative process. An expert group reviewed the resulting 26 items for face and content validity and clarity. The questions were further refined following pilot testing by ICU physicians from Australia, Canada and the UK. We used the online Smart SurveyTM software to administer the survey.
Of 239 respondents (62 from ANZ and 177 from UK) 58% worked in teaching hospitals; most (78.2%) practised in ‘closed’ units with a mixed medical and surgical case mix (71.0%). The most frequently prescribed statins were simvastatin (77.6%) in the UK and atorvastatin (66.1%) in ANZ. The main reasons cited to explain the choice of statin were preadmission prescription and pharmacy availability. Most respondents reported never starting statins to prevent (65.3%) or treat (89.1%) organ dysfunction. Only a minority (10%) disagreed with a statement that the risks of major side effects of statins when prescribed in critically ill patients were low. The majority (84.5%) of respondents strongly agreed that a clinical trial of statins for prevention is needed. More than half (56.5%) favoured rates of organ failure as the primary outcome for such a trial, while a minority (40.6%) favoured mortality.
Despite differences in type of statins prescribed, critical care physicians in the UK and ANZ reported similar prescription practices. Respondents from both communities agreed that a trial is needed to test whether statins can prevent the onset of new organ failure in patients with sepsis.
PMCID: PMC3416708  PMID: 22742644
Survey; Statin; Sepsis; Critical care; Clinical trials
5.  Risk factors for acute organ failure in intensive care unit patients who receive respiratory support in the absence of non-respiratory organ failure: an international prospective cohort study 
Critical Care  2012;16(2):R61.
Many supposed low-risk intensive care unit (ICU) admissions develop acute organ failure (AOF). Identifying patients at high risk of developing AOF and targeting them with preventative strategies may be effective. Our study question was: in a population of ICU patients receiving positive pressure respiratory support (invasive or non-invasive) in the absence of non-respiratory AOF, what is the 14-day incidence of, risk factors for and time to acute organ failure?
In an international prospective cohort study, patients receiving positive pressure respiratory support (invasive or non-invasive) in the absence of non-respiratory AOF were enrolled and followed for 14 days. The primary outcome measure was the incidence of any AOF (defined as SOFA 3 to 4) during follow-up.
A total of 123 of 766 screened patients (16.1%) were enrolled. Data are reported for 121 patients. In total, 45 out of 121 patients (37.2%) developed AOF. Mortality rates were higher in those with AOF: 17.8% versus 4.0% OR 5.11, P = 0.019) for ICU mortality; and 28.9% versus 11.8% (OR 2.80, P = 0.019) for hospital mortality. Median ICU length of stay was also longer in those with AOF (11 versus 3.0 days; P < 0.0001). Hypoxemic respiratory failure (P = 0.001) and cardiovascular dysfunction (that is, SOFA 1 to 2; P = 0.03) were associated with AOF. The median time to first AOF was two days.
Patients receiving positive (invasive or non-invasive) pressure respiratory support in the absence of non-respiratory AOF are commonly admitted to ICU; AOF is frequent in these patients. Organ failure developed within a short period after admission. Hypoxemic respiratory failure and cardiovascular dysfunction were strongly associated with AOF.
PMCID: PMC3681390  PMID: 22512834
6.  Tissue saturation measurement - exciting prospects, but standardisation and reference data still needed 
Critical Care  2010;14(3):169.
Sepsis and shock result in disturbances in microcirculatory perfusion and tissue oxygen utilisation that may not be reflected in global measures of haemodynamics. Near-infrared spectroscopy enables measurement of tissue oxygen saturation (StO2) and provides information on local microvascular and mitochondrial function. This measure could be incorporated with existing targets of goal-directed therapy to provide an integrated approach to haemodynamic resuscitation of both the macro- and microcirculation in various shock states. However, key methodological factors must be addressed before widespread clinical application.
PMCID: PMC2911688  PMID: 20619003
7.  Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study 
Critical Care  2011;15(1):R74.
Observational studies suggest statin therapy reduces incident sepsis, but few studies have examined the impact on new organ failure. We tested the hypothesis that statin therapy, administered for standard clinical indications to ventilated intensive care unit patients, prevents acute organ failure without harming the liver.
We performed a retrospective, single-centre cohort study in a tertiary mixed medical/surgical intensive care unit. Mechanically ventilated patients without nonrespiratory organ failure within 24 hours after admission were assessed (during the first 15 days) for new acute organ failure (defined as Sequential Organ Failure Assessment (SOFA) score 3 or 4), liver failure (defined as new hepatic SOFA ≥3, or a 1.5 times increase of bilirubin from baseline to a value ≥20 mmol/l), and alanine transferase (ALT) > 165 IU/l. The effect of statin administration was explored in generalised linear mixed models.
