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1.  An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial 
Trials  2014;15:199.
Background
Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.
Methods/Design
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg-1.min-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.
Discussion
This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.
Trial registration
Current controlled trials ISRCTN12776039 (19 September 2013)
doi:10.1186/1745-6215-15-199
PMCID: PMC4061524  PMID: 24894386
Levosimendan; Shock; Septic; Multiple Organ Failure; Intensive Care; Critical Care; Randomized Controlled Trial
2.  The rise and fall of β-agonists in the treatment of ARDS 
Critical Care  2012;16(2):208.
doi:10.1186/cc11221
PMCID: PMC3681353  PMID: 22429604
3.  Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial 
Trials  2012;13:170.
Background
Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.
Methods/Design
Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1:1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.
Trial registration
Current Controlled Trials ISRCTN88244364.
doi:10.1186/1745-6215-13-170
PMCID: PMC3543316  PMID: 22985805
Simvastatin; Acute lung injury; Acute respiratory distress syndrome
4.  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
5.  Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial 
Lancet  2012;379(9812):229-235.
Summary
Background
In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
Methods
We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FIO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
Findings
We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03–2·08).
Interpretation
Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
Funding
UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.
doi:10.1016/S0140-6736(11)61623-1
PMCID: PMC3266479  PMID: 22166903
6.  Accuracy of LightCycler® SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review protocol 
BMJ Open  2012;2(1):e000392.
Background
There is growing interest in the potential utility of molecular diagnostics in improving the detection of life-threatening infection (sepsis). LightCycler® SeptiFast is a multipathogen probe-based real-time PCR system targeting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here the protocol of the first systematic review of published clinical diagnostic accuracy studies of this technology when compared with blood culture in the setting of suspected sepsis.
Methods/design
Data sources: the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), The Cochrane Library, MEDLINE, EMBASE, ISI Web of Science, BIOSIS Previews, MEDION and the Aggressive Research Intelligence Facility Database (ARIF). Study selection: diagnostic accuracy studies that compare the real-time PCR technology with standard culture results performed on a patient's blood sample during the management of sepsis. Data extraction: three reviewers, working independently, will determine the level of evidence, methodological quality and a standard data set relating to demographics and diagnostic accuracy metrics for each study. Statistical analysis/data synthesis: heterogeneity of studies will be investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in Receiver Operator Characteristic (ROC) space. Bivariate model method will be used to estimate summary sensitivity and specificity. The authors will investigate reporting biases using funnel plots based on effective sample size and regression tests of asymmetry. Subgroup analyses are planned for adults, children and infection setting (hospital vs community) if sufficient data are uncovered.
Dissemination
Recommendations will be made to the Department of Health (as part of an open-access HTA report) as to whether the real-time PCR technology has sufficient clinical diagnostic accuracy potential to move forward to efficacy testing during the provision of routine clinical care.
Registration
PROSPERO—NIHR Prospective Register of Systematic Reviews (CRD42011001289).
Article summary
Article focus
To describe the plans of a systematic review aimed at determining the diagnostic accuracy of a new real-time PCR technology (LightCycler® SeptiFast), designed to detect bloodborne pathogens in the setting of life-threatening infection (sepsis).
To highlight the unmet need for accurate and rapid infection diagnostics in the setting of life-threatening infection (sepsis).
Key messages
The study will provide the first independent systematic review of clinical validity studies of multiplex real-time PCR technology aimed at detecting circulating pathogen DNA straight from blood in the setting of suspected life-threatening infections (sepsis).
Based on the results of this study, independent recommendations will be made to the UK's Department of Health to help determine whether the real-time PCR technology has sufficient clinical diagnostic accuracy to move forward to efficacy testing during the provision of routine clinical care.
Strengths and limitations
The systematic review is focused on a single Conformité Européenne (CE)-marked real-time PCR technology designed for use in the setting of life-threatening infection (sepsis)
The systematic review is non-commercial and has been planned systematically by a multidisciplinary team of experts, working on behalf of the key stakeholders within a nationalised healthcare system.
