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1.  Protocol for a systematic review and individual patient data meta-analysis of benefit of so-called lung-protective ventilation settings in patients under general anesthesia for surgery 
Systematic Reviews  2014;3:2.
Background
Almost all patients under general anesthesia for surgery need mechanical ventilation. The harmful effects of short-term intra-operative ventilation on pulmonary integrity are increasingly recognized. Recent investigations suggest protection against so-called ventilation-associated lung injury with the use of lower tidal volumes and/or the use of higher levels of positive end-expiratory pressure (PEEP). This review and meta-analysis will evaluate the effects of these protective measures on pulmonary and extra-pulmonary complications, and try to discriminate the effects of lower tidal volumes from those of higher levels of PEEP.
Methods/design
The Medline database will be searched for observational studies and randomized controlled trials of intra-operative ventilation. Individual patient data will be collected from databases obtained via direct contact with corresponding authors of original articles. The primary endpoint is development of postoperative acute respiratory distress syndrome, the most important postoperative pulmonary complication. Secondary endpoints include hospital length of stay and hospital mortality, and reported intra-operative and postoperative pulmonary and extra-pulmonary complications. Emphasis is put on separating the effects of lower tidal volumes from those of higher levels of PEEP.
Discussion
This will be the first meta-analysis of intra-operative ventilation using individual patient data from observational studies and randomized controlled trials. The large sample size could allow discrimination of the effect of the two most frequently used protective measures - that is, lower tidal volumes and higher levels of PEEP. The results of this review and meta-analysis can be used in designing future trials of ventilation.
doi:10.1186/2046-4053-3-2
PMCID: PMC3880983  PMID: 24383428
Surgery; Mechanical ventilation; Individual patient data; Protective ventilation
2.  Soluble receptor for advanced glycation end products as an indicator of pulmonary vascular injury after cardiac surgery 
Background
Cardiac surgery is frequently complicated by an acute vascular lung injury and this may be mediated, at least in part, by the (soluble) receptor for advanced glycation end products (sRAGE).
Methods
In two university hospital intensive care units, circulating sRAGE was measured together with the 68Gallium-transferrin pulmonary leak index (PLI), a measure of pulmonary vascular permeabiliy, in 60 consecutive cardiac surgery patients stratified by the amount of blood transfusion, within 3 hours of admission to the intensive care.
Results
Cardiac surgery resulted in elevated plasma sRAGE levels compared to baseline (315 ± 181 vs 110 ± 55 pg/ml, P = 0.001). In 37 patients the PLI was elevated 50% above normal. The PLI correlated with sRAGE (r2 = 0.11, P = 0.018). Plasma sRAGE discriminated well between those with an elevated PLI and those with a normal PLI (area under the operator curve 0.75; P = 0.035; 95% CI 0.55-0.95), with 91% sensitivity but low specificity of 36% at a cutoff value of 200 pg/mL. Blood transfusion did not influence sRAGE levels.
Conclusions
sRAGE is elevated in plasma after cardiac surgery and indicates increased pulmonary vascular permeability. The level of sRAGE is not affected by transfusion.
doi:10.1186/1471-2466-13-76
PMCID: PMC3866278  PMID: 24341821
sRAGE; Cardiac surgery; Transfusion; Critically ill; Acute lung injury; ARDS; Pulmonary leakage index
3.  Glycemic variability is complex - is glucose complexity variable? 
Critical Care  2012;16(6):178.
Observational studies show an independent association between increased glycemic variability and higher mortality in critically ill patients. Minimization of glycemic variability is therefore suggested as a new target of glycemic control, which may require very frequent or almost continuous monitoring of glucose levels. Brunner and colleagues show the use of real-time subcutaneous continuous glucose monitoring does not decrease glycemic variability. Continuous glucose monitoring, however, may reveal changes in glucose complexity, which may be of interest since both increased and decreased glucose complexity is associated with higher mortality in the critically ill.
doi:10.1186/cc11834
PMCID: PMC3672583  PMID: 23171831
4.  Pulmonary coagulopathy: a potential therapeutic target in different forms of lung injury 
Thorax  2007;62(7):563-564.
The role and source of tissue factor
doi:10.1136/thx.2006.067256
PMCID: PMC2117247  PMID: 17600292
5.  A comparison of RIFLE with and without urine output criteria for acute kidney injury in critically ill patients 
Critical Care  2012;16(5):R200.
