Uncapped Metered-Dose Inhalers: A Risk for Foreign Body Aspiration. A Case Report and Review of the Literature.

The risk of foreign body aspiration associated with uncapped handheld metered-dose inhalers (MDIs) is underestimated. We report a case in which a plastic cable clip accidentally lodged in the mouthpiece of an uncapped pressurized MDI was aspirated during its use. A literature search revealed 16 other cases of foreign body aspiration associated with uncapped handheld inhalers, all but one of which were pressurized inhalers. Patients should be informed of the risk of foreign body aspiration associated with uncapped pocket inhalers. The use of an uncuffed armoured tracheal tube with a separate oxygen tubing during flexible bronchoscopy for foreign body removal ensures a safe airway. Foreign bodies that exceed the lumen size of the tracheal tube can be pulled to the distal opening with forceps and removed when the tube is withdrawn.

Functional limitations 12 months after SARS-CoV-2 infection correlate with initial disease severity: An observational study of cardiopulmonary exercise capacity testing in COVID-19 convalescents.

BACKGROUND: Cardiopulmonary Exercise Testing (CPET) provides a comprehensive assessment of pulmonary, cardiovascular and musculosceletal function. Reduced CPET performance could be an indicator for chronic morbidity after COVID-19. METHODS: Patients ≥18 years with confirmed PCR positive SARS-CoV-2 infection were offered to participate in a prospective observational study of clinical course and outcomes of COVID-19. 54 patients completed CPET, questionnaires on respiratory quality of life and performed pulmonary function tests 12 months after SARS-CoV-2 infection. RESULTS: At 12 months after SARS-CoV-2 infection, 46.3% of participants had a peak performance and 33.3% a peak oxygen uptake of <80% of the predicted values, respectively. Further impairments were observed in diffusion capacity and ventilatory efficiency. Functional limitations were particularly pronounced in patients after invasive mechanical ventilation and extracorporeal membrane oxygenation treatment. Ventilatory capacity was reduced <80% of predicted values in 55.6% of participants, independent from initial clinical severity. Patient reported dyspnea and respiratory quality of life after COVID-19 correlated with CPET performance and parameters of gas exchange. Risk factors for reduced CPET performance 12 months after COVID-19 were prior intensive care treatment (OR 5.58, p = 0.004), SGRQ outcome >25 points (OR 3.48, p = 0.03) and reduced DLCO (OR 3.01, p = 0.054). CONCLUSIONS: Functional limitations causing chronic morbidity in COVID-19 survivors persist over 12 months after SARS-CoV-2 infection. These limitations were particularly seen in parameters of overall performance and gas exchange resulting from muscular deconditioning and lung parenchymal changes. Patient reported reduced respiratory quality of life was a risk factor for adverse CPET performance.

Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: An observational longitudinal study over 12 months.

INTRODUCTION: Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19. METHODS: Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19. RESULTS: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, DLCO from 60.18 to 68.98 and KCO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease. CONCLUSION: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection.

FDG-PET/CT for pretherapeutic lymph node staging in non-small cell lung cancer: A tailored approach to the ESTS/ESMO guideline workflow.

