Hypoxia directed migration of human naïve monocytes is associated with an attenuation of cytokine release: indications for a key role of CCL26.

BACKGROUND: Numerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed migration of naïve human monocytes and to identify responsible autocrine/paracrine factors. METHODS: Monocytes were isolated from peripheral blood mononuclear cells, transferred into chemotaxis chambers and subjected to a defined oxygen gradient with or without the addition of CCL26. Cell migration was recorded and secretome analyses were performed. RESULTS: Cell migration recordings revealed directed migration of monocytes towards the source of hypoxia. Analysis of the monocyte secretome demonstrated a reduced secretion of 70% (19/27) of the analyzed cytokines under hypoxic conditions. The most down-regulated factors were CCL26 (- 99%), CCL1 (- 95%), CX3CL1 (- 95%), CCL17 (- 85%) and XCL1 (- 83%). Administration of recombinant CCL26 abolished the hypoxia-induced directed migration of human monocytes, while the addition of CCL26 under normoxic conditions resulted in a repulsion of monocytes from the source of CCL26. CONCLUSIONS: Hypoxia induces directed migration of human monocytes in-vitro. Autocrine/paracrine released CCL26 is involved in the hypoxia-mediated monocyte migration and may represent a target molecule for the modulation of monocyte migration in-vivo.

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Enteral vs. parenteral nutrition in septic shock: are they equivalent?

PURPOSE OF REVIEW: The current review focuses on recent clinical evidence and updated guideline recommendations on the effects of enteral vs. parenteral nutrition in adult critically ill patients with (septic) shock. RECENT FINDIGS: The largest multicenter randomized-controlled trial showed that the route of nutrient supply was unimportant for 28-day and 90-day mortality, infectious morbidity and length of stay in mechanically ventilated patients with shock. The enteral route, however, was associated with lower macronutrient intake and significantly higher frequency of hypoglycemia and moderate-to-severe gastrointestinal complications. Integrating these findings into recent meta-analyses confirmed that the route per se has no effect on mortality and that interactions with (infectious) morbidity are inconsistent or questionable. SUMMARY: The strong paradigm of favoring the enteral over the parenteral route in critically ill patients has been challenged. As a consequence, updated guidelines recommend withholding enteral nutrition in patients with uncontrolled shock. It is still unclear, however, whether parenteral nutrition is advantageous in patients with shock although benefits are conceivable in light of less gastrointestinal complications. Thus far, no guideline has addressed indications for parenteral nutrition in these patients. By considering recent scientific evidence, specific guideline recommendations, and expert opinions, we present a clinical algorithm that may facilitate decision-making when feeding critically ill patients with shock.

Influence of pathogen and focus of infection on procalcitonin values in sepsis patients with bacteremia or candidemia.

BACKGROUND: This study aimed to evaluate the accuracy of procalcitonin (PCT) serum concentrations to diagnose Gram-negative bacteremia and the association of PCT serum concentrations with more specific pathogens and the focus of infection. METHODS: Secondary analysis of the prospectively collected patient-level dataset from a cluster randomized quality improvement trial was performed. The trial included sepsis patients with organ dysfunction treated in the participating intensive care units from 2011 to 2015. Test performance for the prediction of Gram-negative bacteremia was assessed by receiver operating curve analysis. Independent effects of specific pathogen groups and foci of infection on PCT concentrations were assessed by linear logistic regression models. RESULTS: Blood cultures (BC) and PCT concentrations had been taken in 4858 of 6561 documented patients. PCT was significantly higher in Gram-negative bacteremia compared to Gram-positive bacteremia or candidemia (p < 0.001). The area under the curve was 0.72 (95% confidence interval 0.71-0.74) for the prediction of Gram-negative bacteremia compared to all other blood culture results including negative blood cultures. The optimized cutoff value was 10 ng/ml (sensitivity 69%, specificity 35%). PCT differed significantly between specific groups of pathogens (p < 0.001) with highest concentrations in Escherichia coli, Streptococcus species and other Enterobacteriaceae. PCT was highest in urogenital followed by abdominal infection and lowest in respiratory infection (p < 0.001). In a linear regression model, Streptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT values independent of the pathogen. CONCLUSIONS: Serum PCT concentrations are higher in patients with Gram-negative bacteremia than in patients with Gram-positive bacteremia or candidemia. However, the discriminatory power of this difference is too low to guide therapeutic decisions. Variations in PCT serum concentrations are not determined solely by Gram-negative or Gram-positive bacteria but are also affected by distinct groups of pathogens and different foci of infection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01187134 . Registered on 23 August 2010.

