Effects of prone positioning on lung mechanical power components in patients with acute respiratory distress syndrome: a physiologic study.

BACKGROUND: Prone positioning (PP) homogenizes ventilation distribution and may limit ventilator-induced lung injury (VILI) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The static and dynamic components of ventilation that may cause VILI have been aggregated in mechanical power, considered a unifying driver of VILI. PP may affect mechanical power components differently due to changes in respiratory mechanics; however, the effects of PP on lung mechanical power components are unclear. This study aimed to compare the following parameters during supine positioning (SP) and PP: lung total elastic power and its components (elastic static power and elastic dynamic power) and these variables normalized to end-expiratory lung volume (EELV). METHODS: This prospective physiologic study included 55 patients with moderate to severe ARDS. Lung total elastic power and its static and dynamic components were compared during SP and PP using an esophageal pressure-guided ventilation strategy. In SP, the esophageal pressure-guided ventilation strategy was further compared with an oxygenation-guided ventilation strategy defined as baseline SP. The primary endpoint was the effect of PP on lung total elastic power non-normalized and normalized to EELV. Secondary endpoints were the effects of PP and ventilation strategies on lung elastic static and dynamic power components non-normalized and normalized to EELV, respiratory mechanics, gas exchange, and hemodynamic parameters. RESULTS: Lung total elastic power (median [interquartile range]) was lower during PP compared with SP (6.7 [4.9-10.6] versus 11.0 [6.6-14.8] J/min; P < 0.001) non-normalized and normalized to EELV (3.2 [2.1-5.0] versus 5.3 [3.3-7.5] J/min/L; P < 0.001). Comparing PP with SP, transpulmonary pressures and EELV did not significantly differ despite lower positive end-expiratory pressure and plateau airway pressure, thereby reducing non-normalized and normalized lung elastic static power in PP. PP improved gas exchange, cardiac output, and increased oxygen delivery compared with SP. CONCLUSIONS: In patients with moderate to severe ARDS, PP reduced lung total elastic and elastic static power compared with SP regardless of EELV normalization because comparable transpulmonary pressures and EELV were achieved at lower airway pressures. This resulted in improved gas exchange, hemodynamics, and oxygen delivery. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00017449). Registered June 27, 2019. https://drks.de/search/en/trial/DRKS00017449.

[Artificial intelligence in intensive care medicine]. / Künstliche Intelligenz in der Intensivmedizin.

The integration of artificial intelligence (AI) into intensive care medicine has made considerable progress in recent studies, particularly in the areas of predictive analytics, early detection of complications, and the development of decision support systems. The main challenges remain availability and quality of data, reduction of bias and the need for explainable results from algorithms and models. Methods to explain these systems are essential to increase trust, understanding, and ethical considerations among healthcare professionals and patients. Proper training of healthcare professionals in AI principles, terminology, ethical considerations, and practical application is crucial for the successful use of AI. Careful assessment of the impact of AI on patient autonomy and data protection is essential for its responsible use in intensive care medicine. A balance between ethical and practical considerations must be maintained to ensure patient-centered care while complying with data protection regulations. Synergistic collaboration between clinicians, AI engineers, and regulators is critical to realizing the full potential of AI in intensive care medicine and maximizing its positive impact on patient care. Future research and development efforts should focus on improving AI models for real-time predictions, increasing the accuracy and utility of AI-based closed-loop systems, and overcoming ethical, technical, and regulatory challenges, especially in generative AI systems.

Case Report: Fetoscopic Laparoschisis (FETO-LAP)-A New Therapeutic Route to Explore for Fetuses with Severe Diaphragmatic Hernias.

BACKGROUND: The purpose of this report is to describe the seminal case of a near-term human fetus with a life-threatening left diaphragmatic hernia that underwent fetoscopic tracheal occlusion (FETO) combined with fetoscopic partial removal of herniated bowel from the fetal chest by fetoscopic laparoschisis (FETO-LAP). CASE SUMMARY: A life-threatening left diaphragmatic hernia (liver-up; o/e LHR of ≤25%; MRI lung volume ≤ 20%) was observed in a human fetus at 34 weeks of gestation. After counselling the mother about the high risks of postnatal demise if left untreated, the expected limitations of fetoscopic tracheal occlusion (FETO), and the previously untested option of combining FETO with fetoscopic laparoschisis, i.e., partial removal of the herniated bowel from the fetal chest (FETO-LAP), she consented to the latter novel treatment approach. FETO-LAP was performed at 36 + 5 weeks of gestation under general maternofetal anesthesia. Mother and fetus tolerated the procedure well. The neonate was delivered and the balloon removed on placental support at 37 + 2 weeks of gestation. On ECMO, a rapid increase in tidal volume was seen over the next eight days. Unfortunately, after this period, blood clots obstructed the ECMO circuit and the neonate passed away. DISCUSSION: This seminal case shows that in a fetus with severe left diaphragmatic hernia, partial removal of the herniated organs from the fetal chest is not only possible by minimally invasive fetoscopic techniques but also well tolerated. As the effect of FETO alone is limited in saving severely affected fetuses, combining FETO with fetoscopic laparoschisis (FETO-LAP) offers a new therapeutic route with multiple, potentially life-saving implications.

