Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension.

Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 ± 1.4 g/l) and CTEPH (4.3 ± 1.2 g/l) compared to control patients (3.4 ± 0.5 g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy.

Effects of exercise training programs on physical performance and quality of life in patients with metastatic lung cancer undergoing palliative chemotherapy--a study protocol.

PURPOSE: The aims of the study protocol are to investigate different adapted physical training programs in patients with advanced lung cancer undergoing palliative chemo- or radiotherapy and to evaluate their effects on physical performance, quality of life, symptom burden, and efficacy of oncologic treatment. METHODS: Patients will be randomized into three study arms: interventional group 1 performing aerobic exercise, interventional group 2 performing resistance training, and a control group without specific physical training. Interventional training will be performed for 12 weeks consisting of two supervised and one self-instructed training sessions per week each. Respiratory therapy over 12 weeks is provided in all three study arms as an established supportive therapy in lung cancer patients. Primary efficacy endpoint is physical performance measured by peak oxygen consumption (VO(2)peak). Secondary efficacy endpoints include additional parameters of physical performance (resistance, lung function, perceived exertion, level of physical activity and IPAQ-questionnaire), health-related quality of life (EORTC QLQ C30-questionnaire), disease and treatment related symptoms (Memorial Symptom Assessment Scale), biologic parameter (e.g. body composition, blood values of immune system, chronic inflammation, glucose and lipid metabolisms), and parameter of efficacy of oncologic treatment. DISCUSSION: The results of this study will offer an overview over possible effects of specific training interventions on health related quality of life, physical and psychological symptoms, and on the efficacy of oncologic treatment. The primary aim of this study is to detect adapted intervention programs for metastatic lung cancer undergoing palliative chemotherapy.

Low intensity, long-term outpatient rehabilitation in COPD: a randomised controlled trial.

BACKGROUND: Most pulmonary rehabilitation programmes currently involve 2-3 sessions per week as recommended by international guidelines. We aimed to investigate whether relevant improvements in physical capabilities and quality of life in patients with chronic obstructive pulmonary disease (COPD) could be achieved by a long-term, low intensity, once weekly rehabilitation programme using limited resources. METHODS: 100 patients with moderate to severe COPD were randomised to a continuous outpatient interdisciplinary rehabilitation programme or standard care. Physiotherapy-led supervised outpatient training sessions were performed once weekly in addition to educational elements. Outcome measures at baseline and after 26 weeks were 6-minute-walk-test, cycle ergometry, and health-related quality of life. RESULTS: 37 patients in the training group and 44 patients in the control group completed the study. After 26 weeks there were clinically significant differences between the groups for 6 minute-walk-distance (+59 m, 95% CI 28-89 m), maximum work load (+7.4 Watt, 95% CI 0.5-13.4 Watt) and St. George's Respiratory Questionnaire score (-5 points, 95% CI -10 to -1 points). Total staff costs of the programme per participant were ≤ €625. CONCLUSION: Clinically meaningful improvements in physical capabilities and health-related quality of life may be achieved using long-term pulmonary rehabilitation programmes of lower intensity than currently recommended. TRIAL REGISTRATION: clinicaltrials.gov NCT01195402.

Characterization of Enterobacter cloacae pneumonia: a single-center retrospective analysis.

OBJECTIVES: Enterobacter cloacae (E. cloacae) is a Gram-negative rod commonly found on intensive care units (ICU) causing severe infections with high mortality. Specific characteristics of E. cloacae pneumonia, however, have not been identified. DESIGN: Evaluation of clinical and microbiological records of patients with positive respiratory samples for E. cloacae was performed by a 1-year retrospective study in a large university hospital. RESULTS: Ninety-seven of 115 eligible patients with E. cloacae-positive respiratory samples developed pneumonia. Patients were predominantly male (68%), older (median age = 62 years), and immunodeficient (54%). Seventy-eight percent required ICU admission, of which 97% required mechanical ventilation. Ventilator-associated pneumonia (VAP) occurred in 58%. Those who developed E. cloacae VAP had undergone twice as many surgical procedures under translaryngeal intubation prior to VAP onset (89 vs. 48%, P < 0.0001). Overall, E. cloacae VAP mortality was 24%. In E. cloacae VAP patients, presence of translaryngeal tubes (P = 0.02) and female gender (P = 0.0003) were associated with poor survival. Multivariate analysis confirmed male sex as a protective factor (relative risk: 0.39; P = 0.007). CONCLUSION: Enterobacter cloacae causes VAP with high mortality, predominantly in women. Risk factors for E. cloacae pneumonia seem to match those for VAP. The presence of translaryngeal endotracheal tubes seems to be the specific factor for E. cloacae VAP.

