Search tips
Search criteria

Results 1-25 (130)

Clipboard (0)

Select a Filter Below

Year of Publication
more »
2.  Plasma fractalkine is a sustained marker of disease severity and outcome in sepsis patients 
Critical Care  2015;19:412.
Fractalkine is a chemokine implicated as a mediator in a variety of inflammatory conditions. Knowledge of fractalkine release in patients presenting with infection to the Intensive Care Unit (ICU) is highly limited. The primary objective of this study was to establish whether plasma fractalkine levels are elevated in sepsis and associate with outcome. The secondary objective was to determine whether fractalkine can assist in the diagnosis of infection upon ICU admission.
Fractalkine was measured in 1103 consecutive sepsis patients (including 271 patients with community-acquired pneumonia (CAP)) upon ICU admission and at days 2 and 4 thereafter; in 73 ICU patients treated for suspected CAP in whom this diagnosis was refuted in retrospect; and in 5 healthy humans intravenously injected with endotoxin.
Compared to healthy volunteers, sepsis patients had strongly elevated fractalkine levels. Fractalkine levels increased with the number of organs failing, were higher in patients presenting with shock, but did not vary by site of infection. Non-survivors had sustained elevated fractalkine levels when compared to survivors. Fractalkine was equally elevated in CAP patients and patients treated for CAP but in whom the diagnosis was retrospectively refuted. Fractalkine release induced by intravenous endotoxin followed highly similar kinetics as the endothelial cell marker E-selectin.
Plasma fractalkine is an endothelial cell derived biomarker that, while not specific for infection, correlates with disease severity in sepsis patients admitted to the ICU.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-1125-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4658804  PMID: 26603530
3.  Associations between bolus infusion of hydrocortisone, glycemic variability and insulin infusion rate variability in critically Ill patients under moderate glycemic control 
We retrospectively studied associations between bolus infusion of hydrocortisone and variability of the blood glucose level and changes in insulin rates in intensive care unit (ICU) patients.
‘Glycemic variability’ and ‘insulin infusion rate variability’ were calculated from and expressed as the standard deviation (SD) of all blood glucose levels and insulin infusion rates during stay in the ICU, respectively. Glycemic and insulin infusion rate variability in patients who received bolus infusion of hydrocortisone were compared to those in patients who never received bolus infusion of hydrocortisone. Multivariate analysis was performed to correct for potential covariates including disease severity.
We included 6409 patients over 6 years; of them 962 received bolus infusion of hydrocortisone. Compared to patients who never received bolus infusion of hydrocortisone, patients who received hydrocortisone had their blood glucose level measured more frequently, had higher glycemic variability; were more frequently treated with intravenous insulin and had higher insulin infusion rate variability. The association between hydrocortisone treatment and glycemic variability was independent of disease severity, but the effect of hydrocortisone treatment on blood glucose variability was less strong in the more severely ill patients. The association between hydrocortisone and insulin infusion rate variability was also independent of disease severity, and independent of glycemic variability.
Bolus infusion of hydrocortisone is independently associated with higher glycemic variability and higher insulin infusion rate variability in ICU patients. Studies are needed to see if continuous infusion of hydrocortisone prevents higher glycemic variability and higher insulin infusion rate variability.
Electronic supplementary material
The online version of this article (doi:10.1186/s13613-015-0077-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4630319  PMID: 26525053
Hydrocortisone; Bolus infusion; Blood glucose control; Glycemic control; Blood glucose variability; Insulin; Insulin infusion rate variability
5.  Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study 
Critical Care  2015;19(1):319.
A clinical suspicion of infection is mandatory for diagnosing sepsis in patients with a systemic inflammatory response syndrome. Yet, the accuracy of categorizing critically ill patients presenting to the intensive care unit (ICU) as being infected or not is unknown. We therefore assessed the likelihood of infection in patients who were treated for sepsis upon admission to the ICU, and quantified the association between plausibility of infection and mortality.