Perioperative systemic magnesium sulfate minimizes the incidence of atrial fibrillation after thoracotomy for lung resection: a prospective observational study.

Background: Postoperative atrial fibrillation (POAF) is the most common complication following general thoracic surgery. POAF significantly increases the risk of adverse cardiovascular events, such as thromboembolism, heart failure, and mortality. Additionally, it also leads to prolonged hospital stays and higher costs. The objective of this observational study was to examine the impact of perioperative administration of magnesium sulphate (MgSO4) on the incidence of POAF. Methods: A prospective observational study was conducted, enrolling one hundred patients undergoing thoracotomy for lung resection. We compared the incidence of atrial fibrillation (AF) before and after implementing a change in our standard anesthetic management, which involved the addition of MgSO4. MgSO4 was administered during anesthesia induction at a dose of 40 mg/kg over ten minutes, followed by a 24-hour infusion at a rate of 10 mg/kg/h. The primary outcome was the incidence of POAF within the first seven days after surgery. Results: Within the initial three days following surgery, there was no significant difference in the cumulative incidence of POAF between the MgSO4 group and the control group. However, on postoperative day 7, patients treated with MgSO4 exhibited a reduced incidence of POAF compared to the control group (4% vs. 26%; P=0.01). In the subgroup of patients not receiving pre-existing ß-blockers, the addition of MgSO4 significantly decreased the occurrence of POAF (14% vs. 80%; P<0.001). Conclusions: Prophylactic administration of MgSO4 is a potentially beneficial approach for reducing the incidence of POAF after non-cardiac surgery, particularly in patients not receiving long-term ß-blocker treatment.

Effects of individualised positive end-expiratory pressure titration on respiratory and haemodynamic parameters during the Trendelenburg position with pneumoperitoneum: A randomised crossover physiologic trial.

BACKGROUND: The Trendelenburg position with pneumoperitoneum during surgery promotes dorsobasal atelectasis formation, which impairs respiratory mechanics and increases lung stress and strain. Positive end-expiratory pressure (PEEP) can reduce pulmonary inhomogeneities and preserve end-expiratory lung volume (EELV), resulting in decreased inspiratory strain and improved gas-exchange. The optimal intraoperative PEEP strategy is unclear. OBJECTIVES: To compare the effects of individualised PEEP titration strategies on set PEEP levels and resulting transpulmonary pressures, respiratory mechanics, gas-exchange and haemodynamics during Trendelenburg position with pneumoperitoneum. DESIGN: Prospective, randomised, crossover single-centre physiologic trial. SETTING: University hospital. PATIENTS: Thirty-six patients receiving robot-assisted laparoscopic radical prostatectomy. INTERVENTIONS: Randomised sequence of three different PEEP strategies: standard PEEP level of 5 cmH 2 O (PEEP 5 ), PEEP titration targeting a minimal driving pressure (PEEP ΔP ) and oesophageal pressure-guided PEEP titration (PEEP Poeso ) targeting an end-expiratory transpulmonary pressure ( PTP ) of 0 cmH 2 O. MAIN OUTCOME MEASURES: The primary endpoint was the PEEP level when set according to PEEP ΔP and PEEP Poeso compared with PEEP of 5 cmH 2 O. Secondary endpoints were respiratory mechanics, lung volumes, gas-exchange and haemodynamic parameters. RESULTS: PEEP levels differed between PEEP ΔP , PEEP Poeso and PEEP5 (18.0 [16.0 to 18.0] vs. 20.0 [18.0 to 24.0]vs. 5.0 [5.0 to 5.0] cmH 2 O; P  < 0.001 each). End-expiratory PTP and lung volume were lower in PEEP ΔP compared with PEEP Poeso ( P  = 0.014 and P  < 0.001, respectively), but driving pressure, lung stress, as well as respiratory system and dynamic elastic power were minimised using PEEP ΔP ( P  < 0.001 each). PEEP ΔP and PEEP Poeso improved gas-exchange, but PEEP Poeso resulted in lower cardiac output compared with PEEP 5 and PEEP ΔP . CONCLUSION: PEEP ΔP ameliorated the effects of Trendelenburg position with pneumoperitoneum during surgery on end-expiratory PTP and lung volume, decreased driving pressure and dynamic elastic power, as well as improved gas-exchange while preserving cardiac output. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00028559, date of registration 2022/04/27). https://drks.de/search/en/trial/DRKS00028559.

Corrigendum: Endothelial Progenitor and Mesenchymal Stromal Cells in Newborns With Congenital Diaphragmatic Hernia Undergoing Extracorporeal Membrane Oxygenation.

[This corrects the article DOI: 10.3389/fped.2019.00490.].

