Higher levels of spontaneous breathing reduce lung injury in experimental moderate acute respiratory distress syndrome.

OBJECTIVES: To assess the effects of different levels of spontaneous breathing during biphasic positive airway pressure/airway pressure release ventilation on lung function and injury in an experimental model of moderate acute respiratory distress syndrome. DESIGN: Multiple-arm randomized experimental study. SETTING: University hospital research facility. SUBJECTS: Thirty-six juvenile pigs. INTERVENTIONS: Pigs were anesthetized, intubated, and mechanically ventilated. Moderate acute respiratory distress syndrome was induced by repetitive saline lung lavage. Biphasic positive airway pressure/airway pressure release ventilation was conducted using the airway pressure release ventilation mode with an inspiratory/expiratory ratio of 1:1. Animals were randomly assigned to one of four levels of spontaneous breath in total minute ventilation (n = 9 per group, 6 hr each): 1) biphasic positive airway pressure/airway pressure release ventilation, 0%; 2) biphasic positive airway pressure/airway pressure release ventilation, > 0-30%; 3) biphasic positive airway pressure/airway pressure release ventilation, > 30-60%, and 4) biphasic positive airway pressure/airway pressure release ventilation, > 60%. MEASUREMENTS AND MAIN RESULTS: The inspiratory effort measured by the esophageal pressure time product increased proportionally to the amount of spontaneous breath and was accompanied by improvements in oxygenation and respiratory system elastance. Compared with biphasic positive airway pressure/airway pressure release ventilation of 0%, biphasic positive airway pressure/airway pressure release ventilation more than 60% resulted in lowest venous admixture, as well as peak and mean airway and transpulmonary pressures, redistributed ventilation to dependent lung regions, reduced the cumulative diffuse alveolar damage score across lungs (median [interquartile range], 11 [3-40] vs 18 [2-69]; p < 0.05), and decreased the level of tumor necrosis factor-α in ventral lung tissue (median [interquartile range], 17.7 pg/mg [8.4-19.8] vs 34.5 pg/mg [29.9-42.7]; p < 0.05). Biphasic positive airway pressure/airway pressure release ventilation more than 0-30% and more than 30-60% showed a less consistent pattern of improvement in lung function, inflammation, and damage compared with biphasic positive airway pressure/airway pressure release ventilation more than 60%. CONCLUSIONS: In this model of moderate acute respiratory distress syndrome in pigs, biphasic positive airway pressure/airway pressure release ventilation with levels of spontaneous breath higher than usually seen in clinical practice, that is, more than 30% of total minute ventilation, reduced lung injury with improved respiratory function, as compared with protective controlled mechanical ventilation.

The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration.

INTRODUCTION: We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS). METHODS: In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 µg/kg/h) or intratracheally (bolus, 25 µg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB RESULTS: The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration. CONCLUSION: Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of ß2-agonists on clinical outcome in ARDS.

Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury.

BACKGROUND: Spontaneous breathing (SB) in the early phase of the acute respiratory distress syndrome is controversial. Biphasic positive airway pressure/airway pressure release ventilation (BIPAP/APRV) is commonly used, but the level of SB necessary to maximize potential beneficial effects is unknown. METHODS: Experimental acute respiratory distress syndrome was induced by saline lung lavage in anesthetized and mechanically ventilated pigs (n = 12). By using a Latin square and crossover design, animals were ventilated with BIPAP/APRV at four different levels of SB in total minute ventilation (60 min each): (1) 0% (BIPAP/APRV0%); (2) greater than 0 to 30% (BIPAP/APRV>0-30%); (3) greater than 30 to 60% (BIPAP/APRV>30-60%); and (4) greater than 60% (BIPAP/APRV>60%). Gas exchange, hemodynamics, and respiratory variables were measured. Lung aeration was assessed by high-resolution computed tomography. The distribution of perfusion was marked with Ga-labeled microspheres and evaluated by positron emission tomography. RESULTS: The authors found that higher levels of SB during BIPAP/APRV (1) improved oxygenation; (2) decreased mean transpulmonary pressure (stress) despite increased inspiratory effort; (3) reduced nonaerated lung tissue, with minimal changes in the distribution of perfusion, resulting in decreased low aeration/perfusion zones; and (4) decreased global strain (mean ± SD) (BIPAP/APRV0%: 1.39 ± 0.08; BIPAP/APRV0-30%: 1.33 ± 0.03; BIPAP/APRV30-60%: 1.27 ± 0.06; BIPAP/APRV>60%: 1.25 ± 0.04, P < 0.05 all vs. BIPAP/APRV0%, and BIPAP/APRV>60% vs. BIPAP/APRV0-30%). CONCLUSIONS: In a saline lung lavage model of experimental acute respiratory distress syndrome in pigs, levels of SB during BIPAP/APRV higher than currently recommended for clinical practice, that is, 10 to 30%, improve oxygenation by increasing aeration in dependent lung zones without relevant redistribution of perfusion. In presence of lung recruitment, higher levels of SB reduce global stress and strain despite an increase in inspiratory effort.