We studied a cohort of critically ill patients admitted with clinically suspected sepsis to two tertiary ICUs in the Netherlands between January 2011 and December 2013. The likelihood of infection was categorized as none, possible, probable or definite by post-hoc assessment. We used multivariable competing risks survival analyses to determine the association of the plausibility of infection with mortality.
Among 2579 patients treated for sepsis, 13% had a post-hoc infection likelihood of “none”, and an additional 30% of only “possible”. These percentages were largely similar for different suspected sites of infection. In crude analyses, the likelihood of infection was associated with increased length of stay and complications. In multivariable analysis, patients with an unlikely infection had a higher mortality rate compared to patients with a definite infection (subdistribution hazard ratio 1.23; 95% confidence interval 1.03-1.49).
This study is the first prospective analysis to show that the clinical diagnosis of sepsis upon ICU admission corresponds poorly with the presence of infection on post-hoc assessment. A higher likelihood of infection does not adversely influence outcome in this population.
Trial registration NCT01905033. Registered 11 July 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-1035-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4562354  PMID: 26346055
6.  Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial 
Trials  2015;16:389.
Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients.
The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis.
The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients.
Trial registration
NCT02159196, registered on 6 June 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0865-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4557315  PMID: 26329352
Mechanical ventilation; Nebulization; Intensive care unit; Critical care; Aerosol therapy; Mucolytic agents; Bronchodilators; Acetylcysteine; Salbutamol
7.  Continuous glucose control in the ICU: report of a 2013 round table meeting 
Critical Care  2014;18(3):226.
Achieving adequate glucose control in critically ill patients is a complex but important part of optimal patient management. Until relatively recently, intermittent measurements of blood glucose have been the only means of monitoring blood glucose levels. With growing interest in the possible beneficial effects of continuous over intermittent monitoring and the development of several continuous glucose monitoring (CGM) systems, a round table conference was convened to discuss and, where possible, reach consensus on the various aspects related to glucose monitoring and management using these systems. In this report, we discuss the advantages and limitations of the different types of devices available, the potential advantages of continuous over intermittent testing, the relative importance of trend and point accuracy, the standards necessary for reporting results in clinical trials and for recognition by official bodies, and the changes that may be needed in current glucose management protocols as a result of a move towards increased use of CGM. We close with a list of the research priorities in this field, which will be necessary if CGM is to become a routine part of daily practice in the management of critically ill patients.
PMCID: PMC4078395  PMID: 25041718
8.  PReVENT - protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial 
Trials  2015;16:226.
It is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS.
PReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space.
PReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoint.
Trial registration
The trial is registered at under reference number NCT02153294 on 23 May 2014.
PMCID: PMC4453265  PMID: 26003545
Mechanical ventilation; Ventilator-induced lung injury; Tidal volume; Respiratory rate; Protective ventilation; Intensive care unit; Critical care; Non injured lungs
9.  Impact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study 
Critical Care  2015;19(1):196.
ICU-acquired weakness is thought to mediate physical impairments in survivors of critical illness, but few studies have investigated this thoroughly. The purpose was to investigate differences in post-ICU mortality and physical functioning between patients with and without ICU-acquired weakness at 6 months after ICU discharge.
ICU patients, mechanically ventilated ≥2 days, were included in a single-center prospective observational cohort study. ICU-acquired weakness was diagnosed when the average Medical Research Council score was <4 in awake and attentive patients. Post-ICU mortality was recorded until 6 months after ICU discharge; in surviving patients, physical functioning was assessed using the Short-Form Health Survey physical functioning domain. The independent effect of ICU-acquired weakness on post-ICU mortality was analyzed using a multivariable Cox proportional hazards model. The independent effect of ICU-acquired weakness on the physical functioning domain score was analyzed using a multivariable linear regression model.
