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2.  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.
doi:10.1186/cc13921
PMCID: PMC4078395  PMID: 25041718
3.  PReVENT - protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial 
Trials  2015;16:226.
Background
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.
Methods/Design
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.
Discussion
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 www.clinicaltrials.gov under reference number NCT02153294 on 23 May 2014.
doi:10.1186/s13063-015-0759-1
PMCID: PMC4453265  PMID: 26003545
Mechanical ventilation; Ventilator-induced lung injury; Tidal volume; Respiratory rate; Protective ventilation; Intensive care unit; Critical care; Non injured lungs
4.  Impact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study 
Critical Care  2015;19(1):196.
Introduction
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.
Method
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.
Results
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).
Conclusion
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.
doi:10.1186/s13054-015-0937-2
PMCID: PMC4427976  PMID: 25928709
5.  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.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s13054-015-0755-6
PMCID: PMC4344786  PMID: 25887887
6.  Point accuracy and reliability of an interstitial continuous glucose-monitoring device in critically ill patients: a prospective study 
Critical Care  2015;19(1):34.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s13054-015-0757-4
PMCID: PMC4382831  PMID: 25652770
7.  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
8.  Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia 
Critical Care  2014;18(4):R162.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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
ClinicalTrials.gov NCT01020916, registered 25 November 2009
doi:10.1186/cc14002
PMCID: PMC4261599  PMID: 25078879
9.  Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s13613-014-0023-y
PMCID: PMC4240734  PMID: 25512878
Oxygen; Hyperoxia; Mechanical ventilation; Lung injury; Intensive care medicine; Questionnaire
10.  Glucose prediction by analysis of exhaled metabolites – a systematic review 
BMC Anesthesiology  2014;14:46.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1471-2253-14-46
PMCID: PMC4068184  PMID: 24963286
Glucose; Monitoring; Volatile organic compound; Breath
11.  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, http://ccforum.com/content/17/3/155
doi:10.1186/cc12537
PMCID: PMC3706766  PMID: 23767816
13.  Variable versus conventional lung protective mechanical ventilation during open abdominal surgery: study protocol for a randomized controlled trial 
Trials  2014;15:155.
Background
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.
Methods/Design
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.
Discussion
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
Clinicaltrials.gov NCT01683578 (registered on September 3 3012).
doi:10.1186/1745-6215-15-155
PMCID: PMC4026052  PMID: 24885921
Mechanical ventilation; Variable ventilation; General anesthesia; Abdominal surgery; Lung protective ventilation; Pulmonary complications
15.  Exhaled breath profiling for diagnosing acute respiratory distress syndrome 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2466-14-72
PMCID: PMC4021554  PMID: 24767549
ARDS; Exhaled breath; Electronic nose; Volatile organic compound; Sensitivity and specificity
16.  Significant changes in the practice of chest radiography in Dutch intensive care units: a web-based survey 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/2110-5820-4-10
PMCID: PMC4113284  PMID: 24708581
Chest radiography; Imaging; Intensive care
17.  HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial 
Trials  2014;15:91.
Background
Pulmonary coagulopathy is a hallmark of lung injury following inhalation trauma. Locally applied heparin attenuates lung injury in animal models of smoke inhalation. Whether local treatment with heparin benefits patients with inhalation trauma is uncertain. The present trial aims at comparing a strategy using frequent nebulizations of heparin with standard care in intubated and ventilated burn patients with bronchoscopically confirmed inhalation trauma.
Methods
The Randomized Controlled Trial Investigating the Efficacy and Safety of Nebulized HEParin versus Placebo in BURN Patients with Inhalation Trauma (HEPBURN) is an international multi-center, double-blind, placebo-controlled, two-arm study. One hundred and sixteen intubated and ventilated burn patients with confirmed inhalation trauma are randomized to nebulizations of heparin (the nebulized heparin strategy) or nebulizations of normal saline (the control strategy) every four hours for 14 days or until extubation, whichever comes first. The primary endpoint is the number of ventilator-free days, defined as days alive and breathing without assistance during the first 28 days, if the period of unassisted breathing lasts for at least 24 consecutive hours.