Effects of intravascular volume replacement on lung and kidney function and damage in nonseptic experimental lung injury.

BACKGROUND: Intravascular volume replacement is often required in the presence of increased pulmonary capillary leakage, for example in patients with volutrauma with major hemorrhage. In the present study, the effects of Ringer's acetate (RA), gelatin-polysuccinate (GEL), and a modern hydroxyethyl starch (HES, 6% 130/0.42) on lung and kidney function and damage were compared in a two-hit model of acute lung injury. The authors hypothesized that GEL and HES, compared to RA: (1) reduced lung histological damage, (2) impaired kidney morphology and function. METHODS: Acute lung injury was induced in 30 anesthetized pigs by tidal volumes approximately 40 ml/kg, after saline lung lavage. Protective ventilation was initiated and approximately≈25% of estimated blood volume was drawn. Animals were randomly assigned to receive RA, GEL, or HES (n = 10/group) aimed at approximately 90% of intrathoracic blood volume before blood drainage. RESULTS: Fluid volumes were higher with RA (2,250 ± 764 ml) than GEL (704 ± 159 ml) and HES (837 ± 82 ml) (P < 0.05). Compared to RA, HES reduced diffuse alveolar damage overall, and GEL in nondependent zones only. GEL and HES yielded lower wet-to-dry ratios compared to RA (6.5 ± 0.5 and 6.5 ± 0.6 vs. 7.9 ± 0.9, respectively, P < 0.05). HES and RA resulted in less kidney damage than GEL, but kidney function did not differ significantly among groups. Compared to GEL, HES yielded lower lung elastance (55 ± 12 vs. 45 ± 13 cm H2O/l, P < 0.05) and intra-abdominal pressure (15 ± 5 vs. 11 ± 4 cm 14;H2O, P < 0.05). CONCLUSIONS: In this model of acute lung injury, intravascular volume expansion after major hemorrhage with HES yielded less lung damage than RA and less kidney damage than GEL.

Forceps biopsy and suction catheter for sampling in pulmonary nodules and infiltrates.

Transbronchial lung biopsy with forceps is a standard procedure in bronchoscopic tissue sampling. Suction catheter aspiration is another technique, but it is not widely known and almost no data exist regarding its diagnostic efficiency. 272 patients were included in a prospective and randomised study between February 2007 and October 2009. All were referred for bronchoscopic evaluation of pulmonary nodules/masses or infiltrates. We compared the diagnostic yield of forceps biopsy and suction catheter aspiration for a definite diagnosis and looked at whether such a diagnosis depends on the underlying pulmonary change. All patients underwent bronchoscopy with forceps biopsy and catheter aspiration. A definitive diagnosis was reached in a total of 183 (67.3%) patients, with catheter aspiration in 140 (51.5%) patients and with forceps biopsy in 136 (50.0%) patients. In 90 (33.1%) patients, a definite diagnosis could only be reached with the combination of both techniques. The diagnostic yield of forceps biopsy was better than catheter aspiration in infiltrates (p = 0.027), but was no different in nodules or masses (p = 0.09). Suction catheter aspiration is a useful technique of bronchoscopic tissue sampling. The combination of catheter aspiration and forceps biopsy results in a higher diagnostic yield than either method used alone.

Pulmonary hypertension in chronic hypersensitivity pneumonitis.