Current clinical infection diagnostic reference standards may not have high diagnostic accuracy in all clinical settings and with all infections
doi:10.1136/bmjopen-2011-000392
PMCID: PMC3278490  PMID: 22240646
7.  Epidemiology and outcome of cardiac arrests reported in the lay-press: an observational study 
Objective
The aims of this study were to evaluate the frequency with which cardiac arrests are reported in newspapers, assess the level of detail reported and ascertain whether this coverage gives a realistic portrayal of cardiac arrest outcomes to the lay-reader.
Design
Observational study.
Setting
All UK newspaper articles published between 1 January 2010 and 30 June 2010.
Participants
Articles containing the words ‘cardiac arrest’, ‘CPR’ or ‘resuscitation’ were screen for eligibility. Any articles not involving reference to a real cardiac arrest were excluded.
Main outcome measures
Data relating to patient demographics, arrest characteristics, treatment (CPR and defibrillation) and survival using the Utstein template were extracted. The results were then compared with cardiac arrest statistics from epidemiological studies.
Results
Six hundred and forty-eight articles were reviewed, 203 of which referred to individual cardiac arrest events; 22 events occurred in-hospital and 181 occurred out-of-hospital. In the out-of-hospital cardiac arrest (OHCA) group 32 (17.7%) were reported to survive to hospital discharge, almost all with good neurological outcome. The median age group was 31–45-year-olds, 52 (28.7%) were women and 40 were children. Seventy-five percent of victims received bystander CPR with 13 being attended to by lay-responders using AEDs, eight of which presented with a shockable rhythm of which six made a full recovery.
Conclusion
Survival to hospital discharge rate among newspaper reports was double that of complete epidemiological studies of OHCAs in urban environments. Newspapers may give readers an over-optimistic portrayal of cardiac arrest survival and neurological outcome following successful resuscitation.
doi:10.1258/jrsm.2011.110228
PMCID: PMC3241513  PMID: 22179296
8.  The effect of real-time CPR feedback and post event debriefing on patient and processes focused outcomes: A cohort study: trial protocol 
Background
Cardiac arrest affects 30-35, 000 hospitalised patients in the UK every year. For these patients to be given the best chance of survival, high quality cardiopulmonary resuscitation (CPR) must be delivered, however the quality of CPR in real-life is often suboptimal. CPR feedback devices have been shown to improve CPR quality in the pre-hospital setting and post-event debriefing can improve adherence to guidelines and CPR quality. However, the evidence for use of these improvement methods in hospital remains unclear. The CPR quality improvement initiative is a prospective cohort study of the Q-CPR real-time feedback device combined with post-event debriefing in hospitalised adult patients who sustain a cardiac arrest.
Methods/design
The primary objective of this trial is to assess whether a CPR quality improvement initiative will improve rate of return of sustained spontaneous circulation in in-hospital-cardiac-arrest patients. The study is set in one NHS trust operating three hospital sites. Secondary objectives will evaluate: any return of spontaneous circulation; survival to hospital discharge and patient cerebral performance category at discharge; quality of CPR variables and cardiac arrest team factors. Methods: All three sites will have an initial control phase before any improvements are implemented; site 1 will implement audiovisual feedback combined with post event debriefing, site 2 will implement audiovisual feedback only and site 3 will remain as a control site to measure any changes in outcome due to any other trust-wide changes in resuscitation practice. All adult patients sustaining a cardiac arrest and receiving resuscitation from the hospital cardiac arrest team will be included. Patients will be excluded if; they have a Do-not-attempt resuscitation order written and documented in their medical records, the cardiac arrest is not attended by a resuscitation team, the arrest occurs out-of-hospital or the patient has previously participated in this study. The trial will recruit a total of 912 patients from the three hospital sites.
Conclusion
This trial will evaluate patient and process focussed outcomes following the implementation of a CPR quality improvement initiative using real-time audiovisual feedback and post event debriefing.
Trial registration
ISRCTN56583860
doi:10.1186/1757-7241-19-58
PMCID: PMC3214886  PMID: 22008636
cardiac arrest; cardiopulmonary resuscitation; defibrillation; emergency medicine; guideline adherence; quality; resuscitation
9.  Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: A randomised, double-blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome 
Trials  2011;12:113.