Structural brain changes related to disease duration in patients with asthma.

Dyspnea is the impairing, cardinal symptom patients with asthma repeatedly experience over the course of the disease. However, its accurate perception is also crucial for timely initiation of treatment. Reduced perception of dyspnea is associated with negative treatment outcome, but the underlying brain mechanisms of perceived dyspnea in patients with asthma remain poorly understood. We examined whether increasing disease duration in fourteen patients with mild-to-moderate asthma is related to structural brain changes in the insular cortex and brainstem periaqueductal grey (PAG). In addition, the association between structural brain changes and perceived dyspnea were studied. By using magnetic resonance imaging in combination with voxel-based morphometry, gray matter volumes of the insular cortex and the PAG were analysed and correlated with asthma duration and perceived affective unpleasantness of resistive load induced dyspnea. Whereas no associations were observed for the insular cortex, longer duration of asthma was associated with increased gray matter volume in the PAG. Moreover, increased PAG gray matter volume was related to reduced ratings of dyspnea unpleasantness. Our results demonstrate that increasing disease duration is associated with increased gray matter volume in the brainstem PAG in patients with mild-to-moderate asthma. This structural brain change might contribute to the reduced perception of dyspnea in some patients with asthma and negatively impact the treatment outcome.

Fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation--a feasibility study.

INTRODUCTION: Noninvasive ventilation (NIV) is a standard procedure in selected patients with acute respiratory failure. Previous studies have used noninvasive ventilation to ensure adequate gas exchange during fiberoptic bronchoscopy in spontaneously breathing hypoxemic patients, thus avoiding endotracheal intubation. However, it is unknown whether bronchoscopy can be performed safely in patients with acute hypoxemic respiratory failure already in need of NIV prior to the decision for bronchoscopy. METHODS: We prospectively investigated 40 consecutive, critically ill, adult patients with acute hypoxemic respiratory failure (14 women, 26 men, age 61 ± 15 years, partial pressure for oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 under noninvasive ventilation, Simplified Acute Physiology scores (SAPS II) 47 ± 9.9 points). All patients required noninvasive ventilation prior to the decision to perform bronchoscopy (median 10.5 h; range 2.2 to 114). Blood gases, heart rate, blood pressure and ventilation were monitored before, during and up to 120 minutes after bronchoscopy. RESULTS: Bronchoscopy could be completed in all patients without subsequent complications. Oxygen saturation fell to < 90% in two patients (5%), and the lowest value during the procedure was 84%. The mean PaO2/FiO2 ratio improved from 176 ± 54 at baseline to 240 ± 130 (P < 0.001) at the end of bronchoscopy and 210 ± 79 after 120 minutes. The transient mean partial pressure of carbon dioxide in the arterial blood (PaCO2) increase was 9.4 ± 8.1 mm Hg. Four patients (10%) required endotracheal intubation during the first eight hours after the procedure. Bronchoalveolar lavage yielded diagnostic information in 26 of 38 (68%) patients. CONCLUSIONS: In critically ill patients with acute hypoxemic respiratory failure requiring noninvasive ventilation, bronchoscopy can be performed with an acceptable risk. Since these patients per se have a high likelihood of subsequent endotracheal intubation due to failure of NIV, bronchoscopy should only be performed by experienced clinicians.

Molecular basis of P2-receptor-mediated calcium signaling in activated pancreatic stellate cells.

OBJECTIVES: There is growing evidence that extracellular nucleotide-induced signaling confers to fibrogenesis in liver and pancreas. Pancreatic stellate cells (PSC) are the most important cell type in pancreatic fibrosis. P2 purine and pyrimidine receptors, again, are pivotal mediators of inflammatory and profibrogenic signals. Our aim was to elucidate the underlying signaling components in activated PSC. METHODS: We performed expression analysis of calcium ion (Ca(2+)) signaling components and monitored real-time intracellular Ca(2+) responses to nucleotides in rat PSC. RESULTS: Adenosine monophosphate, adenosine diphosphate, and adenosine-5'-triphosphate elicited detectable rises in intracellular Ca(2+) concentrations. Stimulation of PSC by ATP led to intracellular Ca signals mediated through both P2X and P2Y receptors. Whereas uridine triphosphate-mediated Ca(2+) signals were generated by activation of P2Y receptors only, uridine diphosphate stimulated P2X receptors as well. Of the phospholipase C (PLC)/inositol-1,4,5-trisphosphate pathway, all PLC-facilitating Gα subunits were present in activated cells as were all 3 inositol-1,4,5-trisphosphate receptor isoforms. In addition, transcripts of PLC-ß and PLC-δ isoforms were also strongly detectable. CONCLUSIONS: Activated PSC feature a plethora of elements from the Ca signaling toolkit and functionally express a subset of P2 nucleotide receptors. Purines and pyrimidines elicit robust intracellular Ca(2+) signals likely contributing to the fibrogenetic potential of these cells.

Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease with poor prognosis. Encouraging efforts have been made to target the main vasoproliferative aspects of the disease. Promising emerging therapeutics are tyrosine kinase inhibitors such as imatinib. CASE PRESENTATION: Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi-tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing. CONCLUSION: We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data.

Pulmonary hypertension after ventriculoatrial shunt implantation.

OBJECT: Ventriculoatrial (VA) shunts inserted for the treatment of hydrocephalus are known to be a risk factor for pulmonary hypertension. The aim of this study was to evaluate the incidence of pulmonary hypertension among adult patients with VA shunts. METHODS: All patients who had received a VA shunt at one of two institutions between 1985 and 2000 were invited for a cardiopulmonary evaluation. The investigation included a thorough history taking, clinical examination, echocardiography, and pulmonary function testing including diffusing capacity of the lung for carbon monoxide (DLCO). Pulmonary hypertension was defined as systolic pulmonary artery pressure>35 mm Hg at rest. RESULTS: The study group consisted of 86 patients, of whom 38 (44%) could be examined. The patients' mean age was 47.1±18.4 years; the median interval between shunt insertion and cardiopulmonary evaluation was 15 years (range 5-20 years). Of the 38 patients, 20 (53%) had Doppler velocity profiles of tricuspid regurgitation that were adequate for the estimation of pulmonary artery systolic pressure. Doppler-defined pulmonary hypertension was observed in 3 patients (8%), 2 of whom underwent right heart catheterization. Chronic thromboembolic pulmonary hypertension was confirmed in both patients, and medical therapy, including anticoagulation, was started. The VA shunt was removed in both cases and replaced with a different type of device. Pulmonary function tests revealed a restrictive pattern in 15% and typical obstructive findings in 9% of patients. In 30% of patients the DLCO was less than 80% of predicted, and blood gas analysis showed hypoxemia in 6% of patients. No significant differences in pulmonary function tests were noted between the patients with and without echocardiographic evidence of pulmonary hypertension. However, patients with pulmonary hypertension had significantly lower DLCO values. CONCLUSIONS: The authors detected pulmonary hypertension by using Doppler echocardiography in a significant proportion of patients with VA shunts. It is therefore recommended that practitioners perform regular echocardiography and pulmonary function tests, including single-breath DLCO in these patients to screen for pulmonary hypertension to prevent hazardous late cardiopulmonary complications.

Dyspnea and pain share emotion-related brain network.

The early detection of stimuli signalling threat to an organism is a crucial evolutionary advantage. For example, the perception of aversive bodily sensations such as dyspnea and pain strongly motivates fast adaptive behaviour to ensure survival. Their similarly threatening and motivating characters led to the speculation that both sensations are mediated by common brain areas, which has also been suggested by neuroimaging studies on either dyspnea or pain. By using functional magnetic resonance imaging (fMRI), we formally tested this hypothesis and compared the cortical processing of perceived heat pain and resistive load induced dyspnea in the same group of participants. Here we show that the perception of both aversive sensations is processed in similar brain areas including the insula, dorsal anterior cingulate cortex, amygdala and medial thalamus. These areas have a documented role in the processing of emotions such as fear and anxiety. Thus, the current study highlights the role of a common emotion-related human brain network which underlies the perception of aversive bodily sensations such as dyspnea and pain. This network seems crucial for translating the threatening character of different bodily signals into behavioural consequences that promote survival.

Down-regulation of insular cortex responses to dyspnea and pain in asthma.