BACKGROUND: The purpose of this study was to evaluate the prevalence and outcomes of pulmonary hypertension in chronic hypersensitivity pneumonitis and to examine the relationship between pulmonary function tests and pulmonary hypertension. METHODS: We conducted a retrospective review of 120 patients with hypersensitivity pneumonitis seen at two centers for pulmonary diseases over a 5-year interval and identified patients with chronic hypersensitivity pneumonitis for whom both pulmonary function tests and Doppler echocardiography data were available. RESULTS: Chronic hypersensitivity pneumonitis was identified in 83 patients and Doppler echocardiography data were available for 73 of them. Pulmonary hypertension (sPAP ≥ 50 mmHg) was detected in 14 patients (19%), and was associated with a greater risk of death (median survival = 23 months vs. 98 months; P=0.003). Patients with pulmonary hypertension were older and had a significantly decreased PaO(2). There was a weak correlation between pulmonary function parameters and the underlying sPAP, with significance for FVC, FEV(1), and PaO(2) and inversely with PaCO(2). CONCLUSIONS: Using Doppler echocardiography for evaluation, pulmonary hypertension seems to be common in patients with chronic hypersensitivity pneumonitis, significantly impacts survival, and correlates with FVC, FEV(1), and PaO(2) and inversely with PaCO(2).

Microcurrent transcutaneous electric nerve stimulation in painful diabetic neuropathy: a randomized placebo-controlled study.

OBJECTIVES: Diabetes is a common health care problem in western countries. Painful diabetic neuropathy (PDN) might be one of the consequences of long ongoing diabetes; it is estimated that approximately 20% of European diabetic patients suffer from PDN. Transcutaneous electrical nerve stimulation (TENS) is often used as additional pain treatment. However, recent studies show inconsistent results. We aimed to assess the effect of micro-TENS in reducing neuropathic pain in patients with PDN in a placebo-controlled, single-blinded, and randomized design. DESIGN/SETTING/PATIENTS/OUTCOME MEASURES: 22 diabetic patients have been treated with a micro-TENS therapy and 19 patients have been treated with a placebo therapy. Treatment duration was 4 weeks with three therapeutical settings per week. Standardized questionnaires (Pain Disability Index [PDI], neuropathic pain score [NPS], Center for Epidemiologic Studies Depression Scale [CES-D]) were used to assess pain intensity, pain disability, as well as quality of life at baseline at the end of the treatment period and 4 weeks after treatment termination. RESULTS: Patients with a minimum of 30% reduction in NPS were defined as therapy responders. After 4 weeks of treatment, 6/21 patients in the verum group vs 10/19 patients in the placebo group responded to therapy. The median PDI score after 4 weeks of treatment showed a reduction of 23% in the verum vs 25% in the placebo group. The differences did not reach statistical significance. CONCLUSIONS: The pain reduction with the applied transcutaneous electrotherapy regimen is not superior to a placebo treatment.

Benchmarking improves quality in cystic fibrosis care: a pilot project involving 12 centres.

OBJECTIVE: Health care quality monitoring has been introduced in cystic fibrosis (CF) by a few groups and national registries. Based upon this, continuous quality improvement can be achieved by applying the benchmarking method which is focused on learning from best practice. SETTING: A group of 12 CF centres in Germany, treating a total of 1200 patients of all ages, enrolled in a nationwide pilot benchmarking project from 2004 to 2007. INTERVENTION: Key nutritional and respiratory parameters were used as quality indicators. Numerical benchmarks were set and used for ranking. Applying the plan-do-check-act cycle, quality improvement interventions were introduced, such as harmonization of definitions and references, improvement of measurement standards, data quality, completion of missing data, enforcement of early aggressive antibiotic treatment and individual adaptation of dietary counselling. RESULTS: Ranking alone was not sufficient for identification of the best performing centres unless it was accompanied by longitudinal follow-up. Improvement was possible in the 3 years' period as shown by benchmarking for single centres that introduced new interventions in nutritional and antibiotic treatment most consequently. CONCLUSION: CF provides a model of the link between processes of health care delivery and health outcomes of patients. Quality improvement is a continuous goal in CF care with realistic potential as exemplified by our data. Accountability was introduced and transparency was improved by our pilot benchmarking project. Using the benchmarking procedure, our long-term project will reinforce standards, programmes, and individual attitudes and principles to ensure continuous quality improvement in CF health care.

Gastroenteropancreatic neuroendocrine tumors: standardizing therapy monitoring with 68Ga-DOTATOC PET/CT using the example of somatostatin receptor radionuclide therapy.

