Manual hyperinflation (MH), a frequently applied maneuver in critically ill intubated and mechanically ventilated patients, is suggested to mimic a cough so that airway secretions are mobilized toward the larger airways, where they can easily be removed. As such, MH could prevent plugging of the airways.
We performed a search in the databases of Medline, Embase, and the Cochrane Library from January 1990 to April 2012. We systematically reviewed the literature on evidence for postulated benefits and risks of MH in critically ill intubated and mechanically ventilated patients.
The search identified 50 articles, of which 19 were considered relevant. We included 13 interventional studies and six observational studies. The number of studies evaluating physiological effects of MH is limited. Trials differed too much to permit meta-analysis. It is uncertain whether MH was applied similarly in the retrieved studies. Finally, most studies are underpowered to show clinical benefit of MH. Use of MH is associated with short-term improvements in lung compliance, oxygenation, and secretion clearance, without changes in outcomes. MH has been reported to be associated with short-term and probably clinically insignificant side effects, including decreases in cardiac output, alterations of heart rates, and increased central venous pressures.
Studies have failed to show that MH benefits critically ill intubated and mechanically ventilated patients. MH is infrequently associated with short-term side effects.
Acute respiratory distress syndrome (ARDS) is a potentially fatal disease with high mortality. Our aim was to summarize the current evidence for use of neuromuscular blocking agents (NMBA) in the early phase of ARDS.
Systematic review and meta-analysis of publications between 1966 and 2012. The Medline and CENTRAL databases were searched for studies on NMBA in patients with ARDS. The meta-analysis was limited to: 1) randomized controlled trials; 02) adult human patients with ARDS or acute lung injury; and 03) use of any NMBA in one arm of the study compared with another arm without NMBA. The outcomes assessed were: overall mortality, ventilator-free days, time of mechanical ventilation, adverse events, changes in gas exchange, in ventilator settings, and in respiratory mechanics.
Three randomized controlled trials covering 431 participants were included. Patients treated with NMBA showed less mortality (Risk ratio, 0.71 [95 % CI, 0.55 – 0.90]; number needed to treat, 1 – 7), more ventilator free days at day 28 (p = 0.020), higher PaO2 to FiO2 ratios (p = 0.004), and less barotraumas (p = 0.030). The incidence of critical illness neuromyopathy was similar (p = 0.540).
The use of NMBA in the early phase of ARDS improves outcome.
ARDS; Neuromuscular blocking agents; Meta-analysis; Review
The role and source of tissue factor
To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.
Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.
There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.
The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.
Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.
Prospectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.
We analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively.
Mild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality
Patients with diabetes mellitus (DM) form 23–30% of published cohorts of critically ill patients. Conflicting published evidence links DM to both higher and lower mortality. Other cohort studies have suggest that DM protects against acute lung injury (ALI). We hypothesized that DM is an independent risk factor for mortality. We further hypothesized that DM is a risk factor for cardiac overload (CO) and not for ALI.
Retrospective cohort study.
The intensive care unit (ICU) of a tertiary referral hospital.
From 1 November 2004 to 1 October 2007, a cohort of patients admitted ≥48h to the ICU.
Measurements and Main Results
Of 2,013 patients, 317 had DM. Ninety-day mortality was higher in the DM patients compared to patients without DM (hazard ratio [HR] 1.53, 95% confidence interval 1.29–1.80). This association strengthened after adjusting for confounders and for medication (HR 1.53, 1.07–2.17). We found no association between DM and ALI (relative risk ratio [RRR] 1.01, 0.78–1.32; adjusted RRR 0.99, 0.75–1.31), but DM was a risk factor for CO (RRR 1.91, 1.30–2.81; adjusted RRR 1.45, 0.97–2.18). Statins were associated with both a reduced risk of mortality (HR 0.74, 0.63–0.87; adjusted HR 0.53, 0.44–0.64) and a decreased risk of developing ALI (RRR 0.71, 0.56–0.89; adjusted RRR 0.61, 0.47–0.79).