Introduction
The Risk, Injury, Failure, Loss, and End-Stage Renal Disease (RIFLE) is a consensus-based classification system for diagnosing acute kidney insufficiency (AKI), based on serum creatinine (SCr) and urine output criteria (RIFLESCr+UO). The urine output criteria, however, are frequently discarded and many studies in the literature applied only the SCr criteria (RIFLESCr). We diagnosed AKI using both RIFLE methods and compared the effects on time to AKI diagnosis, AKI incidence and AKI severity.
Methods
This was a prospective observational cohort study during four months in adult critically ill patients admitted to the ICU for at least 48 hours. During the first week patients were scored daily for AKI according to RIFLESCr+UO and RIFLESCr. We assessed urine output hourly and fluid balance daily. The baseline SCr was estimated if a recent pre-ICU admission SCr was unknown. Based on the two RIFLE methods for each patient we determined time to AKI diagnosis (AKI-0) and maximum RIFLE grade.
Results
We studied 260 patients. A pre-ICU admission SCr was available in 101 (39%) patients. The two RIFLE methods resulted in statistically significantly different outcomes for incidence of AKI, diagnosis of AKI for individual patients, distribution of AKI-0 and distribution of the maximum RIFLE grade. Discarding the RIFLE urine criteria for AKI diagnosis significantly underestimated the presence and grade of AKI on admission and during the first ICU week (P < 0,001) and significantly delayed the diagnosis of AKI (P < 0.001). Based on RIFLESCr 45 patients had no AKI on admission but subsequently developed AKI. In 24 of these patients (53%) AKI would have been diagnosed at least one day earlier if the RIFLE urine criteria had been applied. Mortality rate in the AKI population was 38% based on RIFLESCr and 24% based on RIFLESCr+UO (P = 0.02).
Conclusions
The use of RIFLE without the urine criteria significantly underscores the incidence and grade of AKI, significantly delays the diagnosis of AKI and is associated with higher mortality.
doi:10.1186/cc11808
PMCID: PMC3682302  PMID: 23078781
6.  Benefits and risks of manual hyperinflation in intubated and mechanically ventilated intensive care unit patients: a systematic review 
Critical Care  2012;16(4):R145.
Introduction
Manual hyperinflation (MH), a frequently applied maneuver in critically ill intubated and mechanically ventilated patients, is suggested to mimic a cough so that airway secretions are mobilized toward the larger airways, where they can easily be removed. As such, MH could prevent plugging of the airways.
Methods
We performed a search in the databases of Medline, Embase, and the Cochrane Library from January 1990 to April 2012. We systematically reviewed the literature on evidence for postulated benefits and risks of MH in critically ill intubated and mechanically ventilated patients.
Results
The search identified 50 articles, of which 19 were considered relevant. We included 13 interventional studies and six observational studies. The number of studies evaluating physiological effects of MH is limited. Trials differed too much to permit meta-analysis. It is uncertain whether MH was applied similarly in the retrieved studies. Finally, most studies are underpowered to show clinical benefit of MH. Use of MH is associated with short-term improvements in lung compliance, oxygenation, and secretion clearance, without changes in outcomes. MH has been reported to be associated with short-term and probably clinically insignificant side effects, including decreases in cardiac output, alterations of heart rates, and increased central venous pressures.
Conclusions
Studies have failed to show that MH benefits critically ill intubated and mechanically ventilated patients. MH is infrequently associated with short-term side effects.
doi:10.1186/cc11457
PMCID: PMC3580733  PMID: 22863373
7.  Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials 
Background
Acute respiratory distress syndrome (ARDS) is a potentially fatal disease with high mortality. Our aim was to summarize the current evidence for use of neuromuscular blocking agents (NMBA) in the early phase of ARDS.
Methods
Systematic review and meta-analysis of publications between 1966 and 2012. The Medline and CENTRAL databases were searched for studies on NMBA in patients with ARDS. The meta-analysis was limited to: 1) randomized controlled trials; 02) adult human patients with ARDS or acute lung injury; and 03) use of any NMBA in one arm of the study compared with another arm without NMBA. The outcomes assessed were: overall mortality, ventilator-free days, time of mechanical ventilation, adverse events, changes in gas exchange, in ventilator settings, and in respiratory mechanics.