Discussion
As far as the authors know, HEPBURN is the first randomized, placebo-controlled trial, powered to investigate whether local treatment with heparin shortens duration of ventilation of intubated and ventilated burn patients with inhalation trauma.
Trial registration
NCT01773083 (http://www.clinicaltrials.gov), registered on 16 January 2013.
Recruiting. Randomisation commenced on 1 January 2014.
doi:10.1186/1745-6215-15-91
PMCID: PMC3987885  PMID: 24661817
Inhalation trauma; Pulmonary coagulopathy; Nebulization; Heparin; Mechanical ventilation
18.  Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria 
Malaria Journal  2014;13:91.
Background
Acute kidney injury (AKI) complicating severe Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (PfHRP2), as a measure of sequestered parasite burden, with AKI in severe malaria.
Methods
Admission plasma suPAR and PfHRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n = 137). Patients were stratified according to AKI severity based on admission creatinine clearance.
Results
A total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into ‘mild, ‘moderate’ and ‘severe’ AKI groups, respectively. Plasma suPAR and PfHRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and PfHRP2 concentrations were higher in patients who later required RRT (P <0.0001 and P = 0.0004, respectively). In a multivariate analysis, both increasing suPAR and PfHRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (β = 16.54 (95% CI 6.36-26.71) and β = 0.07 (0.02-0.11), respectively).
Conclusions
Both sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria.
doi:10.1186/1475-2875-13-91
PMCID: PMC3995633  PMID: 24618154
Acute kidney injury; Pathophysiology; Falciparum malaria; Soluble urokinase-type plasminogen activator receptor; Histidine rich protein-2
19.  Accuracy and limitations of continuous glucose monitoring using spectroscopy in critically ill patients 
Background
OptiScanner devices, continuous glucose monitoring devices that perform automated blood draws via a central venous catheter and create plasma through centrifugation, measure plasma glucose levels through mid-infrared spectroscopy at the bedside. The objective of this study was to determine accuracy and practicality of the devices in critically ill patients attempting glycemic control.
Methods
The plasma glucose level was measured by the devices and in comparative plasma samples using Yellow Springs Instrument (YSI) plasma analyzers. After adding several previously unrecognized interferences in the interference library, we reanalyzed the mid-infrared signals and compared the resulting plasma glucose level with the reference value. Results are presented in Clarke error grids, glucose prediction errors and Bland-Altman plots and expressed as correlation coefficients.
Results
We analyzed 463 comparative samples from 71 patients (median 6 (4 to 9) samples per patient). After calibrating the system, a Clarke error grid showed 100% of the values in zones A or B. The glucose predictor error demonstrated that 86% of the glucose values < 75 mg/dL were within ± 15 mg/dL of the YSI results and 95% ≥ 75 mg/dL were within 20% of the comparative YSI results. Bland-Altman plot showed a bias of −0.6 with limit of agreement of −24.6 to 23.3. The Pearson correlation coefficient was 0.93 and R2 was 0.87. In one third of the patients the devices had to be disconnected prematurely (that is before planned disconnection) because of repeated occlusion alarms suggesting blood draw errors.
Conclusion
The devices needed calibration for several previously unrecognized interferences. Thereafter, accuracy of the device to measure plasma glucose levels in ‘our cohort’ of critically ill patients improved, but external validation is highly recommended. The automated blood draw system of the devices needs further improvement to make this device of value for clinical use (trial registration (Netherlands Trial Register): NTR2864).
doi:10.1186/2110-5820-4-8
PMCID: PMC3975731  PMID: 24598381
Glucose; Spectroscopy; Point-of-care; Monitoring; ICU
20.  Choosing the correct metrics for glucose control 
Critical Care  2014;18(2):414.
doi:10.1186/cc13758
PMCID: PMC4056047  PMID: 25029332
21.  Neurofilaments as a plasma biomarker for ICU-acquired weakness: an observational pilot study 
Critical Care  2014;18(1):R18.