RATIONALE: Dyspnea is the impairing cardinal symptom of asthma but its accurate perception is also crucial for timely initiation of treatment. However, the underlying brain mechanisms of perceived dyspnea in patients with asthma are unknown. OBJECTIVES: To study brain mechanisms of dyspnea in asthma. METHODS: By using functional magnetic resonance imaging we compared the neuronal responses to experimentally induced dyspnea in patients with asthma and healthy controls. These brain activations were compared with neuronal responses evoked by pain to study neuronal generalization processes to another, similarly unpleasant, physiological sensation. MEASUREMENTS AND MAIN RESULTS: While lying in the scanner, fourteen patients with mild-to-moderate asthma and fourteen matched healthy controls repeatedly underwent conditions of mild dyspnea, severe dyspnea, mild pain and severe pain. Dyspnea was induced by resistive loaded breathing. Heat pain of similar intensity was induced by a contact thermode. Whereas the sensory intensity of both sensations was rated similar by patients and controls, ratings of the affective unpleasantness of dyspnea and pain were reduced in patients. This perceptual difference was mirrored by reduced insular cortex activity, but increased activity in the periaqueductal gray (PAG) in patients during both increased dyspnea and pain. Connectivity analyses showed that asthma-specific down-regulation of the insular cortex during dyspnea and pain was moderated by increased PAG activity. CONCLUSIONS: The results suggest a down-regulation of affect-related insular cortex activity by the PAG during perceived dyspnea and pain in patients with asthma. This might represent a neuronal habituation mechanism reducing the affective unpleasantness of dyspnea in asthma, which generalizes to other unpleasant physiological sensations such as pain.

Development of pulmonary hypertension in adults after ventriculoatrial shunt implantation.

BACKGROUND: The insertion of ventriculoatrial (VA) shunts for the treatment of hydrocephalus is thought to be associated with the development of pulmonary hypertension in adults. OBJECTIVES: It was the aim of this study to describe the frequency and the clinical spectrum of pulmonary hypertension in adults with VA shunts. METHODS: Patients with pulmonary hypertension were retrospectively evaluated from January 1999 to December 2006. RESULTS: Among the 575 patients with pulmonary hypertension, 6 (mean age 42.5 +/- 8.3 years) were identified as having received a VA shunt. Mean pulmonary artery pressure for these patients was 53.3 +/- 14.9 mm Hg. The interval between shunt placement and the diagnosis of pulmonary hypertension was 9-27 years (median 16.5). While ventilation perfusion scans showed multiple bilateral perfusion defects in all patients, chest CT or pulmonary angiography demonstrated pulmonary thromboembolism in only 2 of the 6 patients. These 2 patients subsequently underwent pulmonary endarterectomy. Another patient required heart-lung transplantation because of severe pulmonary hypertension; lung histology showed prominent eccentric medial hypertrophy and intimal proliferation without evidence of thromboembolism. Contrary to earlier reports, outcomes were generally good, with a 100% survival rate for the first 8 years following diagnosis. CONCLUSIONS: Severe pulmonary hypertension can develop in adult patients with VA shunts. Therefore, clinicians should consider pulmonary hypertension as a potential cause for respiratory symptoms in patients who have received VA shunts.

Tracheostomy in the intensive care unit: a nationwide survey.

BACKGROUND: The indication, timing and technique of tracheostomy have changed over the last several years. We performed a survey to assess the current practice of tracheostomy in German intensive care units (ICUs). METHODS: A postal questionnaire was sent to the head physicians of 513 German ICUs, excluding pediatric ICUs. RESULTS: We obtained responses from 455 of the 513 ICUs (89%). In 90% of the ICUs, tracheostomies were performed during the first 14 d of mechanical ventilation. Eighty-six percent of the ICUs routinely performed percutaneous dilatational tracheostomy; the modified Ciaglia technique was the most popular percutaneous technique (69%). The majority (98%) of the percutaneous procedures were performed under bronchoscopic control. Surgical tracheostomy is usually performed in the operating room (72%) by a surgeon (61%), whereas percutaneous dilatational tracheostomies are usually performed at the patient's bedside in the ICU (98%) by an intensivist (93%). Tracheostomized patients were followed up routinely in 26% of the ICUs, and in 45% of the ICUs there were guidelines regarding the indication, the timing and the technique of tracheostomy. CONCLUSION: Percutaneous dilatational tracheostomy is the procedure of choice for tracheostomy in critically ill patients in Germany. The modified Ciaglia technique is the preferred percutaneous technique, and nearly all physicians routinely use bronchoscopic guidance. Most tracheostomies are done during the second week of mechanical ventilation.

Safety of percutaneous dilational tracheostomy in hematopoietic stem cell transplantation recipients requiring long-term mechanical ventilation.