Results
Three randomized controlled trials covering 431 participants were included. Patients treated with NMBA showed less mortality (Risk ratio, 0.71 [95 % CI, 0.55 – 0.90]; number needed to treat, 1 – 7), more ventilator free days at day 28 (p = 0.020), higher PaO2 to FiO2 ratios (p = 0.004), and less barotraumas (p = 0.030). The incidence of critical illness neuromyopathy was similar (p = 0.540).
Conclusions
The use of NMBA in the early phase of ARDS improves outcome.
doi:10.1186/2110-5820-2-33
PMCID: PMC3475105  PMID: 22835162
ARDS; Neuromuscular blocking agents; Meta-analysis; Review
9.  Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations 
Critical Care  2012;16(2):R70.
Background
Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.
Method
We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.
Results
The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.
Conclusion
Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.
doi:10.1186/cc11325
PMCID: PMC3681399  PMID: 22546487
10.  Central venous catheter use in severe malaria: time to reconsider the World Health Organization guidelines? 
Malaria Journal  2011;10:342.
Background
To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.
Methods
Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.
Results
There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.
Conclusion
The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.
doi:10.1186/1475-2875-10-342
PMCID: PMC3228715  PMID: 22082224
12.  Mild hypoglycemia is independently associated with increased mortality in the critically ill 
Critical Care  2011;15(4):R173.
Introduction
Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.
Methods
Prospectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.
Results
We analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively.
Conclusions
Mild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality
doi:10.1186/cc10322
PMCID: PMC3387616  PMID: 21787410
13.  Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial 
Critical Care  2010;14(5):R180.
Introduction
Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.
Methods
Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.
Results
Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.
Conclusions
Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.
Trial registration
The Australian Clinical Trials Registry (ACTR-12608000121369).
doi:10.1186/cc9286
PMCID: PMC3219284  PMID: 20937093
14.  Volatile Metabolites of Pathogens: A Systematic Review 
PLoS Pathogens  2013;9(5):e1003311.
Ideally, invading bacteria are detected as early as possible in critically ill patients: the strain of morbific pathogens is identified rapidly, and antimicrobial sensitivity is known well before the start of new antimicrobial therapy. Bacteria have a distinct metabolism, part of which results in the production of bacteria-specific volatile organic compounds (VOCs), which might be used for diagnostic purposes. Volatile metabolites can be investigated directly in exhaled air, allowing for noninvasive monitoring. The aim of this review is to provide an overview of VOCs produced by the six most abundant and pathogenic bacteria in sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Such VOCs could be used as biological markers in the diagnostic approach of critically ill patients. A systematic review of existing literature revealed 31 articles. All six bacteria of interest produce isopentanol, formaldehyde, methyl mercaptan, and trimethylamine. Since humans do not produce these VOCs, they could serve as biological markers for presence of these pathogens. The following volatile biomarkers were found for identification of specific strains: isovaleric acid and 2-methyl-butanal for Staphylococcus aureus; 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 4-methyl-quinazoline, hydrogen cyanide, and methyl thiocyanide for Pseudomonas aeruginosa; and methanol, pentanol, ethyl acetate, and indole for Escherichia coli. Notably, several factors that may effect VOC production were not controlled for, including used culture media, bacterial growth phase, and genomic variation within bacterial strains. In conclusion, VOCs produced by bacteria may serve as biological markers for their presence. Goal-targeted studies should be performed to identify potential sets of volatile biological markers and evaluate the diagnostic accuracy of these markers in critically ill patients.
doi:10.1371/journal.ppat.1003311
PMCID: PMC3649982  PMID: 23675295
15.  The Extent of Ventilator-Induced Lung Injury in Mice Partly Depends on Duration of Mechanical Ventilation 
Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI. Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls. Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2 to FiO2 ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours. Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.
doi:10.1155/2013/435236
PMCID: PMC3652114  PMID: 23691294
16.  Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study 
Critical Care  2013;17(2):R37.
Introduction
Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients.
Methods
This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes.
Results
Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands >140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associated with increased risk of mortality among patients with and without diabetes and increased glycemic variability, defined as CV >20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes.
Conclusions
Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient's diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes.
See related commentary by Krinsley, http://ccforum.com/content/17/2/131
See related commentary by Finfer and Billot, http://ccforum.com/content/17/2/134
doi:10.1186/cc12547
PMCID: PMC3733432  PMID: 23452622
17.  In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: a cohort study 
Critical care medicine  2012;40(6):1835-1843.