The purpose of this study was to standardize therapy monitoring of hepatic metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) during the course of somatostatin receptor radionuclide therapy (SRRT). In 21 consecutive patients with nonresectable hepatic metastases of GEP-NETs, chromogranin A (CgA) and 68Ga-DOTATOC PET/CT were compared before and after the last SRRT. On 68Ga-DOTATOC PET/CT, the maximum standard uptake values (SUVmax) of normal liver and hepatic metastases were calculated. In addition, the volumes of hepatic metastases (volume of interest [VOI]) were measured using four cut-offs to separate normal liver tissue from metastases (SUVmax of the normal liver plus 10% [VOIliver+10%], 20% [VOIliver+20%], 30% [VOIliver+30%] and SUV  =  10 [VOI10SUV]). The SUVmax of the normal liver was below 10 (7.2 ± 1.3) in all patients and without significant changes. Overall therapy changes (Δ) per patient (mean [95% CI]) were statistically significant with p < .01 for ΔCgA  =  -43 (-69 to -17), ΔSUVmax  =  -22 (-29 to-14), and ΔVOI10SUV  =  -53 (-68 to -38)% and significant with p < .05 for ΔVOIliver+10%  =  -29 (-55 to -3)%, ΔVOIliver+20%  =  -32 (-62 to -2) and ΔVOIliver+30%  =  -37 (-66 to -8). Correlations were found only between ΔCgA and ΔVOI10SUV (r  =  .595; p < .01), ΔSUVmax and ΔVOI10SUV (0.629, p < .01), and SUVmax and ΔSUVmax (r  =  -.446; p < .05). 68Ga-DOTATOC PET/CT allows volumetric therapy monitoring via an SUV-based cut-off separating hepatic metastases from normal liver tissue (10 SUV recommended).

Correlation of heart-type fatty acid-binding protein with mortality and echocardiographic data in patients with pulmonary embolism at intermediate risk.

BACKGROUND: The management strategy in patients presenting with pulmonary embolism at intermediate risk still remains controversial. Our aim was to determine the role of heart-type fatty acid-binding protein (H-FABP) in this patient population. METHODS: One hundred one consecutive patients with confirmed pulmonary embolism and echocardiographic signs of right ventricular overload but without evidence for hypotension or shock, referred to as pulmonary embolism at intermediate risk, were included in the study. Heart-type fatty acid-binding protein and other biomarkers were measured in all patients upon arrival in the emergency department. RESULTS: Of the included 101 patients, 14 had positive H-FABP tests. Ten patients with positive H-FABP (71%) had clinical deterioration during the hospital course and required inotropic support and 8 of these patients died. None of the 87 patients with a negative test worsened or needed inotropic support or died during hospital stay (P < .005). In the H-FABP-positive group, right ventricular function on echocardiography was more impaired (tricuspid annular plane systolic excursion 13 +/- 4 vs 18 +/- 4 mm, RV/LV ratio 1.1 +/- 0.2 vs 0.9 +/- 0.2, presence of paradoxical septal movement 79% vs 46%, presence of McConnell sign 100% vs 60%, respectively, all P < .05) compared to the H-FABP-negative group. After adjusting for potential confounding parameters, in multivariate analysis, H-FABP was the only independent predictor of mortality. CONCLUSIONS: Heart-type fatty acid-binding protein significantly predicts mortality in patients with pulmonary embolism at intermediate risk. Furthermore, it is significantly associated with impaired right ventricular function and shows better correlation with mortality than troponin I. It may be a novel prognostic parameter enabling the optimization of management strategy in the very difficult population of pulmonary embolism at intermediate risk.

Antigen-specific IgG antibodies in feather duvet lung.

BACKGROUND: Feather duvet lung (FDL) is a rare subgroup of bird fancier's lung (BFL). We were interested in determining antigen-specific IgG antibodies in patients with FDL and comparing them with those with BFL. MATERIAL AND METHODS: Specific IgG antibodies against goose and duck feathers, analysed with an automated fluorimetric enzyme immunoassay, were measured in healthy subjects (group A, n = 30), in patients with FDL (group B, n = 10) and with BFL (group C, n = 35); typical specific IgG antibodies of BFL in groups B and C. RESULTS: An optimal threshold value for antibodies against goose or duck feathers to differentiate patients with either BFL or FDL from healthy subjects was determined at 10.85 mg L(-1) for goose feathers and at 8.81 mg L(-1) for duck feathers, respectively. Specific IgG antibodies against goose feathers were significantly higher in group B compared with group C. A ratio of specific IgG antibodies against goose feathers and budgerigar antigens with a threshold value of 0.91 could discriminate between patients with FDL and BFL with a specificity of 97% and a sensitivity of 90%. CONCLUSIONS: We were able to demonstrate the significant difference in IgG antibodies in patients with FDL and BFL and their contribution to discriminate between these similar kinds of extrinsic allergic alveolitis.