OBJECTIVES: In patients with NSCLC, current ESTS and ESMO guidelines recommend invasive lymph node (LN) staging with EBUS-TBNA even if FDG-PET/CT is negative for mediastinal LNs if at least one of three risk factors is present (cN1, non-peripheral primary or primary >3 cm). Modified workflows to avoid unnecessary invasive procedures were evaluated. MATERIALS AND METHODS: Monocentric retrospective analysis of pretherapeutic FDG-PET/CT in 247 patients with NSCLC (62 % male; age, 68 [43-88] years) using an analog or digital PET/CT scanner. PET windowing was standardized. LNs were positive if 'LN uptake > mediastinal blood pool' or short axis >10 mm. Surgery or EBUS-TBNA served as reference for diagnostic accuracy per LN station. In all patients with negative mediastinal LNs by PET/CT, LN histology from surgery was available. RESULTS: Among 700 L N stations analyzed, 180 were malignant. Sensitivity and specificity of PET/CT per LN station were 93 % and 71 %. Following current guidelines, 76 patients with mediastinal negative PET/CT required confirmatory invasive staging. Only 5/76 patients had unexpected pN2 (all had adenocarcinoma). In a modified approach, confirmatory invasive staging was confined to patients with mediastinal negative PET/CT who showed all three risk factors. Using this modification, EBUS-TBNA could have been omitted in 62 (82 %) of the 76 patients who required EBUS-TBNA based on current recommendation. Among these 62 patients, only one patient had unsuspected pN2 (single-level) while the remaining 61 of 62 omitted EBUS-TBNA were deemed unnecessary because mediastinal LNs were confirmed to be negative. No multi-level pN2 would have been missed. CONCLUSION: In the current analysis, 82 % of EBUS-TBNA procedures in patients with mediastinal negative PET/CT could have been omitted by modifying the current guideline workflow as proposed (i.e., restricting EBUS-TBNA in patients with cN0/1 to those with all three risk factors). This was consistent with different PET/CT scanners. Prospective confirmation is required.

Pemetrexed-Based Chemotherapy Is Inferior to Pemetrexed-Free Regimens in Thyroid Transcription Factor 1 (TTF-1)-Negative, EGFR/ALK-Negative Lung Adenocarcinoma: A Propensity Score Matched Pairs Analysis.

INTRODUCTION: Thyroid transcription factor 1 (TTF-1) is a prognostic biomarker in lung adenocarcinoma; however, TTF-1-positive patients also display more favorable factors like actionable target mutations. In contrast, TTF-1-negative cancer is a poorly described entity. We performed a retrospective study to characterize a TTF-1-negative phenotype and to evaluate outcome depending on the chemotherapy regimen applied in the EGFR/ALK-negative population. PATIENTS AND METHODS: Phenotypic traits were analyzed in 741 patients with evaluable TTF-1 expression status, among them 529 patients with platinum-based first-line chemotherapy, with disease diagnosed between 2009 and 2016 at a tertiary referral university hospital. The influence of TTF-1 and several cofactors on progression-free survival and overall survival (OS) were analyzed using a 1:1 propensity score matching model, depending on the platinum doublet chemotherapy's incorporating pemetrexed or not, with subsequent Cox regression. RESULTS: TTF-1 negativity implied a distinct cancer phenotype with the predominance of male sex, worse Eastern Cooperative Oncology Group performance status, greater metastatic burden at primary diagnosis, and more adrenal gland metastases. These patients had improved progression-free survival (hazard ratio, 0.42; P = .001) and OS (hazard ratio, 0.40; P < .001) when gemcitabine-, taxane-, or vinorelbine-based regimens were provided instead of pemetrexed. None of the regimens was superior in TTF-1-positive patients with regard to OS. Overall, TTF-1 expression was strongly prognostic with a substantial increase in progression-free survival (hazard ratio, 0.54; P < .001) and OS (hazard ratio, 0.53; P < .001). CONCLUSION: TTF-1 negativity is associated with a distinct cancer phenotype. Incorporation of this biomarker may be helpful when choosing an appropriate therapy regimen.

Indwelling pleural catheters for non-malignant pleural effusions: report on a single centre's 10 years of experience.