Background
The Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure in critically ill patients. Experimental studies suggest that treatment with beta agonists may be helpful in ARDS. The Beta Agonist Lung Injury TrIal (BALTI-2) is a multicentre, pragmatic, randomised, double-blind, placebo-controlled clinical trial which aims to determine if sustained treatment with intravenous (IV) salbutamol will improve survival in ARDS.
Methods/Design
Patients fulfilling the American-European Consensus Conference Definition of ARDS will be randomised in a 1:1 ratio to receive an IV infusion either of salbutamol (15 μg kg ideal body weight-1 hr-1) or placebo (0.9% sodium chloride solution), for a maximum of seven days. Allocation to randomised groups will use minimisation to ensure balance with respect to hospital of recruitment, age group (<64, 65-84, >85 years) and PaO2/FiO2 ratio (≤6.7, 6.8- 13.2, ≥13.3 kPa). Data will be recorded by participating ICUs until hospital discharge, and all surviving patients will be followed up by post at six and twelve months post randomisation. The primary outcome is mortality at 28 days after randomisation; secondary outcomes are mortality in ICU, mortality in hospital, number of ventilator-free days, number of organ failure-free days, mortality at twelve months post-randomisation, quality of life at six and twelve months, length of stay in ICU, length of stay in hospital, adverse effects (tachycardia, arrhythmia or other side effects sufficient to stop treatment drug). 1,334 patients will be recruited from about fifty ICUs in the UK. An economic evaluation will be conducted alongside the trial.
Trial Registration
Current Controlled Trials ISRCTN38366450.
doi:10.1186/1745-6215-12-113
PMCID: PMC3113985  PMID: 21554679
10.  The Beta Agonist Lung Injury TrIal (BALTI) - prevention trial protocol 
Trials  2011;12:79.
Background
Acute lung injury complicates approximately 25-30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with beta agonists may prevent the development of acute lung injury by decreasing inflammatory cell infiltration, activation and inflammatory cytokine release, enhancing basal alveolar fluid clearance and improving alveolar capillary barrier function.
Methods/Design
The Beta Agonist Lung Injury TrIal (prevention) is a multi-centre, randomised, double blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesphagectomy, if treatment with inhaled salmeterol 100 mcg twice daily started at induction of anaesthesia and continued for 72 hours thereafter compared to placebo affect the incidence of early acute lung injury and other clinical, resource and patient focused outcomes. The primary outcome will be the development of acute lung injury within 72 hours of oesophagectomy. The trial secondary outcomes are the development of acute lung injury during the first 28 days post operatively; PaO2: FiO2 ratio; the number of ventilator and organ failure free days, 28 and 90 day survival; health related quality of life and resource utilisation. The study aims to recruit 360 patients from 10 UK centres.
Trial registration number
Current Controlled Trials ISRCTN47481946
doi:10.1186/1745-6215-12-79
PMCID: PMC3068101  PMID: 21406094
11.  Prehospital randomised assessment of a mechanical compression device in cardiac arrest (PaRAMeDIC) trial protocol 
Background
Survival after out-of-hospital cardiac arrest is closely linked to the quality of CPR, but in real life, resuscitation during prehospital care and ambulance transport is often suboptimal. Mechanical chest compression devices deliver consistent chest compressions, are not prone to fatigue and could potentially overcome some of the limitations of manual chest compression. However, there is no high-quality evidence that they improve clinical outcomes, or that they are cost effective. The Prehospital Randomised Assessment of a Mechanical Compression Device In Cardiac Arrest (PARAMEDIC) trial is a pragmatic cluster randomised study of the LUCAS-2 device in adult patients with non-traumatic out-of-hospital cardiac arrest.
Methods/design
The primary objective of this trial is to evaluate the effect of chest compression using LUCAS-2 on mortality at 30 days post out-of-hospital cardiac arrest, compared with manual chest compression. Secondary objectives of the study are to evaluate the effects of LUCAS-2 on survival to 12 months, cognitive and quality of life outcomes and cost-effectiveness. Methods: Ambulance service vehicles will be randomised to either manual compression (control) or LUCAS arms. Adult patients in out-of-hospital cardiac arrest, attended by a trial vehicle will be eligible for inclusion. Patients with traumatic cardiac arrest or who are pregnant will be excluded. The trial will recruit approximately 4000 patients from England, Wales and Scotland. A waiver of initial consent has been approved by the Research Ethics Committees. Consent will be sought from survivors for participation in the follow-up phase.