Detection of relevant colonic neoplasms with PET/CT: promising accuracy with minimal CT dose and a standardised PET cut-off.

OBJECTIVE: To determine the performance of FDG-PET/CT in the detection of relevant colorectal neoplasms (adenomas > or =10 mm, with high-grade dysplasia, cancer) in relation to CT dose and contrast administration and to find a PET cut-off. METHODS: 84 patients, who underwent PET/CT and colonoscopy (n = 79)/sigmoidoscopy (n = 5) for (79 x 6 + 5 x 2) = 484 colonic segments, were included in a retrospective study. The accuracy of low-dose PET/CT in detecting mass-positive segments was evaluated by ROC analysis by two blinded independent reviewers relative to contrast-enhanced PET/CT. On a per-lesion basis characteristic PET values were tested as cut-offs. RESULTS: Low-dose PET/CT and contrast-enhanced PET/CT provide similar accuracies (area under the curve for the average ROC ratings 0.925 vs. 0.929, respectively). PET demonstrated all carcinomas (n = 23) and 83% (30/36) of relevant adenomas. In all carcinomas and adenomas with high-grade dysplasia (n = 10) the SUV(max) was > or =5. This cut-off resulted in a better per-segment sensitivity and negative predictive value (NPV) than the average PET/CT reviews (sensitivity: 89% vs. 82%; NPV: 99% vs. 98%). All other tested cut-offs were inferior to the SUV(max). CONCLUSION: FDG-PET/CT provides promising accuracy for colorectal mass detection. Low dose and lack of iodine contrast in the CT component do not impact the accuracy. The PET cut-off SUV(max) > or = 5 improves the accuracy.

Regional lung aeration and ventilation during pressure support and biphasic positive airway pressure ventilation in experimental lung injury.

INTRODUCTION: There is an increasing interest in biphasic positive airway pressure with spontaneous breathing (BIPAP+SBmean), which is a combination of time-cycled controlled breaths at two levels of continuous positive airway pressure (BIPAP+SBcontrolled) and non-assisted spontaneous breathing (BIPAP+SBspont), in the early phase of acute lung injury (ALI). However, pressure support ventilation (PSV) remains the most commonly used mode of assisted ventilation. To date, the effects of BIPAP+SBmean and PSV on regional lung aeration and ventilation during ALI are only poorly defined. METHODS: In 10 anesthetized juvenile pigs, ALI was induced by surfactant depletion. BIPAP+SBmean and PSV were performed in a random sequence (1 h each) at comparable mean airway pressures and minute volumes. Gas exchange, hemodynamics, and inspiratory effort were determined and dynamic computed tomography scans obtained. Aeration and ventilation were calculated in four zones along the ventral-dorsal axis at lung apex, hilum and base. RESULTS: Compared to PSV, BIPAP+SBmean resulted in: 1) lower mean tidal volume, comparable oxygenation and hemodynamics, and increased PaCO2 and inspiratory effort; 2) less nonaerated areas at end-expiration; 3) decreased tidal hyperaeration and re-aeration; 4) similar distributions of ventilation. During BIPAP+SBmean: i) BIPAP+SBspont had lower tidal volumes and higher rates than BIPAP+SBcontrolled; ii) BIPAP+SBspont and BIPAP+SBcontrolled had similar distributions of ventilation and aeration; iii) BIPAP+SBcontrolled resulted in increased tidal re-aeration and hyperareation, compared to PSV. BIPAP+SBspont showed an opposite pattern. CONCLUSIONS: In this model of ALI, the reduction of tidal re-aeration and hyperaeration during BIPAP+SBmean compared to PSV is not due to decreased nonaerated areas at end-expiration or different distribution of ventilation, but to lower tidal volumes during BIPAP+SBspont. The ratio between spontaneous to controlled breaths seems to play a pivotal role in reducing tidal re-aeration and hyperaeration during BIPAP+SBmean.

Effects of vaporized perfluorohexane and partial liquid ventilation on regional distribution of alveolar damage in experimental lung injury.