Of the 156 patients included, 80 had ICU-acquired weakness. Twenty-three patients died in the ICU (20 with ICU-acquired weakness); during 6 months follow-up after ICU discharge another 25 patients died (17 with ICU-acquired weakness). Physical functioning domain scores were available for 96 survivors (39 patients with ICU-acquired weakness). ICU-acquired weakness was independently associated with an increase in post-ICU mortality (hazard ratio 3.6, 95% confidence interval, 1.3 to 9.8; P = 0.01) and with a decrease in physical functioning (β: -16.7 points; 95% confidence interval, -30.2 to -3.1; P = 0.02).
ICU-acquired weakness is independently associated with higher post-ICU mortality and with clinically relevant lower physical functioning in survivors at 6 months after ICU discharge.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0937-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4427976  PMID: 25928709
10.  Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis 
Critical Care  2015;19(1):48.
Automated weaning systems may improve adaptation of mechanical support for a patient’s ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. Our objective was to compare mechanical ventilator weaning duration for critically ill adults and children when managed with automated systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.
Electronic databases were searched to 30 September 2013 without language restrictions. We also searched conference proceedings; trial registration websites; and article reference lists. Two authors independently extracted data and assessed risk of bias. We combined data using random-effects modelling.
We identified 21 eligible trials totalling 1,676 participants. Pooled data from 16 trials indicated that automated systems reduced the geometric mean weaning duration by 30% (95% confidence interval (CI) 13% to 45%), with substantial heterogeneity (I2 = 87%, P <0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not with surgical populations or using other systems. Automated systems reduced ventilation duration with no heterogeneity (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of effect on mortality, hospital LOS, reintubation, self-extubation and non-invasive ventilation following extubation. Automated systems reduced prolonged mechanical ventilation and tracheostomy. Overall quality of evidence was high.
Automated systems may reduce weaning and ventilation duration and ICU stay. Due to substantial trial heterogeneity an adequately powered, high quality, multi-centre randomized controlled trial is needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0755-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4344786  PMID: 25887887
11.  Point accuracy and reliability of an interstitial continuous glucose-monitoring device in critically ill patients: a prospective study 
Critical Care  2015;19(1):34.
There is a need for continuous glucose monitoring in critically ill patients. The objective of this trial was to determine the point accuracy and reliability of a device designed for continuous monitoring of interstitial glucose levels in intensive care unit patients.
We evaluated point accuracy by comparing device readings with glucose measurements in arterial blood by using blood gas analyzers. Analytical and clinical accuracy was expressed in Bland-Altman plots, glucose prediction errors, and Clarke error grids. We used a linear mixed model to determine which factors affect the point accuracy. In addition, we determined the reliability, including duration of device start-up and calibration, skips in data acquisition, and premature disconnections of sensors.
We included 50 patients in whom we used 105 sensors. Five patients from whom we could not collect the predefined minimum number of four consecutive comparative blood draws were excluded from the point accuracy analysis. Therefore, we had 929 comparative samples from 100 sensors in 45 patients (11 (7 to 28) samples per patient) during 4,639 hours (46 (27 to 134) hours per patient and 46 (21 to 69) hours per sensor) for the accuracy analysis. Point accuracy did not meet the International Organization for Standardization (ISO) 14971 standard for insulin dosing accuracy but did improve with increasing numbers of calibrations and was better in patients who did not have a history of diabetes. Out of 105 sensors, 60 were removed prematurely for a variety of reasons. The device start-up time was 49 (43 to 58) minutes. The number of skips in data acquisition was low, resulting in availability of real-time data during 95% (89% to 98%) of the connection time per sensor.
The point accuracy of a device designed for continuous real-time monitoring of interstitial glucose levels was relatively low in critically ill patients. The device had few downtimes, but one third of the sensors were removed prematurely because of unresolved sensor- or device-related problems.
Trial registration
Netherlands Trial Registry number: NTR3827. Registered 30 January 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0757-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4382831  PMID: 25652770
12.  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
PMCID: PMC2117247  PMID: 17600292
13.  Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia 
Thrombosis and haemostasis  2015;114(1):115-122.
Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1 (-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ∼50%. Homozygous lowTFPI mice and heterozygous controls had ∼10% and ∼50% of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ∼10 % (but not with ∼50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.
PMCID: PMC4786014  PMID: 25832548
Coagulation inhibitors; inflammation; lung; bacterial infection; Streptococcus pneumoniae
14.  The receptor for advanced glycation end products in ventilator-induced lung injury 
Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. We hypothesized that RAGE signaling contributes to the pro-inflammatory state induced by MV.
RAGE expression was analyzed in lung brush and lavage cells obtained from ventilated patients and lung tissue of ventilated mice. Healthy wild-type (WT) and RAGE knockout (KO) mice were ventilated with relatively low (approximately 7.5 ml/kg) or high (approximately 15 ml/kg) tidal volume. Positive end-expiratory pressure was set at 2 cm H2O during both MV strategies. Also, WT and RAGE KO mice with lipopolysaccharide (LPS)-induced lung injury were ventilated with the above described ventilation strategies. In separate experiments, the contribution of soluble RAGE, a RAGE isoform that may function as a decoy receptor, in ventilated RAGE KO mice was investigated. Lung wet-to-dry ratio, cell and neutrophil influx, cytokine and chemokine concentrations, total protein levels, soluble RAGE, and high-mobility group box 1 (HMGB1) presence in lung lavage fluid were analyzed.
MV was associated with increased RAGE mRNA levels in both human lung brush samples and lung tissue of healthy mice. In healthy high tidal volume-ventilated mice, RAGE deficiency limited inflammatory cell influx. Other VILI parameters were not affected. In our second set of experiments where we compared RAGE KO and WT mice in a 2-hit model, we observed higher pulmonary cytokine and chemokine levels in RAGE KO mice undergoing LPS/high tidal volume MV as compared to WT mice. Third, in WT mice undergoing the LPS/high tidal volume MV, we observed HMGB1 presence in lung lavage fluid. Moreover, MV increased levels of soluble RAGE in lung lavage fluid, with the highest levels found in LPS/high tidal volume-ventilated mice. Administration of soluble RAGE to LPS/high tidal volume-ventilated RAGE KO mice attenuated the production of inflammatory mediators.
RAGE was not a crucial contributor to the pro-inflammatory state induced by MV. However, the presence of sRAGE limited the production of pro-inflammatory mediators in our 2-hit model of LPS and high tidal volume MV.
Electronic supplementary material
The online version of this article (doi:10.1186/s40635-014-0022-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4678142  PMID: 26215707
Acute lung injury; Mechanical ventilation; Receptor for advanced glycation end products; Inflammation; Innate immunity
15.  Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia 
Critical Care  2014;18(4):R162.
Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest.
A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined.
In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C.
Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest.
Trial registration NCT01020916, registered 25 November 2009
PMCID: PMC4261599  PMID: 25078879
16.  Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses 
High inspiratory oxygen concentrations are frequently administered in ventilated patients in the intensive care unit (ICU) but may induce lung injury and systemic toxicity. We compared beliefs and actual clinical practice regarding oxygen therapy in critically ill patients.
In three large teaching hospitals in the Netherlands, ICU physicians and nurses were invited to complete a questionnaire about oxygen therapy. Furthermore, arterial blood gas (ABG) analysis data and ventilator settings were retrieved to assess actual oxygen practice in the same hospitals 1 year prior to the survey.
In total, 59% of the 215 respondents believed that oxygen-induced lung injury is a concern. The majority of physicians and nurses stated that minimal acceptable oxygen saturation and partial arterial oxygen pressure (PaO2) ranges were 85% to 95% and 7 to 10 kPa (52.5 to 75 mmHg), respectively. Analysis of 107,888 ABG results with concurrent ventilator settings, derived from 5,565 patient admissions, showed a median (interquartile range (IQR)) PaO2 of 11.7 kPa (9.9 to 14.3) [87.8 mmHg], median fractions of inspired oxygen (FiO2) of 0.4 (0.4 to 0.5), and median positive end-expiratory pressure (PEEP) of 5 (5 to 8) cm H2O. Of all PaO2 values, 73% were higher than the upper limit of the commonly self-reported acceptable range, and in 58% of these cases, neither FiO2 nor PEEP levels were lowered until the next ABG sample was taken.
