The effects of tidal volume size and driving pressure levels on pulmonary complement activation: an observational study in critically ill patients.

BACKGROUND: Mechanical ventilation can induce or even worsen lung injury, at least in part via overdistension caused by too large volumes or too high pressures. The complement system has been suggested to play a causative role in ventilator-induced lung injury. AIMS AND METHODS: This was a single-center prospective study investigating associations between pulmonary levels of complement activation products and two ventilator settings, tidal volume (VT) and driving pressure (ΔP), in critically ill patients under invasive ventilation. A miniature bronchoalveolar lavage (BAL) was performed for determination of pulmonary levels of C5a, C3b/c, and C4b/c. The primary endpoint was the correlation between BAL fluid (BALF) levels of C5a and VT and ΔP. Levels of complement activation products were also compared between patients with and without ARDS or with and without pneumonia. RESULTS: Seventy-two patients were included. Median time from start of invasive ventilation till BAL was 27 [19 to 34] hours. Median VT and ΔP before BAL were 6.7 [IQR 6.1 to 7.6] ml/kg predicted bodyweight (PBW) and 15 [IQR 11 to 18] cm H2O, respectively. BALF levels of C5a, C3b/c and C4b/c were neither different between patients with or without ARDS, nor between patients with or without pneumonia. BALF levels of C5a, and also C3b/c and C4b/c, did not correlate with VT and ΔP. Median BALF levels of C5a, C3b/c, and C4b/c, and the effects of VT and ΔP on those levels, were not different between patients with or without ARDS, and in patients with or without pneumonia. CONCLUSION: In this cohort of critically ill patients under invasive ventilation, pulmonary levels of complement activation products were independent of the size of VT and the level of ΔP. The associations were not different for patients with ARDS or with pneumonia. Pulmonary complement activation does not seem to play a major role in VILI, and not even in lung injury per se, in critically ill patients under invasive ventilation.

Pulmonary complement depositions in autopsy of critically ill patients have no relation with ARDS.

BACKGROUND: The complement system has frequently been suggested to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS). The current study explored the association between pulmonary depositions of a complement activation product and the clinical diagnosis of ARDS. METHODS: Lung tissue material from autopsied critically ill patients who died whilst on invasively mechanical ventilation was collected and stained for complement C3d. The diagnosis of ARDS was by the Berlin Definition. Lung injury scores (LIS) and driving pressures were calculated, 48 and 24 h prior to death. A pathologist who remained blinded for the clinical data scored the extent of C3d depositions, using a C3d deposition score (a minimum and maximum score of 0 and 24), and of diffuse alveolar damage (DAD). The primary analysis focused on the association between the C3d deposition score and the clinical diagnosis of ARDS. Secondary analyses focused on associations between the C3d deposition score and the presence of diffuse alveolar damage (DAD) in histopathology, and LIS and driving pressures in the last 2 days before death. RESULTS: Of 36 patients of whom autopsy material was available, 12 were diagnosed as having had ARDS. In all patients, C3d depositions were found in various parts of the lungs, and to a different extent. Notably, C3d deposition scores were similar for patients with ARDS and those without ARDS (4.5 [3.3-6.8] vs. 5.0 [4.0-6.0]; not significant). C3d deposition scores were also independent from the presence or absence of DAD, and correlations between C3d scores and LIS and driving pressures prior to death were poor. CONCLUSION: Pulmonary C3d depositions are found in the lungs of all deceased ICU patients, independent of the diagnosis of ARDS. The presence of complement C3d was not associated with the presence of DAD on histopathology and had a poor correlation with ventilation characteristics prior to death.

Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study.

BACKGROUND: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin-angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. METHODS: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days-18 years), 26 adults (18-65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. RESULTS: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. CONCLUSIONS: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.

No association between systemic complement activation and intensive care unit-acquired weakness.

BACKGROUND: The main risk factors for intensive care unit-acquired weakness (ICU-AW) are sepsis, the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction. These risk factors are associated with systemic complement activation. We hypothesized that critically ill patients who develop ICU-AW have increased systemic complement activation compared to critically ill patients who do not develop ICU-AW. METHODS: Complement activation products C3b/c, C4b/c and C5a were measured in plasma of ICU patients with mechanical ventilation for ≥48 hours. Samples were collected at admission to the ICU and for 6 consecutive days. ICU-AW was defined by a mean Medical Research Council (MRC) score <4. We compared the level of complement activation products between patients who did and who did not develop ICU-AW. RESULTS: Muscle strength measurements and complement assays were available in 27 ICU patients, of whom 13 patients developed ICU-AW. Increased levels of C4b/c were seen in all patients. Neither admission levels, nor maximum, minimum and mean levels of complement activation products were different between patients who did and did not develop ICU-AW. CONCLUSIONS: Complement activation is seen in critically ill patients, but is not different between patients who did and who did not develop ICU-AW.