PURPOSE: Recent reports have shown that the outcome of mechanically ventilated patients after hematopoietic stem cell transplantation (HSCT) has improved. This study was conducted to clarify if percutaneous dilational tracheostomy is safe in this group of patients and to report the outcome of HSCT recipients requiring long-term mechanical ventilation. METHODS: A retrospective review of our 8-year experience with patients with acute respiratory insufficiency after HSCT, requiring long-term mechanical ventilation and percutaneous dilational tracheostomy and an analysis of patient outcomes were made. RESULTS: Percutaneous dilational tracheostomy was safely performed in all 51 patients. Although 1 patient (2%) developed a pneumothorax that required drainage, stoma infections or severe bleeding complications were not observed. Of the 51 patients in the study, 14 (27%) survived the intensive care unit stay, and 10 of them were ventilated for more than 20 days. The intensive care unit survival rate for the period from 1998 to 2001 was 11% compared with 38% for the period from 2002 to 2005 (P = .053). CONCLUSIONS: Percutaneous dilational tracheostomy can be safely performed on patients with acute respiratory failure after HSCT. This procedure did not result in postoperative wound infections or significant bleeding complications. Furthermore, the results of our study indicate that today even patients with prolonged mechanical ventilation (>20 days) have a chance of long-term survival.

The unpleasantness of perceived dyspnea is processed in the anterior insula and amygdala.

RATIONALE: The subjective perception of dyspnea, which is an impairing symptom in various cardiopulmonary diseases, consists of sensory (intensity) and affective aspects (unpleasantness). However, little is known about the cortical processing of the perception of dyspnea. OBJECTIVES: To investigate the cortical areas associated with the processing of the affective unpleasantness of perceived dyspnea. METHODS: Brain imaging study using functional magnetic resonance imaging in 14 healthy volunteers. MEASUREMENTS AND MAIN RESULTS: Dyspnea was induced by inspiratory resistive loaded breathing with concomitant positive and negative emotional stimulation by viewing standardized emotional picture series. The blood oxygen level-dependent contrast was measured as an index of local neuronal activity while respiration was continuously monitored. Negative emotional stimulation during loaded breathing was associated with higher unpleasantness of perceived dyspnea when compared with loaded breathing with concomitant positive emotional stimulation (P < 0.05). The levels of intensity of perceived dyspnea, respiratory responses, and load magnitude were similar between both conditions. Higher unpleasantness of dyspnea was associated with neuronal activations in the limbic system-that is, in the right anterior insula and in the right amygdala (respective Z values = 3.93 and 3.15; P < 0.05). CONCLUSIONS: The results of the present brain imaging study suggest that the unpleasantness of subjectively perceived dyspnea is processed in the right human anterior insula and amygdala.

Percutaneous tracheostomy is safe in patients with severe thrombocytopenia.

STUDY OBJECTIVES: Severe thrombocytopenia has been described as a contraindication for percutaneous tracheostomy (PT). The objective of this study was to assess the safety of PT in mechanically ventilated patients with severe thrombocytopenia (defined by a platelet count of < 50 x 10(9) cells/L). DESIGN: Retrospective, single-center cohort study. SETTING: Medical ICU of the University Hospital Hamburg-Eppendorf, Germany. PATIENTS: Forty-two medical patients with acute respiratory failure and severe thrombocytopenia. INTERVENTIONS: Bedside PT under bronchoscopic guidance using the Griggs guidewire forceps technique. MEASUREMENTS AND MAIN RESULTS: The mean (+/- SD) intubation time prior to undergoing PT was 6.7 +/- 3.9 days (range, 1 to 20 days). The mean platelet count was 26.4 +/- 11.6 x 10(9) cells/L (range, 1 x 10(9) to 47 x 10(9) cells/L). The median transfusion of platelets before the procedure in 40 of the 42 patients was 6 +/- 2.5 U (range, 3 to 12 U). Twenty-two patients (52%) had an additional coagulopathy (activated partial thromboplastin time [APTT], > 40 s; international normalized ratio, > 1.5). PT was safely performed in all 42 patients. Only two (5%) patients developed major postprocedural bleeding complications that required suturing. Both of these patients had an elevated APTT due to heparin therapy. CONCLUSIONS: When performed by experienced personnel, PT with bronchoscopic guidance has a low complication rate in patients with severe thrombocytopenia, provided that platelets are administered beforehand. However, in order to minimize bleeding complications heparin infusions should be temporarily interrupted during the procedure.