Most ICU clinicians acknowledge the potential adverse effects of prolonged exposure to hyperoxia and report a low tolerance for high oxygen levels. However, in actual clinical practice, a large proportion of their ICU patients was exposed to higher arterial oxygen levels than self-reported target ranges.
PMCID: PMC4240734  PMID: 25512878
Oxygen; Hyperoxia; Mechanical ventilation; Lung injury; Intensive care medicine; Questionnaire
17.  Glucose prediction by analysis of exhaled metabolites – a systematic review 
BMC Anesthesiology  2014;14:46.
In critically ill patients, glucose control with insulin mandates time– and blood–consuming glucose monitoring. Blood glucose level fluctuations are accompanied by metabolomic changes that alter the composition of volatile organic compounds (VOC), which are detectable in exhaled breath. This review systematically summarizes the available data on the ability of changes in VOC composition to predict blood glucose levels and changes in blood glucose levels.
A systematic search was performed in PubMed. Studies were included when an association between blood glucose levels and VOCs in exhaled air was investigated, using a technique that allows for separation, quantification and identification of individual VOCs. Only studies on humans were included.
Nine studies were included out of 1041 identified in the search. Authors of seven studies observed a significant correlation between blood glucose levels and selected VOCs in exhaled air. Authors of two studies did not observe a strong correlation. Blood glucose levels were associated with the following VOCs: ketone bodies (e.g., acetone), VOCs produced by gut flora (e.g., ethanol, methanol, and propane), exogenous compounds (e.g., ethyl benzene, o–xylene, and m/p–xylene) and markers of oxidative stress (e.g., methyl nitrate, 2–pentyl nitrate, and CO).
There is a relation between blood glucose levels and VOC composition in exhaled air. These results warrant clinical validation of exhaled breath analysis to monitor blood glucose levels.
PMCID: PMC4068184  PMID: 24963286
Glucose; Monitoring; Volatile organic compound; Breath
18.  Clinical review: Consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults 
Critical Care  2013;17(3):229.
The management reporting and assessment of glycemic control lacks standardization. The use of different methods to measure the blood glucose concentration and to report the performance of insulin treatment yields major disparities and complicates the interpretation and comparison of clinical trials. We convened a meeting of 16 experts plus invited observers from industry to discuss and where possible reach consensus on the most appropriate methods to measure and monitor blood glucose in critically ill patients and on how glycemic control should be assessed and reported. Where consensus could not be reached, recommendations on further research and data needed to reach consensus in the future were suggested. Recognizing their clear conflict of interest, industry observers played no role in developing the consensus or recommendations from the meeting. Consensus recommendations were agreed for the measurement and reporting of glycemic control in clinical trials and for the measurement of blood glucose in clinical practice. Recommendations covered the following areas: How should we measure and report glucose control when intermittent blood glucose measurements are used? What are the appropriate performance standards for intermittent blood glucose monitors in the ICU? Continuous or automated intermittent glucose monitoring - methods and technology: can we use the same measures for assessment of glucose control with continuous and intermittent monitoring? What is acceptable performance for continuous glucose monitoring systems? If implemented, these recommendations have the potential to minimize the discrepancies in the conduct and reporting of clinical trials and to improve glucose control in clinical practice. Furthermore, to be fit for use, glucose meters and continuous monitoring systems must match their performance to fit the needs of patients and clinicians in the intensive care setting.
See related commentary by Soto-Rivera and Agus,
PMCID: PMC3706766  PMID: 23767816
20.  The Impact of HIV Co-Infection on the Genomic Response to Sepsis 
PLoS ONE  2016;11(2):e0148955.