A total of 1,397 patients were included. Two hundred and nineteen patients received a median (interquartile range) of three (two, eight) statin doses. Patients receiving statins were older (67.4 vs. 55.5 years, P < 0.0001), less likely female (25.1% vs. 37.9%, P = 0.0003) and sicker (Acute Physiology and Chronic Health Evaluation (APACHE) II score 20.3 vs. 17.8, P < 0.0001). Considering outcome events at least 1 day after statin administration, statin patients were equally likely to develop acute organ failure (28.4% vs. 22.3%, P = 0.29) and hepatic failure (9.5% vs. 7.6%, P = 0.34), but were more likely to experience an ALT increase to > 165 IU/l ((11.2% vs. 4.8%, P = 0.0005). Multivariable analysis showed that APACHE II score (odds ratio (OR) = 1.05 per point; 95% confidence interval (CI) = 1.03 to 1.07) and APACHE II admission category (P < 0.0001), but not statin administration (OR = 1.21; 95% CI = 0.92 to 1.62), were significantly associated with acute organ failure occurring on or after the day of first statin administration. Statin administration was not associated with liver impairment (OR = 1.08; 95% CI = 0.66 to 1.77) but was associated with a rise in ALT > 165 IU/l (OR = 2.25; 95% CI = 1.32 to 3.84), along with APACHE II score (P = 0.016) and admission ALT (P = 0.0001).
Concurrent statin therapy does not appear to protect against the development of new acute organ failure in critically ill, ventilated patients. The lack of effect may be due to residual confounding, a relatively low number of doses received, or an absence of true effect. Randomised controlled trials are needed to confirm a protective effect.
PMCID: PMC3222007  PMID: 21356051
8.  Year in review 2008: Critical Care - cardiology 
Critical Care  2009;13(5):229.
We review key research papers in cardiology and intensive care published during 2008 in Critical Care. We quote studies on the same subject published in other journals if appropriate. Papers have been grouped into three categories: (a) cardiovascular biomarkers in critical illness, (b) haemodynamic management of septic shock, and (c) haemodynamic monitoring.
PMCID: PMC2784349  PMID: 19863768
9.  Statin research in critical illness: hampered by poor trial design? 
Critical Care  2009;13(6):1015.
Statin therapy may prevent an excessive inflammatory response after cardiopulmonary bypass for cardiac surgery. In a recent issue of Critical Care, Morgan and colleagues present data from a well-conducted systematic review and meta-analysis of randomised controlled trials using inflammatory markers as primary outcome measure. They find that pre-operative statin therapy, compared with placebo, may reduce various post-operative markers of systemic inflammation (IL-6, IL-8, C-reactive protein, tumour necrosis factor-alpha). Their ability to make definitive conclusions is limited, however, by the suboptimal methodological quality of the primary studies. Their review suggests that ICU researchers should focus on developing valid surrogate markers and use these to accurately describe the mechanisms and effectiveness of novel therapies before proceeding to large pragmatic trials using mortality as primary outcome.
PMCID: PMC2811942  PMID: 20017899
10.  Year in review 2007: Critical Care – cardiology 
Critical Care  2008;12(5):232.
This review summarises key research papers in the fields of cardiology and intensive care published during 2007 in Critical Care. To create a context and for comparison with the papers described in the review, we cite studies on the same subject published in other journals. The papers have been grouped into four categories: venous oximetry, cardiac surgery, perioperative fluid optimisation, and haemodynamic monitoring.
PMCID: PMC2592741  PMID: 18983703
11.  Statins, bugs and prophylaxis: intriguing possibilities 
Critical Care  2006;10(5):168.
Statin therapy may represent a potential prophylactic intervention in certain high-risk scenarios, for example in pandemic influenza and in those undergoing aggressive medical treatments. Emerging data indicate a potential prophylactic role in these high-risk groups.
PMCID: PMC1751082  PMID: 17094793
12.  Do statins have a role in preventing or treating sepsis? 
Critical Care  2006;10(1):113.
Statins have a variety of properties that are independent of their lipid lowering ability. These anti-inflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. Severe sepsis is an intense infection-induced inflammatory syndrome that ultimately results in organ dysfunction. Because so many cascades are triggered during sepsis, merely blocking a single component may be insufficient to arrest the inflammatory process. A growing body of evidence suggests that statins may indeed have a protective effect against severe sepsis and reduce the rate of infection-related mortality. This novel primary prevention concept may have far-reaching implications for the future management of serious infections. Moreover, it was recently shown that statins potentially improve outcome after the onset of sepsis. The stage is now set for randomized clinical trials that will determine the precise role, if any, that statins may have in preventing and treating sepsis.
PMCID: PMC1550787  PMID: 16469122

Results 1-13 (13)