Conclusion
The trial will assess the clinical and cost effectiveness of the LUCAS-2 mechanical chest compression device. Trial Registration: The trial is registered on the International Standard Randomised Controlled Trial Number Registry (ISRCTN08233942).
doi:10.1186/1757-7241-18-58
PMCID: PMC2993645  PMID: 21054860
13.  Outcomes following oesophagectomy in patients with oesophageal cancer: a secondary analysis of the ICNARC Case Mix Programme Database 
Critical Care  2009;13(Suppl 2):S1.
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.
doi:10.1186/cc7868
PMCID: PMC2791299  PMID: 20003248
14.  Type XVIII collagen degradation products in acute lung injury 
Critical Care  2009;13(2):R52.
Introduction
In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge.
Methods
Endostatin was measured by ELISA and western blotting.
Results
Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels.
Conclusions
Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation.
doi:10.1186/cc7779
PMCID: PMC2689499  PMID: 19358707
15.  Kerbs von Lungren 6 antigen is a marker of alveolar inflammation but not of infection in patients with acute respiratory distress syndrome 
Critical Care  2008;12(1):R12.
Background
Kerbs von Lungren 6 antigen (KL-6) is expressed on the surface of alveolar type II cells, and elevated plasma and epithelial lining fluid levels of KL-6 have previously been shown to correlate with the severity of disease and survival in acute respiratory distress syndrome (ARDS). The relationship between alveolar inflammation and KL-6 measurements has not been ascertained. We hypothesized that the elevation of KL-6 in ARDS is dependent upon the severity of neutrophilic inflammation. Furthermore we were interested in the relationship between significant alveolar infection and KL-6 levels.
Methods
Plasma arterial samples were collected from ARDS patients on day 1 and when possible on day 4 along with bronchoalveolar lavage fluid (BALF) samples on the same day. Bacterial growth in the BALF was determined by quantitative cultures and was defined as significant at counts >1 × 104 colony-forming units.
Results
Plasma KL-6 levels in ARDS patients were elevated compared with at-risk control individuals (P = 0.014) and with normal control individuals (P = 0.02). The plasma KL-6 level correlated with the Murray Lung Injury Score (r = 0.68, P = 0.001) and with BALF KL-6 (r = 0.3260, P = 0.04). The BALF KL-6 level was detectable in all ARDS cases and was lower on both day 0 and day 4 in those who survived. BALF KL-6 also correlated with the BALF myeloperoxidase activity (r = 0.363, P = 0.027), with the BALF cell count per millilitre (r = 0.318, P = 0.038), with BALF epithelial-cell-derived neutrophil attractant 78; (r = 0.37, P = 0.016) and with BALF vascular endothelial growth factor (r = 0.35, P = 0.024). The BALF KL-6 level of ARDS patients with significant pathogenic bacterial growth was similar compared with those without significant infection.
Conclusion
KL-6 may represent a useful marker of alveolar type II cell dysfunction in ARDS since the levels reflect the severity of lung injury and neutrophilic inflammation. KL-6 release across the alveolar epithelial barrier is associated with a poor prognosis. The pathophysiological roles of KL-6 in the development of ARDS warrant further study.
doi:10.1186/cc6785
PMCID: PMC2374609  PMID: 18269741
16.  Bench-to-bedside review: β2-Agonists and the acute respiratory distress syndrome 
Critical Care  2003;8(1):25-32.