OBJECTIVE: To determine whether the patterns of distribution of histological effects of vaporized perfluorohexane (PFH) and partial liquid ventilation (PLV) differ significantly in acute lung injury. DESIGN AND SETTING: Experimental study in an animal research laboratory. SUBJECTS: Eighteen pigs. INTERVENTIONS: After induction of acute lung injury by means of infusion of oleic acid animals were randomly assigned to PFH, PLV, or gas ventilation (GV) groups. Six hours thereafter animals were killed, and lung tissue samples were taken for analysis. MEASUREMENTS AND RESULTS: Histopathological analysis revealed less damage with PFH than with GV or PLV in the nondependent and central regions. PFH and PLV showed less injury in the dependent regions than GV. GV and PFH were associated with less histological damage in the nondependent than the dependent regions, whereas PLV presented the opposite pattern. Morphometric analysis showed increased aeration in nondependent than dependent regions with PFH and GV. PLV led to more aeration in the periphery than in central areas. CONCLUSIONS: PFH was associated with a more homogeneous attenuation of alveolar damage across the lungs, although this therapy had more pronounced effects in nondependent zones. PLV showed the opposite pattern, with more important reduction in alveolar damage in dependent lung regions. Interestingly, reduction in alveolar damage with PFH was as effective as with PLV in dependent zones. Our findings suggest that vaporized perfluorocarbon could be advantageous as adjunctive therapy in the treatment of acute lung injury.

Sino nasal inhalation of isotonic versus hypertonic saline (6.0%) in CF patients with chronic rhinosinusitis - Results of a multicenter, prospective, randomized, double-blind, controlled trial.

BACKGROUND: Chronic rhinosinusitis is a hallmark of Cystic fibrosis (CF) impairing the patients' quality of life and overall health. However, therapeutic options have not been sufficiently evaluated. Bronchial inhalation of mucolytic substances is a gold standard in CF therapy. Previously, we found that sinonasal inhalation of dornase alfa as vibrating aerosol reduces symptoms of chronic rhinosinusitis more effectively than NaCl 0.9% (net treatment benefit: -5.87±2.3 points, p=0.017; SNOT-20 total score). This multicenter study compares the effect of NaCl 6.0% vs. NaCl 0.9% following the protocol from our preceding study with dornase alfa. METHODS: Sixty nine CF patients with chronic rhinosinusitis in eleven German CF centers were randomized to receive sinonasal vibrating inhalation of either NaCl 6.0% or NaCl 0.9% for 28days. After 28days of wash-out, patients crossed over to the alternative treatment. The primary outcome parameter was symptom score in the disease-specific quality of life Sino-Nasal Outcome Test-20 (SNOT-20). Additionally, pulmonary function was assessed, as well as rhinomanometry and inflammatory markers in nasal lavage (neutrophil elastase, interleukin (IL)-1ß, IL-6, and IL-8) in a subgroup. RESULTS: Both therapeutic arms were well tolerated and showed slight improvements in SNOT-20 total scores (NaCl 6.0%: -3.1±6.5 points, NaCl 0.9%: -5.1±8.3 points, ns). In both treatment groups, changes of inflammatory parameters in nasal lavage from day 1 to day 29 were not significant. We suppose that the irritating properties of NaCl 6.0% reduced the suitability of the SNOT-20 scores as an outcome parameter. Alternative primary outcome parameters such as MR-imaging or the quantity of sinonasal secretions mobilized with both saline concentrations were, however, not feasible. CONCLUSION: Sinonasal inhalation with NaCl 6.0% did not lead to superior results vs. NaCl 0.9%, whereas dornase alfa had been significantly more effective than NaCl 0.9%.

Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. METHODS: Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. RESULTS: 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). CONCLUSIONS: In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00669760.

Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial.

BACKGROUND: Chronic rhinosinusitis significantly impairs CF patients' quality of life and overall health. The Pari-Sinus™ device delivers vibrating aerosol effectively to paranasal sinuses. After a small pilot study to assess sinonasal inhalation of dornase alfa and placebo (isotonic saline) on potential sinonasal outcome measures, we present the subsequent prospective double-blind placebo-controlled crossover-trial. METHODS: 23 CF patients were randomised to inhale either dornase alfa or isotonic saline for 28 days with the Pari-Sinus™ and after 28 days (wash-out) crossed over to the alternative treatment. The primary outcome parameter was primary nasal symptom score in the disease-specific quality of life Sino-Nasal Outcome-Test-20 (SNOT-20: nasal obstruction/sneezing/runny nose/thick nasal discharge/reduced smelling). RESULTS: Primary nasal symptoms improved significantly with dornase alfa compared with no treatment, while small improvements with isotonic saline did not reach significance. SNOT-20 overall scores improved significantly after dornase alfa compared with isotonic saline (p=0.017). Additionally, sinonasal dornase alfa but not isotonic saline significantly improved pulmonary function (FEF75-25: p=0.021). CONCLUSION: Vibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in CF.