DM is an independent risk factor for mortality in critically ill patients and failure to adjust for statins underestimates the size of this association. DM is not associated with ALI but is associated with CO. A diagnosis of CO excludes a diagnosis of ALI. Investigators who do not account for CO as a competing alternative outcome may therefore falsely conclude that DM protects from ALI.
diabetes mellitus; intensive care; acute lung injury; acute respiratory distress syndrome; mortality; heart failure; hydroxymethylglutaryl-CoA reductase inhibitors; confounding factors (epidemiology); multinomial logistic regression; Cox regression
Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.
Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLERISK days, RIFLEINJURY days, and RIFLEFAILURE days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27–0.63) and 0.53 (CI 0.38–0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33–0.62) and 0.48 (CI 0.33–0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37–0.58) and 0.26 (CI 0.03–0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.
Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.
Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.
Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.
Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.
The Australian Clinical Trials Registry (ACTR-12608000121369).
Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value.
A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia.
Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of-disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR.
The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers.
Soluble uPAR; Soluble urokinase plasminogen activator receptor (suPAR); Biomarker; Intensive care; Critical illness; Sepsis
There is evidence that percutaneous dilatational tracheotomy (PDT) can be safely performed in patients with severe coagulation disorders if these are carefully corrected immediately before the procedure. However, it is currently unclear whether PDT can be performed safely in patients in an Intensive Care Unit (ICU) with uncorrected mild coagulation disorders.
Materials and methods
In a randomised controlled trial we determined the effect of correction of mild coagulation disorders on bleeding during and after PDT. ICU patients planned for bedside PDT with: (i) a prothrombin time (PT) between 14.7–20.0 seconds, (ii) a platelet count between 40–100×109/L and/or (iii) active treatment with acetylsalicylic acid were randomised to receive infusion with fresh-frozen plasma (FFP) and/or platelets (“correction”) versus no transfusion (“no correction”) before PDT.
We randomised 35 patients to the “correction” group and 37 patients to the “no correction” group. In patients who received FFP, the decrease in PT was marginal (mean decrease 0.40±0.56 seconds); the median increase in platelet counts after transfusion of platelets was 35 [11–47]x109/L. The median blood loss was 3 [IQR: 1–6] grams in the “correction” group and 3 [IQR: 2–6] grams in the “no correction” group (P=0.96).
Bleeding during and after bedside PDT in ICU patients with mild coagulation disorders is rare in our setting. Correction of subclinical coagulation disorders by transfusion of FFP and/or platelets does not affect bleeding.
percutaneous tracheostomy; coagulation disorders; transfusion
To provide clinicians practicing in resource-limited settings with a framework to improve the diagnosis and treatment of pediatric and adult patients with sepsis.
The medical literature on sepsis management was reviewed. Specific attention was paid to identify clinical evidence on sepsis management from resource-limited settings.
Recommendations are grouped into acute and post-acute interventions. Acute interventions include liberal fluid resuscitation to achieve adequate tissue perfusion, normal heart rate and arterial blood pressure, use of epinephrine or dopamine for inadequate tissue perfusion despite fluid resuscitation, frequent measurement of arterial blood pressure in hemodynamically unstable patients, administration of hydrocortisone or prednisolone to patients requiring catecholamines, oxygen administration to achieve an oxygen saturation >90%, semi-recumbent and/or lateral position, non-invasive ventilation for increased work of breathing or hypoxemia despite oxygen therapy, timely administration of adequate antimicrobials, thorough clinical investigation for infectious source identification, fluid/tissue sampling and microbiological work-up, removal, drainage or debridement of the infectious source. Post-acute interventions include regular re-assessment of antimicrobial therapy, administration of antimicrobials for an adequate but not prolonged duration, avoidance of hypoglycemia, pharmacological or mechanical deep vein thrombosis prophylaxis, resumption of oral food intake after resuscitation and regaining of consciousness, careful use of opioids and sedatives, early mobilization, and active weaning of invasive support. Specific considerations for malaria, puerperal sepsis and HIV/AIDS patients with sepsis are included.
Only scarce evidence exists for the management of pediatric and adult sepsis in resource-limited settings. The presented recommendations may help to improve sepsis management in middle- and low-income countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2468-5) contains supplementary material, which is available to authorized users.
Sepsis; Intensive care; Resource-limited settings; Middle-income countries; Low-income countries; Recommendations; Management
Preventing tissue-factor-(TF-) mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI). We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI.
Heterozygous TF knockout (TF+/−) mice and their wild-type (TF+/+) littermates were sedated (controls) or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours.
Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF+/+ mice, TF+/− mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF+/− and TF+/+ mice. Notably, pulmonary levels of cytokines were significantly higher in TF+/− as compared to TF+/+ mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators.
Hypoglycemia is associated with increased mortality in critically ill patients. The impact of hypoglycemia on resource utilization has not been investigated. The objective of this investigation was to evaluate the association of hypoglycemia, defined as a blood glucose concentration (BG) < 70 mg/dL, and intensive care unit (ICU) length of stay (LOS) in three different cohorts of critically ill patients.
This is a retrospective investigation of prospectively collected data, including patients from two large observational cohorts: 3,263 patients admitted to Stamford Hospital (ST) and 2,063 patients admitted to three institutions in The Netherlands (NL) as well as 914 patients from the GLUCONTROL trial (GL), a multicenter prospective randomized controlled trial of intensive insulin therapy.
Patients with hypoglycemia were more likely to be diabetic, had higher APACHE II scores, and higher mortality than did patients without hypoglycemia. Patients with hypoglycemia had longer ICU LOS (median [interquartile range]) in ST (3.0 [1.4-7.1] vs. 1.2 [0.8-2.3] days, P < 0.0001), NL (5.2 [2.6-10.3] vs. 2.0 [1.3-3.2] days, P < 0.0001), and GL (9 [5-17] vs. 5 [3-9] days, P < 0.0001). For the entire cohort of 6,240 patients ICU LOS was 1.8 (1.0-3.3) days for those without hypoglycemia and 3.0 (1.5-6.7) days for those with a single episode of hypoglycemia (P < 0.0001). This was a consistent finding even when patients were stratified by severity of illness or survivor status. There was a strong positive correlation between the number of episodes of hypoglycemia and ICU LOS among all three cohorts.
This multicenter international investigation demonstrated that hypoglycemia was consistently associated with significantly higher ICU LOS in heterogeneous cohorts of critically ill patients, independently of severity of illness and survivor status. More effective methods to prevent hypoglycemia in these patients may positively impact their cost of care.
hypoglycemia; intensive care unit; length of stay; resource utilization; APACHE II; mortality; intensive insulin therapy
Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LVT) or high tidal volumes (HVT). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HVT as compared to LVT. In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.
Glycemic control aiming at normoglycemia, frequently referred to as 'strict glycemic control' (SGC), decreased mortality and morbidity of adult critically ill patients in two randomized controlled trials (RCTs). Five successive RCTs, however, failed to show benefit of SGC with one trial even reporting an unexpected higher mortality. Consequently, enthusiasm for the implementation of SGC has declined, hampering translation of SGC into daily ICU practice. In this manuscript we attempt to explain the variances in outcomes of the RCTs of SGC, and point out other limitations of the current literature on glycemic control in ICU patients. There are several alternative explanations for why the five negative RCTs showed no beneficial effects of SGC, apart from the possibility that SGC may indeed not benefit ICU patients. These include, but are not restricted to, variability in the performance of SGC, differences among trial designs, changes in standard of care, differences in timing (that is, initiation) of SGC, and the convergence between the intervention groups and control groups with respect to achieved blood glucose levels in the successive RCTs. Additional factors that may hamper translation of SGC into daily ICU practice include the feared risk of severe hypoglycemia, additional labor associated with SGC, and uncertainties about who the primarily responsible caregiver should be for the implementation of SGC.
Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza.
To systematically review the medical literature on the association between glucose variability measures and mortality in critically ill patients.
Studies assessing the association between a measure of glucose variability and mortality that reported original data from a clinical trial or observational study on critically ill adult patients were searched in Ovid MEDLINE® and Ovid EMBASE®. Data on patient populations, study designs, glucose regulations, statistical approaches, outcome measures, and glucose variability indicators (their definition and applicability) were extracted.
Twelve studies met the inclusion criteria; 13 different indicators were used to measure glucose variability. Standard deviation and the presence of both hypo- and hyperglycemia were the most common indicators. All studies reported a statistically significant association between mortality and at least one glucose variability indicator. In four studies both blood glucose levels and severity of illness were considered as confounders, but only one of them checked model assumptions to assert inference validity.