BACKGROUND: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of infectious pleurisy and non-malignant diseases like congestive heart failure (CHF) or liver cirrhosis with hepatic hydrothorax (HH). With regard to the chronic character of the underlying diseases, indwelling pleural catheters (IPC) are increasingly used, not only assuring immediate symptom relief but also potentially leading to pleurodesis without sclerosing agents. PATIENTS AND METHODS: In this single-centre retrospective observational study, patient characteristics, procedural variables and outcome in patients with IPC in non-malignant pleural effusion (NMPE) were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2017, 54 patients received 62 IPC, of whom 48.4% with CHF and 43.5% with HH. The median length of insertion was 1.5 months (IQR 0.6-2.9 months), the median survival time after insertion 3.2 months (IQR 1.1-16.0). An adequate symptom relief was achieved in 93.2% with no need for subsequent interventions. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 45.9%, being associated to age (<55 years, p=0.02), the primary diagnosis (p=0.03) and interventions for the underlying disease (p<0.001). Complications occurred in 24.2% of all procedures (n=15), the majority concerning mechanical obstructions (n=10) and infections (n=4). Patients with HH had an excess risk for complications (37.3%). CONCLUSION: Efficacy in symptom relief and a generally manageable safety profile recommend IPC as a first-line treatment option in NMPE, where disease-specific treatments are exhausted. Caution is warranted in patients with HH due to an excess risk for complications.

Indwelling pleural catheters for malignancy-associated pleural effusion: report on a single centre's ten years of experience.

INTRODUCTION: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of malignant diseases. Chemical pleurodesis had been the only definitive treatment option until two decades ago. Indwelling pleural catheters (IPC) emerged as an alternative, not only assuring immediate symptom relief but also potentially leading to pleurodesis in the absence of sclerosing agents. METHODS: In this single-centre retrospective observational study patient characteristics, procedural variables and outcome in a large population of patients with IPC in malignancy were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2016, 395 patients received 448 IPC, of whom 121 (30.6%) had ovarian, 91 (23.0%) lung and 45 (11.4%) breast cancer. The median length of IPC remaining in place was 1.2 months (IQR, 0.5-2.6), the median survival time after insertion 2.0 months (IQR, 0.6-6.4). An adequate symptom relief was achieved in 94.9% of all patients, with no need for subsequent interventions until last visit or death. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 44.5% and was more common in patients < 60 years (HR, 1.72; 95% CI, 1.05-2.78; p = 0.03). The use of an additional talc slurry via the IPC was highly predictive for pleurodesis (HR 6.68; 95% CI, 1.44-31.08; p = 0.02). Complications occurred in 13.4% of all procedures (n = 60), 41.8% concerning infections (local infections at the tunnel/exit site (n = 14) and empyema (n = 11)), and 98.3% being low or mild grade (n = 59). Complication rates were higher in men than women (18.6 vs. 12.4%, p = 0.023). CONCLUSION: High efficacy in symptom relief and a favourable safety profile confirm IPC as suitable first line option in most malignant pleural effusions. The study presents the largest dataset on IPC in gynaecologic cancer to date. Gender-specific differences in complication rates warrant further study.

Local ablative treatment for synchronous single organ oligometastatic lung cancer-A propensity score analysis of 180 patients.

INTRODUCTION: Local ablative treatment (LAT) improves outcome in lung cancer with oligometastatic disease (OMD) and potentially leads to long term survival. The aim of this retrospective study was to evaluate and quantify the additional benefit of LAT in synchronous OMD and to further identify prognostic factors for survival. PATIENTS AND METHODS: A propensity score-matched pairs analysis was performed on a set of patient and disease variables in 180 patients, treated for synchronous single organ OMD including non small-cell and neuroendocrine lung cancer with ≤4 metastases between 2000 and 2016 in 3 lung cancer centers in Berlin, Germany. Patients either received LAT for all sites of disease (intervention group) by means of surgery or stereotactic radiotherapy, or standard chemotherapy, if necessary combined with a local treatment with palliative intent (control group). RESULTS: Median follow-up time was 32.2 and 18.8 months for the intervention and control group, respectively. Substantial benefits in median progression-free survival (PFS, 25.1 vs. 8.2 months; HR, 0.30; 95% CI, 0.21-0.43; p < 0.001) and overall survival (OS, 60.4 vs. 22.5 months; HR, 0.42; 95% CI, 0.28-0.62; p < 0.001) were associated with LAT. Histology of adenocarcinoma and T1a primaries also predicted a favorable prognosis concerning PFS and OS. More favorable nodal stage (N0-2 vs. 3) and solitary metastases were associated with an extended PFS, whereas initial ECOG-PS (0-1 vs. 2) predicted OS. CONCLUSIONS: LAT was the strongest predictor for PFS and OS in OMD with ≤4 metastases. Survival in the control group identifies OMD as a subset of lung cancer with a generally more favorable prognosis.