Doxycycline protects human intestinal cells from hypoxia/reoxygenation injury: Implications from an in-vitro hypoxia model.

Intestinal ischemia/reperfusion (I/R) injury is a grave clinical emergency and associated with high morbidity and mortality rates. Based on the complex underlying mechanisms, a multimodal pharmacological approach seems necessary to prevent intestinal I/R injury. The antibiotic drug doxycycline, which exhibits a wide range of pleiotropic therapeutic properties, might be a promising candidate for also reducing I/R injury in the intestine. To investigate possible protective effects of doxycycline on intestinal I/R injury, human intestinal CaCo-2 cells were exposed to doxycycline at clinically relevant concentrations. In order to mimic I/R injury, CaCo-2 were thereafter subjected to hypoxia/reoxygenation by using our recently described two-enzyme in-vitro hypoxia model. Investigations of cell morphology, cell damage, apoptosis and hydrogen peroxide formation were performed 24h after the hypoxic insult. Hypoxia/reoxygenation injury resulted in morphological signs of cell damage, elevated LDH concentrations in the respective culture media (P<0.001) and increased protein expression of proapoptotic caspase-3 (P<0.05) in the intestinal cultures. These events were associated with increased levels hydrogen peroxide (P<0.001). Preincubation of CaCo-2 cells with different concentrations of doxycycline (5µM, 10µM, 50µM) reduced the hypoxia induced signs of cell damage and LDH release (P<0.001 for all concentrations). The reduction of cellular damage was associated with a reduced expression of caspase-3 (5µM, P<0.01; 10µM, P<0.01; 50µM, P<0.05), while hydrogen peroxide levels remained unchanged. In summary, doxycycline protects human intestinal cells from hypoxia/reoxygenation injury in-vitro. Further animal and clinical studies are required to prove the protective potential of doxycycline on intestinal I/R injury under in-vivo conditions.

Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Enteral nutrition (EN) is recommended as the preferred route for early nutrition therapy in critically ill adults over parenteral nutrition (PN). A recent large randomized controlled trial (RCT) showed no outcome differences between the two routes. The objective of this systematic review was to evaluate the effect of the route of nutrition (EN versus PN) on clinical outcomes of critically ill patients. METHODS: An electronic search from 1980 to 2016 was performed identifying relevant RCTs. Individual trial data were abstracted and methodological quality of included trials scored independently by two reviewers. The primary outcome was overall mortality and secondary outcomes included infectious complications, length of stay (LOS) and mechanical ventilation. Subgroup analyses were performed to examine the treatment effect by dissimilar caloric intakes, year of publication and trial methodology. We performed a test of asymmetry to assess for the presence of publication bias. RESULTS: A total of 18 RCTs studying 3347 patients met inclusion criteria. Median methodological score was 7 (range, 2-12). No effect on overall mortality was found (1.04, 95 % CI 0.82, 1.33, P = 0.75, heterogeneity I(2) = 11 %). EN compared to PN was associated with a significant reduction in infectious complications (RR 0.64, 95 % CI 0.48, 0.87, P = 0.004, I(2) = 47 %). This was more pronounced in the subgroup of RCTs where the PN group received significantly more calories (RR 0.55, 95 % CI 0.37, 0.82, P = 0.003, I(2) = 0 %), while no effect was seen in trials where EN and PN groups had a similar caloric intake (RR 0.94, 95 % CI 0.80, 1.10, P = 0.44, I(2) = 0 %; test for subgroup differences, P = 0.003). Year of publication and methodological quality did not influence these findings; however, a publication bias may be present as the test of asymmetry was significant (P = 0.003). EN was associated with significant reduction in ICU LOS (weighted mean difference [WMD] -0.80, 95 % CI -1.23, -0.37, P = 0.0003, I(2) = 0 %) while no significant differences in hospital LOS and mechanical ventilation were observed. CONCLUSIONS: In critically ill patients, the use of EN as compared to PN has no effect on overall mortality but decreases infectious complications and ICU LOS. This may be explained by the benefit of reduced macronutrient intake rather than the enteral route itself.

Functional Regions of Interest in Electrical Impedance Tomography: A Secondary Analysis of Two Clinical Studies.