Glucose variability has been quantified in many different ways, and in each study at least one of them appeared to be associated with mortality. Because of methodological limitations and the possibility of reporting bias, it is still unsettled whether and in which quantification this association is independent of other confounders. Future research will benefit from using an indicator reference subset for glucose variability, metrics that are linked more directly to negative physiological effects, more methodological rigor, and/or better reporting.
Blood glucose; Blood glucose variability; Glycemic control; Mortality; Systematic review
Mechanically ventilated critically ill patients frequently develop ventilator-associated pneumonia (VAP), a life-threatening complication. Proposed preventive measures against VAP include, but are not restricted to, selective decontamination of the digestive tract (SDD), selective oropharyngeal decontamination (SOD) and the use of probiotics. Probiotics are live bacteria that could have beneficial effects on the host by altering gastrointestinal flora. Similar to SDD and SOD, a prescription of probiotics aims at the prevention of secondary colonization of the upper and/or lower digestive tract.
We performed a literature review to describe the differences and similarities between SDD/SOD and probiotic preventive strategies, focusing on (a) efficacy, (b) risks, and (c) the routing of these strategies.
Reductions in the incidence of VAP have been achieved with SDD and SOD. Two large randomized controlled trials even showed reduced mortality with these preventive strategies. Randomized controlled trials of probiotic strategies also showed a reduction of the incidence of VAP, but trials were too small to draw firm conclusions. Preventive strategies with antibiotics and probiotics may be limited due to the risk of emerging resistance to the locally applied antibiotics and the risk of probiotic-related infections, respectively. The majority of trials of SDD and SOD did not exhaustively address the issue of emerging resistance. Likewise, trials of probiotic strategies did not adequately address the risk of colonization with probiotics and probiotic-related infection. In studies of SDD and SOD the preventive strategy aimed at decontamination of the oral cavity, throat, stomach and intestines, and the oral cavity and throat, respectively. In the vast majority of studies of probiotic therapy the preventive strategy aimed at decontamination of the stomach and intestines.
Prophylactic use of antibiotics in critically ill patients is effective in reducing the incidence of VAP. Probiotic strategies deserve consideration in future well-powered trials. Future studies are needed to determine if preventive antibiotic and probiotic strategies are safe with regard to development of antibiotic resistance and probiotic infections. It should be determined whether the efficacy of probiotics improves when these agents are provided to the mouth and the intestines simultaneously.
Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation.
Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O (‘low’ tidal volume ∼7.5 ml/kg; LVT) or 18 cmH2O (‘high’ tidal volume ∼15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal). Non-ventilated mice served as controls.
HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1β caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression.
Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.
To evaluate whether cystatin C in serum (sCyC) and urine (uCyC) can predict early acute kidney injury (AKI) in a mixed heterogeneous intensive care unit (ICU), and also whether these biomarkers can predict the need for renal replacement therapy (RRT).
Multicenter prospective observational cohort study in patients ≥18 years old and with expected ICU stay ≥72 h. The RIFLE class for AKI was calculated daily, while sCyC and uCyC were determined on days 0, 1, and alternate days until ICU discharge. Test characteristics were calculated to assess the diagnostic performance of CyC.
One hundred fifty-one patients were studied, and three groups were defined: group 0 (N = 60), non-AKI; group 1 (N = 35), AKI after admission; and group 2 (N = 56), AKI at admission. We compared the two days prior to developing AKI from group 1 with the first two study days from group 0. On Day –2, median sCyC was significantly higher (0.93 versus 0.80 mg/L, P = 0.01), but not on Day –1 (0.98 versus 0.86 mg/L, P = 0.08). The diagnostic performance for sCyC was fair on Day –2 [area under the curve (AUC) 0.72] and poor on Day –1 (AUC 0.62). Urinary CyC had no diagnostic value on either of the two days prior to AKI (AUC <0.50). RRT was started in 14 patients with AKI; sCyC and uCyC determined on Day 0 were poor predictors for the need for RRT (AUC ≤0.66).
In this study, sCyC and uCyC were poor biomarkers for prediction of AKI and the need for RRT.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-2087-y) contains supplementary material, which is available to authorized users.
Urine cystatin C; Serum cystatin C; Acute kidney injury; Renal replacement therapy; Predictive biomarkers; Intensive care unit