[Infectious Causes of Granulomatous Lung Diseases]. / Infektiologische Differenzialdiagnosen bei granulomatösen Lungenerkrankungen.

Infections are the most common cause of granulomatous lung diseases. A variety of different pathogens can cause granuloma formation. The diagnosis requires consideration of endemic characteristics, patients' predispositions as well as specific requirements for pathogen detection. The aim of this review is to give a short overview of the most important causative pathogens and facilitate the differential diagnostic approach of granulomatous lung diseases.

A diagnostic predicament: activated sarcoidosis or pulmonary histoplasmosis. A case report.

We report a case of a 41-year-old man presenting with persisting fevers over 2 weeks. The patient had spent 4 weeks in Central America. He was in control of a stable stage II sarcoidosis. Laboratory and various microbiological tests as well as chest radiography led to no diagnosis. Activated sarcoidosis was hypothesized as the most likely diagnosis. However, we considered an infectious process as a differential diagnosis, in detail, the travel history imposed histoplasmosis. Chest-CT documented localized interstitial consolidations. Bronchoscopy with bronchoalveolar lavage (BAL) and biopsy was performed. Results of BAL fluid, biopsy, distinct sarcoidosis serum markers and a borderline positive histoplasmosis-serology yielded in a diagnostic dilemma as no distinct diagnosis was drawable. After the patient was already started on a prednisolone trial, the final diagnosis - pulmonary histoplasmosis - could be achieved via positive culture and PCR out of the BAL fluid. This case shows the difficult differentiation between an acute exacerbation of a chronic pulmonary disease and a concomitant infection, which was especially aggravated in this case as the histoplasmosis masqueraded an acute picture of sarcoidosis.

Outcomes of Endobronchial Valve Treatment Based on the Precise Criteria of an Endobronchial Catheter for Detection of Collateral Ventilation under Spontaneous Breathing.

BACKGROUND: Endoscopic lung volume reduction with valves is a valid therapeutic option for COPD patients with severe emphysema. The exclusion of interlobar collateral ventilation (CV) is an important predictor of clinical success. OBJECTIVES: Recently, a catheter-based endobronchial in vivo measurement system (Chartis, Pulmonx, USA) has become routine in the clinical evaluation of CV status in target lobes, but the criteria for phenotyping CV by Chartis evaluation have not yet been defined. We asked the questions, how many phenotypes can be identified using Chartis, what are the exact criteria to distinguish them, and how do the Chartis phenotypes respond to valve insertion? METHODS: In a retrospective study, 406 Chartis assessments of 166 patients with severe COPD were analyzed. Four Chartis phenotypes, CV positive (CV+), CV negative (CV-), low flow (LF) and low plateau were identified. Fifty-two patients without CV were treated with valves and followed for 3 months. RESULTS: The Chartis phenotypes were discriminated with respect to decline in expiratory peak flow, increase in resistance index and change in total exhaled volume after 1, 2, 3, 4 and 5 min of measurement time (p < 0.0001, ANOVA), and the cutoff criteria were defined accordingly. To examine the application of these phenotyping criteria, students applied them to 100 Chartis assessments, and they demonstrated almost perfect inter- and intraobserver agreements (x03BA; > 0.9). Compared to baseline, CV- and LF patients with ipsilateral CV- lobe showed an improvement in FEV1 (p < 0.05), vital capacity (p < 0.05) and target lobe volume reduction (p < 0.005) after valve insertion. CONCLUSION: This study describes the most prevalent Chartis phenotypes.

Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker.

Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50-75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy.

Pulmonary toxicity among cancer patients treated with a combination of docetaxel and gemcitabine: a meta-analysis of clinical trials.