Plasma suPAR as a prognostic biological marker for ICU mortality in ARDS patients.

PURPOSE: We investigated the prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) on day 1 in patients with the acute respiratory distress syndrome (ARDS) for intensive care unit (ICU) mortality and compared it with established disease severity scores on day 1. METHODS: suPAR was determined batchwise in plasma obtained within 24 h after admission. RESULTS: 632 ARDS patients were included. Significantly (P = 0.02) higher median levels of suPAR were found with increasing severity of ARDS: 5.9 ng/ml [IQR 3.1-12.8] in mild ARDS (n = 82), 8.4 ng/ml [IQR 4.1-15.0] in moderate ARDS (n = 333), and 9.0 ng/ml [IQR 4.5-16.0] in severe ARDS (n = 217). Non-survivors had higher median levels of suPAR [12.5 ng/ml (IQR 5.1-19.5) vs. 7.4 ng/ml (3.9-13.6), P < 0.001]. The area under the receiver operator characteristic curve (ROC-AUC) for mortality of suPAR (0.62) was lower than the ROC-AUC of the APACHE IV score (0.72, P = 0.007), higher than that of the ARDS definition classification (0.53, P = 0.005), and did not differ from that of the SOFA score (0.68, P = 0.07) and the oxygenation index (OI) (0.58, P = 0.29). Plasma suPAR did not improve the discrimination of the established disease severity scores, but did improve net reclassification of the APACHE score (29%), SOFA score (23%), OI (38%), and Berlin definition classification (39%). CONCLUSION: As a single biological marker, the prognostic value for death of plasma suPAR in ARDS patients is low. Plasma suPAR, however, improves the net reclassification, suggesting a potential role for suPAR in ICU mortality prediction models.

Mechanical ventilation with heliox in an animal model of acute respiratory distress syndrome.

BACKGROUND: Heliox has a lower density and higher diffusion capacity compared to oxygen-in-air. We hypothesized that heliox ventilation allows for a reduction in minute volume ventilation and inspiratory pressures needed for adequate gas exchange in an animal model of an acute lung injury. METHODS: After intratracheal instillation of lipopolysaccharide (10 mg/kg), adult rats were randomized to ventilation with either a gas mixture of helium/oxygen (50:50%) or oxygen/air (50:50%). They were mechanically ventilated according to the ARDSnet recommendations with tidal volumes of 6 ml/kg and monitored with a pneumotachometer. Bronchoalveolar lavage fluid was analyzed for markers of lung injury, and embedded lung sections were histologically scored for lung injury. RESULTS: Heliox limited the increase in driving pressures needed to achieve preset tidal volumes, with a concomitant decrease in loss of compliance. Heliox did neither allow for reduced minute volume ventilation in this model nor improve gas exchange. Also, heliox did not reduce lung injury. CONCLUSIONS: Heliox modestly improved respiratory mechanics but did not improve lung injury in this rat model of acute respiratory distress syndrome.

Heliox allows for lower minute volume ventilation in an animal model of ventilator-induced lung injury.

BACKGROUND: Helium is a noble gas with a low density, allowing for lower driving pressures and increased carbon dioxide (CO2) diffusion. Since application of protective ventilation can be limited by the development of hypoxemia or acidosis, we hypothesized that therefore heliox facilitates ventilation in an animal model of ventilator-induced lung injury. METHODS: Sprague-Dawley rats (N=8 per group) were mechanically ventilated with heliox (50% oxygen; 50% helium). Controls received a standard gas mixture (50% oxygen; 50% air). VILI was induced by application of tidal volumes of 15 mL kg(-1); lung protective ventilated animals were ventilated with 6 mL kg(-1). Respiratory parameters were monitored with a pneumotach system. Respiratory rate was adjusted to maintain arterial pCO2 within 4.5-5.5 kPa, according to hourly drawn arterial blood gases. After 4 hours, bronchoalveolar lavage fluid (BALF) was obtained. Data are mean (SD). RESULTS: VILI resulted in an increase in BALF protein compared to low tidal ventilation (629 (324) vs. 290 (181) µg mL(-1); p<0.05) and IL-6 levels (640 (8.7) vs. 206 (8.7) pg mL(-1); p<0.05), whereas cell counts did not differ between groups after this short course of mechanical ventilation. Ventilation with heliox resulted in a decrease in mean respiratory minute volume ventilation compared to control (123 ± 0.6 vs. 146 ± 8.9 mL min(-1), P<0.001), due to a decrease in respiratory rate (22 (0.4) vs. 25 (2.1) breaths per minute; p<0.05), while pCO2 levels and tidal volumes remained unchanged, according to protocol. There was no effect of heliox on inspiratory pressure, while compliance was reduced. In this mild lung injury model, heliox did not exert anti-inflammatory effects. CONCLUSIONS: Heliox allowed for a reduction in respiratory rate and respiratory minute volume during VILI, while maintaining normal acid-base balance. Use of heliox may be a useful approach when protective tidal volume ventilation is limited by the development of severe acidosis.

Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients.

OBJECTIVES: Correct classification of the source of infection is important in observational and interventional studies of sepsis. Centers for Disease Control and Prevention criteria are most commonly used for this purpose, but the robustness of these definitions in critically ill patients is not known. We hypothesized that in a mixed ICU population, the performance of these criteria would be generally reduced and would vary among diagnostic subgroups. DESIGN: Prospective cohort. SETTING: Data were collected as part of a cohort of 1,214 critically ill patients admitted to two hospitals in The Netherlands between January 2011 and June 2011. PATIENTS: Eight observers assessed a random sample of 168 of 554 patients who had experienced at least one infectious episode in the ICU. Each patient was assessed by two randomly selected observers who independently scored the source of infection (by affected organ system or site), the plausibility of infection (rated as none, possible, probable, or definite), and the most likely causative pathogen. Assessments were based on a post hoc review of all available clinical, radiological, and microbiological evidence. The observed diagnostic agreement for source of infection was classified as partial (i.e., matching on organ system or site) or complete (i.e., matching on specific diagnostic terms), for plausibility as partial (2-point scale) or complete (4-point scale), and for causative pathogens as an approximate or exact pathogen match. Interobserver agreement was expressed as a concordant percentage and as a kappa statistic. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 206 infectious episodes were observed. Agreement regarding the source of infection was 89% (183/206) and 69% (142/206) for a partial and complete diagnostic match, respectively. This resulted in a kappa of 0.85 (95% CI, 0.79-0.90). Agreement varied from 63% to 91% within major diagnostic categories and from 35% to 97% within specific diagnostic subgroups, with the lowest concordance observed in cases of ventilator-associated pneumonia. In the 142 episodes for which a complete match on source of infection was obtained, the interobserver agreement for plausibility of infection was 83% and 65% on a 2- and 4-point scale, respectively. For causative pathogen, agreement was 78% and 70% for an approximate and exact pathogen match, respectively. CONCLUSIONS: Interobserver agreement for classifying sources of infection using Centers for Disease Control and Prevention criteria was excellent overall. However, full concordance on all aspects of the diagnosis between independent observers was rare for some types of infection, in particular for ventilator-associated pneumonia.

A short course of infusion of a hydrogen sulfide-donor attenuates endotoxemia induced organ injury via stimulation of anti-inflammatory pathways, with no additional protection from prolonged infusion.

Organ failure is associated with increased mortality and morbidity in patients with systemic inflammatory response syndrome. Previously, we showed that a short course of infusion of a hydrogen sulfide (H(2)S) donor reduced metabolism with concurrent reduction of lung injury. Here, we hypothesize that prolonged H(2)S infusion is more protective than a short course in endotoxemia with organ failure. Also, as H(2)S has both pro- and anti-inflammatory effects, we explored the effect of H(2)S on interleukin production. Endotoxemia was induced by an intravenous bolus injection of LPS (7.5mg/kg) in mechanically ventilated rats. H(2)S donor NaHS (2mg/kg) or vehicle (saline) was infused and organ injury was determined after either 4 or 8h. A short course of H(2)S infusion was associated with reduction of lung and kidney injury. Prolonged infusion did not enhance protection. Systemically, infusion of H(2)S increased both the pro-inflammatory response during endotoxemia, as demonstrated by increased TNF-α levels, as well as the anti-inflammatory response, as demonstrated by increased IL-10 levels. In LPS-stimulated whole blood of healthy volunteers, co-incubation with H(2)S had solely anti-inflammatory effects, resulting in decreased TNF-α levels and increased IL-10 levels. Co-incubation with a neutralizing IL-10 antibody partly abrogated the decrease in TNF-α levels. In conclusion, a short course of H(2)S infusion reduced organ injury during endotoxemia, at least in part via upregulation of IL-10.