INTRODUCTION: Patients with acute respiratory distress syndrome (ARDS) typically show a high degree of ventilation inhomogeneity, which is associated with morbidity and unfavorable outcomes. Electrical impedance tomography (EIT) is able to detect ventilation inhomogeneity, but it is unclear which method for defining the region of interest (ROI) should be used for this purpose. The aim of our study was to compare the functional region of interest (fROI) method to both the lung area estimation method (LAEM) and no ROI when analysing global parameters of ventilation inhomogeneity. We assumed that a good method for ROI determination would lead to a high discriminatory power for ventilation inhomogeneity, as defined by the area under the receiver operating characteristics curve (AUC), comparing patients suffering from ARDS and control patients without pulmonary pathologies. METHODS: We retrospectively analysed EIT data from 24 ARDS patients and 12 control patients without pulmonary pathology. In all patients, a standardized low-flow-pressure volume maneuver had been performed and was used for EIT image generation. We compared the AUC for global inhomogeneity (GI) index and coefficient of variation (CV) between ARDS and control patients using all EIT image pixels, the fROI method and the LAEM for ROI determination. RESULTS: When analysing all EIT image pixels, we found an acceptable AUC both for the GI index (AUC = 0.76; 95% confidence interval (CI) 0.58-0.94) and the CV (AUC = 0.74; 95% CI 0.55-0.92). With the fROI method, we found a deteriorating AUC with increasing threshold criteria. With the LAEM, we found the best AUC both for the GI index (AUC = 0.89; 95% CI 0.78-1.0) and the CV (AUC = 0.89; 95% CI 0.78-1.0) using a threshold criterion of 50% of the maximum tidal impedance change. CONCLUSION: In the assessment of ventilation inhomogeneity with EIT, functional regions of interest obscure the difference between patients with ARDS and control patients without pulmonary pathologies. The LAEM is preferable to the fROI method when assessing ventilation inhomogeneity.

When and how should sepsis patients be fed?

PURPOSE OF REVIEW: To provide an overview on the recent literature regarding metabolism during sepsis and outcome-related effects of nutrition therapy in septic patients. The question when and how these patients should be fed with respect to macronutrient intake is elaborated. RECENT FINDINGS: Although the incidence of severe sepsis has steadily increased over the past years, still no strong evidence is available with respect to the role of energy and protein provision in these patients. On the basis of recent large randomized trials in mixed patient populations, the updated sepsis guidelines recommend early but limited nutrition via the enteral route rather than targeted feeding. Lately, the results of a large trial challenged the importance of the route of feeding on the clinical outcome of critically ill patients. Four post-hoc analyses of prospective randomized trials including a large number of severely septic patients yielded conflicting results. One reported significant mortality reduction with near-target calorie and protein intake by exclusive enteral nutrition, whereas the second showed an advantage of enteral compared to combined nutrition, albeit resulting in a lower calorie and protein provision. The other two analyses found no association at all of either lower or higher daily caloric or protein intake, respectively, with clinical outcomes. SUMMARY: In the absence of strong clinical evidence, pathophysiological findings are discussed and nutritional strategies for septic patients derived. Future studies should explore the individual response to specific exogenous supply of macronutrients and micronutrients in the acute and persistent phase of severe systemic inflammation.

Acid sphingomyelinase serum activity predicts mortality in intensive care unit patients after systemic inflammation: a prospective cohort study.

INTRODUCTION: Acid sphingomyelinase is involved in lipid signalling pathways and regulation of apoptosis by the generation of ceramide and plays an important role during the host response to infectious stimuli. It thus has the potential to be used as a novel diagnostic marker in the management of critically ill patients. The objective of our study was to evaluate acid sphingomyelinase serum activity (ASM) as a diagnostic and prognostic marker in a mixed intensive care unit population before, during, and after systemic inflammation. METHODS: 40 patients admitted to the intensive care unit at risk for developing systemic inflammation (defined as systemic inflammatory response syndrome plus a significant procalcitonin [PCT] increase) were included. ASM was analysed on ICU admission, before (PCT before), during (PCT peak) and after (PCT low) onset of SIRS. Patients undergoing elective surgery served as control (N = 8). Receiver-operating characteristics curves were computed. RESULTS: ASM significantly increased after surgery in the eight control patients. Patients from the intensive care unit had significantly higher ASM on admission than control patients after surgery. 19 out of 40 patients admitted to the intensive care unit developed systemic inflammation and 21 did not, with no differences in ASM between these two groups on admission. In patients with SIRS and PCT peak, ASM between admission and PCT before was not different, but further increased at PCT peak in non-survivors and was significantly higher at PCT low compared to survivors. Survivors exhibited decreased ASM at PCT peak and PCT low. Receiver operating curve analysis on discrimination of ICU mortality showed an area under the curve of 0.79 for ASM at PCT low. CONCLUSIONS: In summary, ASM was generally higher in patients admitted to the intensive care unit compared to patients undergoing uncomplicated surgery. ASM did not indicate onset of systemic inflammation. In contrast to PCT however, it remained high in non-surviving ICU patients after systemic inflammation.