PURPOSE: The combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast, and pancreatic cancers and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some trials. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel-gemcitabine-dependent pulmonary toxicity. METHODS: We searched MEDLINE/Pubmed, EMBASE, and Cochrane Clinical Trials database for prospective full-text studies that used a schedule of docetaxel and gemcitabine to treat a malignant disease. We performed a meta-analysis for proportions using the arcsine transformation and a meta-regression using a generalized linear mixed model based on a binomial distribution and a logit link. RESULTS: We included 103 trials with 113 treatment arms comprising 5,065 patients (major entities included non-small cell lung cancer (n = 2,550), breast cancer (n = 1,119), pancreatic cancer (n = 466), and urothelial cancer (n = 161)). For the incidence of severe lung toxicity (common toxicity criteria [CTC] grades 3-5), we found a combined estimate of 2.70% (95% CI 2.26, 3.14). The estimate for the proportion of fatal cases was 0.35% (95% CI 0.21, 0.58). We found that the sequence of the chemotherapy schedule had no influence on the incidence of severe pulmonary adverse events (F-test F = 0.65, df = 3,113, P = 0.58) nor did the study phase, treatment line or ethnicity of the participants. We found that patients with breast cancer, compared to lung cancer patients, developed severe lung toxicity less frequently (OR = 0.18, 95% CI (0.09, 0.36)). CONCLUSION: We could not demonstrate that a particular chemotherapy sequence of docetaxel-gemcitabine is associated with excess pulmonary toxicity. Patients with lung cancer are at a higher risk for severe pulmonary side effects with docetaxel-gemcitabine than are patients with breast cancer.

A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer.

INTRODUCTION: The combination of docetaxel and cisplatin is an effective first-line regimen in patients with advanced non-small cell lung cancer. However, the recommended three-weekly schedule is associated with frequent neutropenia and infections. Because of the toxicity of cisplatin, patients may need to be hospitalized to ensure adequate hydration. The aim of this study was to assess the efficacy and tolerability of a weekly schedule of docetaxel and cisplatin. PATIENTS AND METHODS: Patients with inoperable stage International Union Against Cancer IIIB (malignant effusion) or IV non-small cell lung cancer received docetaxel (35 mg/m(2), 30 minutes infusion) and cisplatin (25 mg/m(2), 30 minutes infusion) on days 1, 8, and 15, every 4 weeks for 4 to 6 cycles. Ondansetron (8 mg) and dexamethasone (8 mg) were given intravenously before chemotherapy. The patients received oral dexamethasone 2 x 4 mg daily from the day before until the day after chemotherapy. NK1-antagonists were given at the investigator's discretion. The majority of patients was treated in outpatient departments. Safety was assessed using CTCAE v3.0. The primary end point was response rate (RECIST). RESULTS: Forty-four patients were included. Twelve of 44 patients achieved an objective response (11 partial, 1 complete, intent-to-treat response rate 27%). Median time to progression was 4.4 months (95% confidence interval: 4.0-4.7) and median survival 9.6 months (95% confidence interval: 2.9-16.2). Patients received a median of three full cycles. Four patients (9%) required dose reductions. No cases of febrile neutropenia or grade 2 to 4 thrombocytopenia were observed. One patient (2%) experienced grade 3/4 nausea and vomiting. CONCLUSIONS: Weekly docetaxel-cisplatin demonstrated comparable efficacy with three-weekly schedules. Although the frequencies of neutropenia and febrile neutropenia were low, non-neutropenic infections remained a problem. Because of relatively short hydration, the schedule can be safely administered in an outpatient setting.

Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro.