Introduction
Early diagnosis of intensive care unit – acquired weakness (ICU-AW) using the current reference standard, that is, assessment of muscle strength, is often hampered due to impaired consciousness. Biological markers could solve this problem but have been scarcely investigated. We hypothesized that plasma levels of neurofilaments are elevated in ICU-AW and can diagnose ICU-AW before muscle strength assessment is possible.
Methods
For this prospective observational cohort study, neurofilament levels were measured using ELISA (NfHSMI35 antibody) in daily plasma samples (index test). When patients were awake and attentive, ICU-AW was diagnosed using the Medical Research Council scale (reference standard). Differences and discriminative power (using the area under the receiver operating characteristic curve; AUC) of highest and cumulative (calculated using the area under the neurofilament curve) neurofilament levels were investigated in relation to the moment of muscle strength assessment for each patient.
Results
Both the index test and reference standard were available for 77 ICU patients. A total of 18 patients (23%) fulfilled the clinical criteria for ICU-AW. Peak neurofilament levels were higher in patients with ICU-AW and had good discriminative power (AUC: 0.85; 95% CI: 0.72 to 0.97). However, neurofilament levels did not peak before muscle strength assessment was possible. Highest or cumulative neurofilament levels measured before muscle strength assessment could not diagnose ICU-AW (AUC 0.59; 95% CI 0.37 to 0.80 and AUC 0.57; 95% CI 0.32 to 0.81, respectively).
Conclusions
Plasma neurofilament levels are raised in ICU-AW and may serve as a biological marker for ICU-AW. However, our study suggests that an early diagnosis of ICU-AW, before muscle strength assessment, is not possible using neurofilament levels in plasma.
Electronic supplementary material
The online version of this article (doi:10.1186/cc13699) contains supplementary material, which is available to authorized users.
doi:10.1186/cc13699
PMCID: PMC4057240  PMID: 24443841
22.  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
23.  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
24.  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
25.  Brain computer tomography in critically ill patients - a prospective cohort study 
BMC Medical Imaging  2012;12:34.
Background
Brain computer tomography (brain CT) is an important imaging tool in patients with intracranial disorders. In ICU patients, a brain CT implies an intrahospital transport which has inherent risks. The proceeds and consequences of a brain CT in a critically ill patient should outweigh these risks. The aim of this study was to critically evaluate the diagnostic and therapeutic yield of brain CT in ICU patients.
Methods
In a prospective observational study data were collected during one year on the reasons to request a brain CT, expected abnormalities, abnormalities found by the radiologist and consequences for treatment. An “expected abnormality” was any finding that had been predicted by the physician requesting the brain CT. A brain CT was “diagnostically positive”, if the abnormality found was new or if an already known abnormality was increased. It was “diagnostically negative” if an already known abnormality was unchanged or if an expected abnormality was not found. The treatment consequences of the brain CT, were registered as “treatment as planned”, “treatment changed, not as planned”, “treatment unchanged”.
Results
Data of 225 brain CT in 175 patients were analyzed. In 115 (51%) brain CT the abnormalities found were new or increased known abnormalities. 115 (51%) brain CT were found to be diagnostically positive. In the medical group 29 (39%) of brain CT were positive, in the surgical group 86 (57%), p 0.01. After a positive brain CT, in which the expected abnormalities were found, treatment was changed as planned in 33%, and in 19% treatment was changed otherwise than planned.
Conclusions
The results of this study show that the diagnostic and therapeutic yield of brain CT in critically ill patients is moderate. The development of guidelines regarding the decision rules for performing a brain CT in ICU patients is needed.
doi:10.1186/1471-2342-12-34
PMCID: PMC3584725  PMID: 23234494
Computer tomography; Critically ill; Brain imaging; Diagnostic value

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