HIV patients have an increased risk to develop sepsis and HIV infection affects several components of the immune system involved in sepsis pathogenesis. We hypothesized that HIV infection might aggrevate the aberrant immune response during sepsis, so we aimed to determine the impact of HIV infection on the genomic host response to sepsis. We compared whole blood leukocyte gene expression profiles among sepsis patients with or without HIV co-infection in the intensive care unit (ICU) and validated our findings in a cohort of patients admitted to the same ICUs in a different time frame. To examine the influence of HIV infection per se, we also determined the expression of genes of interest in a cohort of asymptomatic HIV patients. We identified a predominantly common host response in sepsis patients with or without HIV co-infection. HIV positive sepsis patients in both ICU cohorts showed overexpression of genes involved in granzyme signaling (GZMA, GZMB), cytotoxic T-cell signaling (CD8A, CD8B) and T-cell inhibitory signaling (LAG3), compared to HIV negative patients. Enhanced expression of CD8A, CD8B and LAG3 was also unmasked in asymptomatic HIV patients. Plasma levels of granzymes in sepsis patients were largely below detection limit, without differences according to HIV status. These results demonstrate that sepsis is characterized by a massive common response with few differences between HIV positive and HIV negative sepsis patients. Observed differences in granzyme signaling, cytotoxic T-cell signaling and T-cell inhibitory signaling appear to be changes commonly observed in asymptomatic HIV patients which persist during sepsis.
PMCID: PMC4752296  PMID: 26871709
21.  Variable versus conventional lung protective mechanical ventilation during open abdominal surgery: study protocol for a randomized controlled trial 
Trials  2014;15:155.
General anesthesia usually requires mechanical ventilation, which is traditionally accomplished with constant tidal volumes in volume- or pressure-controlled modes. Experimental studies suggest that the use of variable tidal volumes (variable ventilation) recruits lung tissue, improves pulmonary function and reduces systemic inflammatory response. However, it is currently not known whether patients undergoing open abdominal surgery might benefit from intraoperative variable ventilation.
The PROtective VARiable ventilation trial (‘PROVAR’) is a single center, randomized controlled trial enrolling 50 patients who are planning for open abdominal surgery expected to last longer than 3 hours. PROVAR compares conventional (non-variable) lung protective ventilation (CV) with variable lung protective ventilation (VV) regarding pulmonary function and inflammatory response. The primary endpoint of the study is the forced vital capacity on the first postoperative day. Secondary endpoints include further lung function tests, plasma cytokine levels, spatial distribution of ventilation assessed by means of electrical impedance tomography and postoperative pulmonary complications.
We hypothesize that VV improves lung function and reduces systemic inflammatory response compared to CV in patients receiving mechanical ventilation during general anesthesia for open abdominal surgery longer than 3 hours. PROVAR is the first randomized controlled trial aiming at intra- and postoperative effects of VV on lung function. This study may help to define the role of VV during general anesthesia requiring mechanical ventilation.
Trial registration NCT01683578 (registered on September 3 3012).
PMCID: PMC4026052  PMID: 24885921
Mechanical ventilation; Variable ventilation; General anesthesia; Abdominal surgery; Lung protective ventilation; Pulmonary complications
22.  Assessment of intensive care unit‐acquired weakness in young and old mice: An E. coli septic peritonitis model 
Muscle & Nerve  2015;53(1):127-133.
Introduction: There are few reports of in vivo muscle strength measurements in animal models of ICU‐acquired weakness (ICU‐AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU‐AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU‐AW is age‐dependent in this model. Methods: Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined. Results: E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls. Conclusions: This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU‐AW. Muscle Nerve 53: 127–133, 2016
PMCID: PMC4744984  PMID: 26015329
animal model; critical illness myopathy; critical illness polyneuropathy; grip strength; intensive care unit‐acquired weakness
24.  Exhaled breath profiling for diagnosing acute respiratory distress syndrome 
The acute respiratory distress syndrome (ARDS) is a common, devastating complication of critical illness that is characterized by pulmonary injury and inflammation. The clinical diagnosis may be improved by means of objective biological markers. Electronic nose (eNose) technology can rapidly and non–invasively provide breath prints, which are profiles of volatile metabolites in the exhaled breath. We hypothesized that breath prints could facilitate accurate diagnosis of ARDS in intubated and ventilated intensive care unit (ICU) patients.