Leakage of the gut mucosal barrier in the critically ill patient may allow translocation of bacteria and their virulence factors, thereby perpetuating sepsis and inflammation. Present evidence suggests that adrenomedullin (AM) improves endothelial barrier function and stabilizes circulatory function in systemic inflammation. We tested the hypothesis that exogenously applied AM stabilizes gut epithelial barrier function. Infusion of Staphylococcus aureus alpha-toxin induced septic shock in rats. AM infusion in a therapeutic setting reduced translocation of labeled dextran from the gut into the systemic circulation in this model. AM also reduced alpha-toxin and hydrogen peroxide (H2O2)-related barrier disruption in Caco-2 cells in vitro and reduced H2O2-related rat colon barrier malfunction in Ussing chamber experiments. AM was shown to protect endothelial barrier function via cAMP elevation, but AM failed to induce cAMP accumulation in Caco-2 cells. cAMP is degraded via phosphodiesterases (PDE), and Caco-2 cells showed high activity of cAMP-degrading PDE3 and 4. However, AM failed to induce cAMP accumulation in Caco-2 cells even in the presence of sufficient PDE3/4 inhibition, whereas adenylyl cyclase activator forskolin induced strong cAMP elevation. Furthermore, PDE3/4 inhibition neither amplified AM-induced epithelial barrier stabilization nor affected AM cAMP-related rat colon short-circuit current, furthermore indicating that AM may act independently of cAMP in Caco-2 cells. Finally, experiments using chemical inhibitors indicated that PKC, phosphatidylinositide 3-kinase, p38, and ERK did not contribute to AM-related stabilization of barrier function in Caco-2 cells. In summary, during severe inflammation, elevated AM levels may substantially contribute to the stabilization of gut barrier function.

Acute respiratory failure after aspiration of activated charcoal with recurrent deposition and release from an intrapulmonary cavern.

OBJECTIVE: To report on the recurrent release of charcoal from an intrapulmonary cavern in a case of acute respiratory failure after charcoal aspiration. DESIGN: Case report. SETTING: Anaesthesiological ICU, university hospital. PATIENT: An 18-year-old ethanol intoxicated comatose patient regurgitated and aspirated activated charcoal during orotracheal intubation. TREATMENT: After 2 days of mechanical ventilation, the patient was transferred to a tertiary care university hospital. On admission, acute respiratory distress syndrome with bilateral pulmonary infiltrations was diagnosed. The patient's recovery was hampered by recurrent release of charcoal from an intrapulmonary cavern. Sophisticated ventilatory support, prone positioning, secretolytics, repetitive bronchoscopy, and antibiotic therapy may have facilitated bronchoalveolar clearance and weaning after 18 days. CONCLUSION: Aspiration may be a dramatic complication if charcoal is administered in comatose patients without airway protection. In this case report, advanced intensive care measures were necessary to tackle the special feature of charcoal release from an intrapulmonary cavern.

Adrenomedullin and endothelial barrier function.

Although loss of endothelial barrier function is a hallmark of every acute inflammation and contributes to fatal loss of organ function during severe infections, there is no sufficient therapy for stabilization of endothelial barrier function. Endogenous peptide adrenomedullin (AM) serum levels were shown to be increased during severe infection including sepsis and septic shock. In different in-vitro and in-vivo models AM acted as a potent therapeutic endothelial barrier function-stabilizing agent. Activation of specific receptors by AM results in elevation of second messenger cAMP. AM inhibits actin-myosin based endothelial cell contraction and junctional disassembly, thereby preventing paracellular permeability and oedema formation. The peptide furthermore possesses several protective cardiovascular qualities, including protection of the microcirculation during inflammation, and was proven as an efficient counter-regulatory molecule in various models of sepsis and septic shock. Overall, AM may be an attractive molecule to combat against cardiovascular malfunction during severe infection.

Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock.

OBJECTIVE: Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival. DESIGN: Prospective randomized controlled animal study. SUBJECTS: Male Sprague-Dawley rats (270 g). INTERVENTIONS: We used 4.8 x 10(3) U/kg of Staphylococcus aureus alpha-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 microg/kg per hour. Adrenomedullin was started 1 h after alpha-toxin administration. MEASUREMENT AND RESULTS: Infusion of alpha-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. alpha-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after alpha-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 microg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement. CONCLUSIONS: These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.

Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus aureus alpha-toxin--an intravital microscopic study on an isolated rat ileum.

