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1.  Statins in pneumonia - magic versus science? 
Critical Care  2012;16(5):157.
Several studies have investigated the use of statins as an adjunct in the treatment of pneumonia, some with conflicting conclusions. The most recent of these large observational studies again suggests statin use is associated with an improved outcome for patients with pneumonia. How best to incorporate these findings into current practice is of great interest. Hidden confounders plague database interrogation and so cast doubt on the real or causal nature of observed associations. Data from large, observational studies must be complemented by smaller biological studies and randomised controlled trials in an effort to complete missing pieces in the biological puzzle of the use of statins in patients with pneumonia.
doi:10.1186/cc11479
PMCID: PMC3682249  PMID: 23025797
2.  Association of pre-transplant statin use with delayed graft function in kidney transplant recipients 
BMC Nephrology  2012;13:111.
Background
Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function.
Methods
All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times.
Results
Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 – 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56).
Conclusions
The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.
doi:10.1186/1471-2369-13-111
PMCID: PMC3507677  PMID: 22985048
3.  Statin therapy in critical illness: an international survey of intensive care physicians’ opinions, attitudes and practice 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-12-13
PMCID: PMC3416708  PMID: 22742644
Survey; Statin; Sepsis; Critical care; Clinical trials
4.  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.
Introduction
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?
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/cc11306
PMCID: PMC3681390  PMID: 22512834
5.  A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial 
Trials  2011;12:70.
Background
Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.
Methods/Design
A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.
Discussion
Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.
Trial Registration Number
ISRCTN45190901
doi:10.1186/1745-6215-12-70
PMCID: PMC3068961  PMID: 21388549
6.  Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients 
BMC Anesthesiology  2011;11:3.
Background
Critical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam.
Methods/Design
This is an observational pharmacokinetic study of patients with trauma (cefazolin) or with sepsis (piperacillin-tazobactam). Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration of the antibiotic. Participants will be administered sinistrin, indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes resulting from pathology. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters of antibiotics.
Discussion
The study will describe cefazolin and piperacillin-tazobactam concentrations in plasma and the interstitial fluid of tissues in trauma and sepsis patients respectively. The results of this study will guide clinicians to effectively dose these antibiotics in order to maximize the concentration of antibiotics in the interstitial fluid of tissues.
doi:10.1186/1471-2253-11-3
PMCID: PMC3050838  PMID: 21333028
7.  Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution 
Critical Care  2011;15(1):R21.
Introduction
As even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB.
Methods
Thirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4).
Results
Acetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups.
Conclusions
Use of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055
doi:10.1186/cc9966
PMCID: PMC3222055  PMID: 21235742
8.  Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients 
Critical Care  2010;14(6):R216.
Introduction
Recent reports have highlighted the prevalence of vitamin D deficiency and suggested an association with excess mortality in critically ill patients. Serum vitamin D concentrations in these studies were measured following resuscitation. It is unclear whether aggressive fluid resuscitation independently influences serum vitamin D.
Methods
Nineteen patients undergoing cardiopulmonary bypass were studied. Serum 25(OH)D3, 1α,25(OH)2D3, parathyroid hormone, C-reactive protein (CRP), and ionised calcium were measured at five defined timepoints: T1 - baseline, T2 - 5 minutes after onset of cardiopulmonary bypass (CPB) (time of maximal fluid effect), T3 - on return to the intensive care unit, T4 - 24 hrs after surgery and T5 - 5 days after surgery. Linear mixed models were used to compare measures at T2-T5 with baseline measures.
Results
Acute fluid loading resulted in a 35% reduction in 25(OH)D3 (59 ± 16 to 38 ± 14 nmol/L, P < 0.0001) and a 45% reduction in 1α,25(OH)2D3 (99 ± 40 to 54 ± 22 pmol/L P < 0.0001) and i(Ca) (P < 0.01), with elevation in parathyroid hormone (P < 0.0001). Serum 25(OH)D3 returned to baseline only at T5 while 1α,25(OH)2D3 demonstrated an overshoot above baseline at T5 (P < 0.0001). There was a delayed rise in CRP at T4 and T5; this was not associated with a reduction in vitamin D levels at these time points.
Conclusions
Hemodilution significantly lowers serum 25(OH)D3 and 1α,25(OH)2D3, which may take up to 24 hours to resolve. Moreover, delayed overshoot of 1α,25(OH)2D3 needs consideration. We urge caution in interpreting serum vitamin D in critically ill patients in the context of major resuscitation, and would advocate repeating the measurement once the effects of the resuscitation have abated.
doi:10.1186/cc9341
PMCID: PMC3219984  PMID: 21110839
9.  Plasma protein C levels in immunocompromised septic patients are significantly lower than immunocompetent septic patients: a prospective cohort study 
Introduction
Activated Protein C [APC] improves outcome in immunocompetent patients with severe sepsis particularly in those who are perceived to have high mortality risk. Before embarking on a trial of APC administration in immunocompromised septic patients, a preliminary study on plasma levels of protein C in this cohort is essential.
Objective
To assess serum Protein C concentrations in immunocompromised patients as compared to immunocompetent patients during sepsis, severe sepsis, septic shock and recovery.
Methods
Prospective cohort study in a tertiary hospital. Patients satisfying inclusion criteria were enrolled after informed consent. Clinical variables were noted with sample collection when patients met criteria for sepsis, severe sepsis, septic shock and recovery. Protein C levels were measured using monoclonal antibody based fluorescence immunoassay.
Results
Thirty one patients participated in this study (22 immunocompromised, 9 immunocompetent). Protein C levels were found to be significantly lower in the immunocompromised group compared to the immunocompetent group, particularly observed in severe sepsis [2.27 (95% CI: 1.63-2.9) vs 4.19 (95% CI: 2.87-5.52) mcg/ml] (p = 0.01) and sepsis [2.59 (95% CI: 1.98-3.21) vs 3.64 (95% CI: 2.83-4.45) mcg/ml] (p = 0.03). SOFA scores were similar in both the groups across sepsis, severe sepsis and septic shock categories. Protein C levels improved significantly in recovery (p = 0.001) irrespective of immune status.
Conclusion
Protein C levels were significantly lower in immunocompromised patients when compared to immunocompetent patients in severe sepsis and sepsis categories. Our study suggests a plausible role for APC in severely septic immunocompromised patients which need further elucidation.
doi:10.1186/1756-8722-2-43
PMCID: PMC2772189  PMID: 19840396

Results 1-9 (9)