Objectives
Patients with diabetes mellitus (DM) form 23–30% of published cohorts of critically ill patients. Conflicting published evidence links DM to both higher and lower mortality. Other cohort studies have suggest that DM protects against acute lung injury (ALI). We hypothesized that DM is an independent risk factor for mortality. We further hypothesized that DM is a risk factor for cardiac overload (CO) and not for ALI.
Design
Retrospective cohort study.
Setting
The intensive care unit (ICU) of a tertiary referral hospital.
Patients
From 1 November 2004 to 1 October 2007, a cohort of patients admitted ≥48h to the ICU.
Interventions
None
Measurements and Main Results
Of 2,013 patients, 317 had DM. Ninety-day mortality was higher in the DM patients compared to patients without DM (hazard ratio [HR] 1.53, 95% confidence interval 1.29–1.80). This association strengthened after adjusting for confounders and for medication (HR 1.53, 1.07–2.17). We found no association between DM and ALI (relative risk ratio [RRR] 1.01, 0.78–1.32; adjusted RRR 0.99, 0.75–1.31), but DM was a risk factor for CO (RRR 1.91, 1.30–2.81; adjusted RRR 1.45, 0.97–2.18). Statins were associated with both a reduced risk of mortality (HR 0.74, 0.63–0.87; adjusted HR 0.53, 0.44–0.64) and a decreased risk of developing ALI (RRR 0.71, 0.56–0.89; adjusted RRR 0.61, 0.47–0.79).
Conclusions
DM is an independent risk factor for mortality in critically ill patients and failure to adjust for statins underestimates the size of this association. DM is not associated with ALI but is associated with CO. A diagnosis of CO excludes a diagnosis of ALI. Investigators who do not account for CO as a competing alternative outcome may therefore falsely conclude that DM protects from ALI.
doi:10.1097/CCM.0b013e31824e1696
PMCID: PMC3379571  PMID: 22488007
diabetes mellitus; intensive care; acute lung injury; acute respiratory distress syndrome; mortality; heart failure; hydroxymethylglutaryl-CoA reductase inhibitors; confounding factors (epidemiology); multinomial logistic regression; Cox regression
18.  Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury 
Critical Care  2011;15(6):235.
Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.
doi:10.1186/cc10437
PMCID: PMC3388678  PMID: 22216838
19.  Systemic and Urinary Neutrophil Gelatinase-Associated Lipocalins Are Poor Predictors of Acute Kidney Injury in Unselected Critically Ill Patients 
Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLERISK days, RIFLEINJURY days, and RIFLEFAILURE days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27–0.63) and 0.53 (CI 0.38–0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33–0.62) and 0.48 (CI 0.33–0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37–0.58) and 0.26 (CI 0.03–0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.
doi:10.1155/2012/712695
PMCID: PMC3483834  PMID: 23119153
20.  Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review 
Intensive Care Medicine  2012;38(9):1418-1428.
Purpose
Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value.
Methods
A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia.
Results
Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR.
Conclusions
The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.
doi:10.1007/s00134-012-2613-1
PMCID: PMC3423568  PMID: 22706919
Soluble uPAR; Soluble urokinase plasminogen activator receptor (suPAR); Biomarker; Intensive care; Critical illness; Sepsis
21.  Correction of subclinical coagulation disorders before percutaneous dilatational tracheotomy 
Blood Transfusion  2012;10(2):213-220.
Background
There is evidence that percutaneous dilatational tracheotomy (PDT) can be safely performed in patients with severe coagulation disorders if these are carefully corrected immediately before the procedure. However, it is currently unclear whether PDT can be performed safely in patients in an Intensive Care Unit (ICU) with uncorrected mild coagulation disorders.
Materials and methods
In a randomised controlled trial we determined the effect of correction of mild coagulation disorders on bleeding during and after PDT. ICU patients planned for bedside PDT with: (i) a prothrombin time (PT) between 14.7–20.0 seconds, (ii) a platelet count between 40–100×109/L and/or (iii) active treatment with acetylsalicylic acid were randomised to receive infusion with fresh-frozen plasma (FFP) and/or platelets (“correction”) versus no transfusion (“no correction”) before PDT.