OBJECTIVE: Disturbances of intestinal microcirculation associated with sepsis and septic shock result in diminished mucosal oxygenation. Tissue hypoxia as well as mediator formation may lead to intestinal mucosa dysfunction. As a consequence, bacteria and their products as well as gut-derived inflammatory mediators may further perpetuate septic and inflammatory events. Adrenomedullin is produced in the mucosa of the gastrointestinal tract and has been shown to improve survival in experimental sepsis. Using pore-forming Staphylococcus aureus alpha-toxin as a potent initiator of inflammatory reactions, we tested the hypothesis that exogenously added adrenomedullin improves ileal mucosal perfusion. DESIGN: Prospective, experimental study. SETTING: University laboratory. SUBJECTS: Isolated perfused ileum from male Sprague-Dawley rats INTERVENTIONS: Adrenomedullin treatment of S. aureus alpha-toxin infused ileum. MEASUREMENT AND MAIN RESULTS: An infusion of alpha-toxin (0.05 microg/mL) induced a significant decrease of red blood cell velocity in villus terminal arterioles from 1.7 to 0.7 mm/sec assessed by intravital microscopy. This was accompanied by a significant reduction of mucosal hemoglobin oxygenation from 71.8% to 17.5% and impaired oxygen uptake. At constant bulk flow and oxygen delivery, these data indicate a redistribution of blood perfusion away from mucosa. Subsequent intervention with 0.1 microM adrenomedullin redistributed blood flow back toward the mucosa, causing an improvement of mucosal hemoglobin oxygenation and of organ oxygen uptake. CONCLUSION: These data suggest that exogenously added adrenomedullin protects ileum mucosa by diminishing alpha-toxin-induced microcirculatory disturbances. Further investigations will have to clarify the therapeutic potential of adrenomedullin in sepsis-related gut dysfunction.

Adrenomedullin reduces Staphylococcus aureus alpha-toxin-induced rat ileum microcirculatory damage.

OBJECTIVE: Increased microvascular permeability and perfusion mismatch are hallmarks of sepsis or septic shock. The intestinal mucosa is very sensitive to tissue hypoxia. Intestinal mucosa dysfunction may allow translocation of bacteria and their products, thereby perpetuating sepsis and inflammation. Staphylococcus aureus alpha-toxin is a major pathogenicity determinant of this bacterium, provoking cardiovascular collapse. Current evidence suggests that the endogenous peptide adrenomedullin stabilizes circulatory homeostasis in systemic inflammatory response. Using alpha-toxin as a well-defined strong initiator of an inflammatory reaction, we tested the hypothesis that exogenously applied adrenomedullin stabilizes gut microcirculation. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university hospital. SUBJECTS: Isolated, perfused ileum from male Sprague-Dawley rats and human umbilical vein endothelial cells. INTERVENTIONS: Administration of S. aureus alpha-toxin before or after infusion of adrenomedullin. MEASUREMENTS AND MAIN RESULTS: Injection of a bolus of 1 microg of alpha-toxin in the superior mesenteric artery in a constant-flow, blood-perfused preparation of rat ileum increased perfusion pressure and relative hemoglobin concentration and decreased mucosal hemoglobin oxygen saturation. Continuous infusion of adrenomedullin (0.1 micromol/L) significantly reduced these alpha-toxin-related effects. Severe microvascular hyperpermeability observed in alpha-toxin-exposed ileum was abolished by adrenomedullin pretreatment. In addition, adrenomedullin blocked alpha-toxin-induced endothelial myosin light chain phosphorylation, endothelial cell contraction, and subsequent loss of endothelial barrier function in vitro. Treatment of alpha-toxin (infusion of 0.05 microg/mL)-exposed ileum with adrenomedullin (0.1 micromol/L) started 10 mins after onset of toxin application also significantly reduced superior mesenteric artery pressure and permeability increase. CONCLUSIONS: In summary, these data suggest that exogenous adrenomedullin protects ileum by reducing alpha-toxin-induced microcirculatory disturbances and by stabilizing endothelial barrier function.