Elevation of procalcitonin after implantation of an interventional lung assist device in critically ill patients.

A pumpless interventional arteriovenous lung assist device (iLA) facilitates the removal of carbon dioxide from the blood and is used as part of the lung-protective ventilation strategy in patients with acute respiratory distress syndrome (ARDS). In case of bacterial infection, delayed antimicrobial therapy increases the mortality in this group of high-risk critically ill patients, whereas overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs. Besides clinical signs and symptoms, antimicrobial treatment is based on the kinetics of biomarkers such as procalcitonin (PCT). We hereby report an up to 10-fold increase in PCT serum concentrations in four mechanically ventilated patients with ARDS detected within 12-20 hours after iLA implantation in the absence of any infection. Procalcitonin concentrations returned to nearly baseline values in all patients on the fourth day after iLA implantation. We discuss the possible mechanisms of PCT induction in this specific patient population and recommend the onset of antibiotics administration after iLA implantation to be carefully considered in the context of other clinical findings and not solely based on the PCT kinetics. Repeated PCT measurements in short time intervals should be performed in these patients.

Dynamics of regional lung aeration determined by electrical impedance tomography in patients with acute respiratory distress syndrome.

BACKGROUND: Lung tissue of patients with acute respiratory distress syndrome (ARDS) is heterogeneously damaged and prone to develop atelectasis. During inflation, atelectatic regions may exhibit alveolar recruitment accompanied by prolonged filling with air in contrast to regions with already open alveoli with a fast increase in regional aeration. During deflation, derecruitment of injured regions is possible with ongoing loss in regional aeration. The aim of our study was to assess the dynamics of regional lung aeration in mechanically ventilated patients with ARDS and its dependency on positive end-expiratory pressure (PEEP) using electrical impedance tomography (EIT). METHODS: Twelve lung healthy and twenty ARDS patients were examined by EIT during sustained step increases in airway pressure from 0, 8 and 15 cm H2O to 35 cm H2O and during subsequent step decrease to the corresponding PEEP. Regional EIT waveforms in the ventral and dorsal lung regions were fitted to bi-exponential equations. Regional fast and slow respiratory time constants and the sizes of the fast and slow compartments were subsequently calculated. RESULTS: ARDS patients exhibited significantly lower fast and slow time constants than the lung healthy patients in ventral and dorsal regions. The time constants were significantly affected by PEEP and differed between the regions. The size of the fast compartment was significantly lower in ARDS patients than in patients with healthy lung under all studied conditions. CONCLUSION: These results show that regional lung mechanics can be assessed by EIT. They reflect the lower respiratory system compliance of injured lungs and imply more pronounced regional recruitment and derecruitment in ARDS patients.

Regional lung opening and closing pressures in patients with acute lung injury.

PURPOSE: In acute lung injury (ALI), the application of positive end-expiratory pressure (PEEP) is known to prevent the alveoli from cyclic collapse and reopening and to homogenize ventilation. The setting of adequate PEEP could be optimized by the knowledge of regional lung opening and closing pressures at the bedside. The aim of our study was to determine regional opening and closing pressures in ventilated patients by electrical impedance tomography (EIT). MATERIALS AND METHODS: Eight patients with healthy lungs and 18 patients with ALI were studied. A low-flow inflation and deflation maneuver with constant gas flow was performed. Regional opening and closing pressures were calculated for every pixel of the EIT scan. These pressures were defined as those values of global airway pressure at which the lung areas opened up or started to close. RESULTS: Injured lungs exhibited significantly higher regional opening pressures compared with healthy lungs (P < .05). In ALI, significantly higher opening pressures were found in the dependent lung regions. Regional closing pressures did not significantly differ between healthy and injured lungs. CONCLUSIONS: Regional lung opening and closing pressures can be assessed by EIT. This information may facilitate the setting of adequate PEEP levels in patients in future.