Prospective single-center cohort study with training and temporal external validation cohort. Breath of newly intubated and mechanically ventilated ICU-patients was analyzed using an electronic nose within 24 hours after admission. ARDS was diagnosed and classified by the Berlin clinical consensus definition. The eNose was trained to recognize ARDS in a training cohort and the diagnostic performance was evaluated in a temporal external validation cohort.
In the training cohort (40 patients with ARDS versus 66 controls) the diagnostic model for ARDS showed a moderate discrimination, with an area under the receiver–operator characteristic curve (AUC–ROC) of 0.72 (95%–confidence interval (CI): 0.63-0.82). In the external validation cohort (18 patients with ARDS versus 26 controls) the AUC–ROC was 0.71 [95%–CI: 0.54 – 0.87]. Restricting discrimination to patients with moderate or severe ARDS versus controls resulted in an AUC–ROC of 0.80 [95%–CI: 0.70 – 0.90]. The exhaled breath profile from patients with cardiopulmonary edema and pneumonia was different from that of patients with moderate/severe ARDS.
An electronic nose can rapidly and non–invasively discriminate between patients with and without ARDS with modest accuracy. Diagnostic accuracy increased when only moderate and severe ARDS patients were considered. This implicates that breath analysis may allow for rapid, bedside detection of ARDS, especially if our findings are reproduced using continuous exhaled breath profiling.
Trial registration
NTR2750, registered 11 February 2011.
PMCID: PMC4021554  PMID: 24767549
ARDS; Exhaled breath; Electronic nose; Volatile organic compound; Sensitivity and specificity
25.  Significant changes in the practice of chest radiography in Dutch intensive care units: a web-based survey 
ICU patients frequently undergo chest radiographs (CXRs). The diagnostic and therapeutic efficacy of routine CXRs are now known to be low, but the discussion regarding specific indications for CXRs in critically ill patients and the safety of abandoning routine CXRs is still ongoing. We performed a survey of Dutch intensivists on the current practice of chest radiography in their departments.
Web-based questionnaires, containing questions regarding ICU characteristics, ICU patients, daily CXR strategies, indications for routine CXRs and the practice of radiologic evaluation, were sent to the medical directors of all adult ICUs in the Netherlands. CXR strategies were compared between all academic and non-academic hospitals and between ICUs of different sizes. A comparison was made between the survey results obtained in 2006 and 2013.
Of the 83 ICUs that were contacted, 69 (83%) responded to the survey. Only 7% of responding ICUs were currently performing daily routine CXRs for all patients, and 61% of the responding ICUs were said never to perform CXRs on a routine basis. A daily meeting with a radiologist is an established practice in 72% of the responding ICUs and is judged to be important or even essential by those ICUs. The therapeutic efficacy of routine CXRs was assumed by intensivists to be lower than 10% or to be between 10 and 20%. The efficacy of ‘on-demand’ CXRs was assumed to be between 10 and 60%. There is a consensus between intensivists to perform a routine CXR after endotracheal intubation, chest tube placement or central venous catheterization.
The strategy of daily routine CXRs for critically ill and mechanically ventilated patients has turned from being a common practice in 2006 to a rare current practice. Other routine strategies and an ‘on-demand only’ strategy have become more popular. Intensivists still assume the value of CXRs to be higher than the efficacy that is reported in the literature.
PMCID: PMC4113284  PMID: 24708581
Chest radiography; Imaging; Intensive care

Results 1-25 (130)