Reliability of brain CT evaluation by stroke neurologists in telemedicine.

OBJECTIVE: To determine the reliability and therapeutic impact of standardized cerebral CT evaluation and quantification of early ischemic changes (EIC) with the Alberta Stroke Program Early CT Score (ASPECTS) by stroke neurologists in the Stroke Eastern Saxony Network (SOS-NET), which provides telemedical consultations for patients with acute ischemic stroke. METHODS: Two neuroradiologists re-evaluated all CT scans of consecutive SOS-NET patients in 2009 blinded to clinical information providing reference standard. We defined discrepant CT findings as all false-positive or false-negative EIC and brain pathology findings and ASPECTS deviations >1 point. We subsequently discussed the clinical impact of discrepant CT findings unblinded to clinical information. Weighted kappa (κ(w)) statistic was used to determine the interobserver agreement for ASPECTS. RESULTS: Of 582 patients, complete imaging data were available for 536 patients (351 cerebral ischemic events, 105 primary intracranial hemorrhages, and 80 stroke mimics). The neuroradiologists detected discrepant CT findings in 43 patients (8.0%) that were rated as clinically relevant in 9 patients (1.7%). Stroke neurologists recommended IV thrombolysis in 8 patients despite extensive EIC (ASPECTS ≤5). One of these patients had symptomatic intracranial hemorrhage. In 1 nonthrombolyzed patient, the stroke neurologist missed subdural hematoma. The interobserver agreement on ASPECTS between stroke neurologists and expert readers was substantial (κ(w) = 0.62; 95% confidence interval 0.54-0.71). CONCLUSIONS: Clinically relevant misinterpretation of the CT scans was rare in our acute telestroke service. ASPECTS is a reliable tool to assess the extent of EIC by stroke neurologists in telemedicine in real time.

Rationale and study design of ViPS - variable pressure support for weaning from mechanical ventilation: study protocol for an international multicenter randomized controlled open trial.

BACKGROUND: In pressure support ventilation (PSV), a non-variable level of pressure support is delivered by the ventilator when triggered by the patient. In contrast, variable PSV delivers a level of pressure support that varies in a random fashion, introducing more physiological variability to the respiratory pattern. Experimental studies show that variable PSV improves gas exchange, reduces lung inflammation and the mean pressure support, compared to non-variable PSV. Thus, it can theoretically shorten weaning from the mechanical ventilator. METHODS/DESIGN: The ViPS (variable pressure support) trial is an international investigator-initiated multicenter randomized controlled open trial comparing variable vs. non-variable PSV. Adult patients on controlled mechanical ventilation for more than 24 hours who are ready to be weaned are eligible for the study. The randomization sequence is blocked per center and performed using a web-based platform. Patients are randomly assigned to one of the two groups: variable PSV or non-variable PSV. In non-variable PSV, breath-by-breath pressure support is kept constant and targeted to achieve a tidal volume of 6 to 8 ml/kg. In variable PSV, the mean pressure support level over a specific time period is targeted at the same mean tidal volume as non-variable PSV, but individual levels vary randomly breath-by-breath. The primary endpoint of the trial is the time to successful weaning, defined as the time from randomization to successful extubation. DISCUSSION: ViPS is the first randomized controlled trial investigating whether variable, compared to non-variable PSV, shortens the duration of weaning from mechanical ventilation in a mixed population of critically ill patients. This trial aims to determine the role of variable PSV in the intensive care unit. TRIAL REGISTRATION: clinicaltrials.gov NCT01769053.

Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.

OBJECTIVE: To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. RESEARCH DESIGN AND METHODS: The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS: WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P<0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P=0.049). Mean duration of remission in WSD was 2.3±2.4 vs. 1.6±2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P<0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c>7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). CONCLUSIONS: Endoplasmic reticulum stress-mediated decline of ß-cells in WSD occurs earlier in life than autoimmune-mediated ß-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.