The acute respiratory distress syndrome (ARDS) is a devastating constellation of clinical, radiological and pathological signs characterized by failure of gas exchange and refractory hypoxia. Despite nearly 30 years of research, no specific pharmacological therapy has yet proven to be efficacious in manipulating the pathophysiological processes that underlie this condition. Several in vitro and in vivo animal or human studies suggest a potential role for β2-agonists in the treatment of ARDS. These agents have been shown to reduce pulmonary neutrophil sequestration and activation, accelerate alveolar fluid clearance, enhance surfactant secretion, and modulate the inflammatory and coagulation cascades. They are also used widely in clinical practice and are well tolerated in critically ill patients. The present review examines the evidence supporting a role for β2-agonists as a specific pharmacological intervention in patients with ARDS.
doi:10.1186/cc2417
PMCID: PMC420065  PMID: 14975042
acute lung injury; acute respiratory distress syndrome; alveolar epithelium; β2-agonists; pharmacotherapy
17.  Discrepancies between clinical and postmortem diagnoses in critically ill patients: an observational study 
Critical Care  2003;7(6):R129-R132.
Introduction
The autopsy has long been regarded as an important tool for confirming the clinical cause of death, education and quality assurance. Concerns surrounding informed consent and the retention of organs have heightened clinicians' anxieties in requesting permission to perform an autopsy. The present study was conducted to determine whether the autopsy still has a role to play in extending knowledge about the cause of death in a group of patients who died while receiving intensive care.
Method
We retrospectively investigated trends in postmortem examination rates and discrepancies between premortem clinical and postmortem diagnoses in a population of critically ill patients admitted to a 13 bed, general medical/surgical intensive care unit between January 1998 and June 2001. Agreement between diagnoses before death and postmortem findings were compared using the Goldman system.
Results
Out of total 636 deaths, 49 (7.7%) underwent postmortem examinations. Of these, 38 (78%) cases were available for review. We found that postmortem findings were in complete agreement with predeath diagnoses in fewer than half of the cases (n = 17, 45%). Major missed diagnoses were present in 15 cases (39%). Myocardial infarction, carcinoma and pulmonary embolism represented the most frequently missed diagnoses.
Conclusion
Postmortem examinations remain a useful tool in confirming diagnostic accuracy and should be considered in all patients who die in the intensive care unit. Recognition of the diagnoses missed before death may improve outcome or avoid unnecessary prolongation of life where terminal disease is present.
PMCID: PMC374369  PMID: 14624686
autopsy; clinical diagnosis; critical illness; death; intensive care
18.  Do changes in pulse oximeter oxygen saturation predict equivalent changes in arterial oxygen saturation? 
Critical Care  2003;7(4):R67-R71.
Introduction
This study investigates the relation between changes in pulse oximeter oxygen saturation (SpO2) and changes in arterial oxygen saturation (SaO2) in the critically ill, and the effects of acidosis and anaemia on precision of using pulse oximetry to predict SaO2.
Patients and methods
Forty-one consecutive patients were recruited from a nine-bed general intensive care unit into a 2-month study. Patients with significant jaundice (bilirubin >40 μmol/l) or inadequate pulse oximetry tracing were excluded.
Results
A total of 1085 paired readings demonstrated only moderate correlation (r= 0.606; P < 0.01) between changes in SpO2 and those in SaO2, and the pulse oximeter tended to overestimate actual changes in SaO2. Anaemia increased the degree of positive bias whereas acidosis reduced it. However, the magnitude of these changes was small.
Conclusion
Changes in SpO2 do not reliably predict equivalent changes in SaO2 in the critically ill. Neither anaemia nor acidosis alters the relation between SpO2 and SaO2 to any clinically important extent.
PMCID: PMC270702  PMID: 12930558
acidosis; anaemia; arterial oxygen saturation; critical care; pulse oximetry
19.  Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial 
Trials  2013;14:100.
Background
Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function.
Methods/Design
The ‘Vitamin D to prevent lung injury following oesophagectomy trial’ is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres.
Discussion
This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy.
Trial registration
Current Controlled Trials ISRCTN27673620
doi:10.1186/1745-6215-14-100
PMCID: PMC3680967  PMID: 23782429
Acute lung injury; One lung ventilation; Oesophagectomy; Vitamin D
20.  Randomized 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.
Introduction
Several 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.
Methods
A 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.
Results
100 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).
Conclusions
Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings.
Trial Registration
International Standard Randomized Control Trial Registry ISRCTN64637517.
doi:10.1186/cc11895
PMCID: PMC3672620  PMID: 23232151

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