Results
We randomised 35 patients to the “correction” group and 37 patients to the “no correction” group. In patients who received FFP, the decrease in PT was marginal (mean decrease 0.40±0.56 seconds); the median increase in platelet counts after transfusion of platelets was 35 [11–47]x109/L. The median blood loss was 3 [IQR: 1–6] grams in the “correction” group and 3 [IQR: 2–6] grams in the “no correction” group (P=0.96).
Discussion
Bleeding during and after bedside PDT in ICU patients with mild coagulation disorders is rare in our setting. Correction of subclinical coagulation disorders by transfusion of FFP and/or platelets does not affect bleeding.
doi:10.2450/2012.0086-11
PMCID: PMC3320783  PMID: 22337277
percutaneous tracheostomy; coagulation disorders; transfusion
23.  Recommendations for sepsis management in resource-limited settings 
Intensive Care Medicine  2012;38(4):557-574.
Purpose
To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis.
Methods
The medical literature on sepsis management was reviewed. Specific attention was paid to identify clinical evidence on sepsis management from resource-limited settings.
Results
Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, normal heart rate and arterial blood pressure, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, frequent measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation >90%, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, timely administration of adequate antimicrobials, thorough clinical investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. Specific considerations for malaria, puerperal sepsis and HIV/AIDS patients with sepsis are included.
Conclusion
Only scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. The presented recommendations may help to improve sepsis management in middle- and low-income countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2468-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-012-2468-5
PMCID: PMC3307996  PMID: 22349419
Sepsis; Intensive care; Resource-limited settings; Middle-income countries; Low-income countries; Recommendations; Management
24.  Relative Tissue Factor Deficiency Attenuates Ventilator-Induced Coagulopathy but Does Not Protect against Ventilator-Induced Lung Injury in Mice 
Preventing tissue-factor-(TF-) mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI). We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI. Heterozygous TF knockout (TF+/−) mice and their wild-type (TF+/+) littermates were sedated (controls) or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours. Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF+/+ mice, TF+/− mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF+/− and TF+/+ mice. Notably, pulmonary levels of cytokines were significantly higher in TF+/− as compared to TF+/+ mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators.
doi:10.1155/2012/130410
PMCID: PMC3238356  PMID: 22195278
25.  Mild hypoglycemia is strongly associated with increased intensive care unit length of stay 
Background
Hypoglycemia is associated with increased mortality in critically ill patients. The impact of hypoglycemia on resource utilization has not been investigated. The objective of this investigation was to evaluate the association of hypoglycemia, defined as a blood glucose concentration (BG) < 70 mg/dL, and intensive care unit (ICU) length of stay (LOS) in three different cohorts of critically ill patients.
Methods
This is a retrospective investigation of prospectively collected data, including patients from two large observational cohorts: 3,263 patients admitted to Stamford Hospital (ST) and 2,063 patients admitted to three institutions in The Netherlands (NL) as well as 914 patients from the GLUCONTROL trial (GL), a multicenter prospective randomized controlled trial of intensive insulin therapy.
Results
Patients with hypoglycemia were more likely to be diabetic, had higher APACHE II scores, and higher mortality than did patients without hypoglycemia. Patients with hypoglycemia had longer ICU LOS (median [interquartile range]) in ST (3.0 [1.4-7.1] vs. 1.2 [0.8-2.3] days, P < 0.0001), NL (5.2 [2.6-10.3] vs. 2.0 [1.3-3.2] days, P < 0.0001), and GL (9 [5-17] vs. 5 [3-9] days, P < 0.0001). For the entire cohort of 6,240 patients ICU LOS was 1.8 (1.0-3.3) days for those without hypoglycemia and 3.0 (1.5-6.7) days for those with a single episode of hypoglycemia (P < 0.0001). This was a consistent finding even when patients were stratified by severity of illness or survivor status. There was a strong positive correlation between the number of episodes of hypoglycemia and ICU LOS among all three cohorts.
Conclusions
This multicenter international investigation demonstrated that hypoglycemia was consistently associated with significantly higher ICU LOS in heterogeneous cohorts of critically ill patients, independently of severity of illness and survivor status. More effective methods to prevent hypoglycemia in these patients may positively impact their cost of care.
doi:10.1186/2110-5820-1-49
PMCID: PMC3273438  PMID: 22115519
hypoglycemia; intensive care unit; length of stay; resource utilization; APACHE II; mortality; intensive insulin therapy

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