Increased mobilization of mesenchymal stem cells in patients with acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is characterized by pulmonary epithelial and endothelial barrier dysfunction and injury. In severe forms of ARDS, extracorporeal membrane oxygenation (ECMO) is often the last option for life support. Endothelial progenitor (EPC) and mesenchymal stem cells (MSC) can regenerate damaged endothelium and thereby improve pulmonary endothelial dysfunction. However, we still lack sufficient knowledge about how ECMO might affect EPC- and MSC-mediated regenerative pathways in ARDS. Therefore, we investigated if ECMO impacts EPC and MSC numbers in ARDS patients. METHODS: Peripheral blood mononuclear cells from ARDS patients undergoing ECMO (n = 16) and without ECMO support (n = 12) and from healthy volunteers (n = 16) were isolated. The number and presence of circulating EPC and MSC was detected by flow cytometry. Serum concentrations of vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) were determined. RESULTS: In the ECMO group, MSC subpopulations were higher by 71% compared to the non-ECMO group. Numbers of circulating EPC were not significantly altered. During ECMO, VEGF and Ang2 serum levels remained unchanged compared to the non-ECMO group (p = 0.16), but Ang2 serum levels in non-survivors of ARDS were significantly increased by 100% (p = 0.02) compared to survivors. CONCLUSIONS: ECMO support in ARDS is specifically associated with an increased number of circulating MSC, most likely due to enhanced mobilization, but not with a higher numbers of EPC or serum concentrations of VEGF and Ang2.

Endothelial Progenitor and Mesenchymal Stromal Cells in Newborns With Congenital Diaphragmatic Hernia Undergoing Extracorporeal Membrane Oxygenation.

Background: Endothelial progenitor (EPC) and mesenchymal stromal cells (MSC) can regenerate damaged endothelium and thereby improve pulmonary endothelial dysfunction. We do not know, how extracorporeal membrane oxygenation (ECMO) might affect EPC- and MSC-mediated regenerative pathways in patients with congenital diaphragmatic hernia (CDH). Therefore, we investigated, if ECMO support impacts EPC and MSC numbers in CDH patients. Methods: Peripheral blood mononuclear cells from newborns with ECMO-dependent (n = 18) and ECMO-independent CDH (n = 12) and from healthy controls (n = 12) were isolated. The numbers of EPC and MSC were identified by flowcytometry. Serum levels of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 were determined. Results: EPC and MSC were elevated in newborns with CDH. ECMO-dependent infants had higher EPC subpopulation counts (2,1-7,6-fold) before treatment compared to ECMO-independent infants. In the disease course, EPC and MSC subpopulation counts in ECMO-dependent infants were lower than before ECMO initiation. During ECMO, VEGF serum levels were significantly reduced (by 90.5%) and Ang2 levels significantly increased (by 74.8%). Conclusions: Our data suggest that ECMO might be associated with a rather impaired mobilization of EPC and MSC and with a depression of VEGF serum levels in newborns with CDH.

Impact of different emulsifiers on biocompatibility and inflammatory potential of Perfluorohexyloctane (F6H8) emulsions for new intravenous drug delivery systems.

BACKGROUND: Emulsions on the basis of Perfluorohexyloctane (F6H8), a semifluorinated alkane (SFA), have shown to dissolve and transport highly lipophilic compounds. It is unknown how F6H8-containing emulsions (F6H8-cEM) interact with compartment blood, the reticuloendothelial system (RES), or influence injured organs in vivo. The current study was conducted to investigate the in vitro biocompatibility of F6H8-cEM and their drug delivery properties. Afterward, an in vivo study was performed as a proof-of-concept study in a rat model of acute kidney injury (AKI), which focused on the potential influence of F6H8-cEM on inflammation in an injured organ. METHODS: Two different F6H8-cEM were stabilized by the emulsifying agents Poloxamer 188 (Pluronic® F68) or lecithin (S75). The two resulting emulsions F6H8-Pluronic or F6H8-lecithin were tested in vitro for the potential modulation of acute inflammation via whole blood assay, FACS, and ELISA. Antioxidant capacity and drug delivery properties were measured with an oxidation assay. Secondly, AKI was induced in the rats, which were treated with the F6H8-lecithin emulsion. Renal function and inflammation were assessed. RESULTS: Both F6H8-cEM were phagocytized by monocytes and both dose-dependently affected apoptosis (Annexin V binding) in monocytes. TNF-α expression increased dose-dependency for F6H8-Pluronic emulsion but not for F6H8-lecithin in a whole blood assay. Both F6H8-cEM were able to carry α-tocopherol as a model drug. Animals with AKI treated with the F6H8-lecithin emulsion showed a significantly better renal function and less infiltration of inflammatory cells in renal tissue compared to the control, while inflammatory markers in renal tissue, except HO-1, were not affected by F6H8-lecithin. CONCLUSIONS: Pluronic® F68 does not seem suitable as a biocompatible surfactant for F6H8-cEM. The injured kidney was not negatively influenced by the F6H8-lecithin emulsion. Lecithin-stabilized F6H8-cEM could be tested for preclinical studies as a carrier system for lipophilic agents.

Intravenous delivery of granulocyte-macrophage colony stimulating factor impairs survival in lipopolysaccharide-induced sepsis.

BACKGROUND: Cell-based therapies with bone marrow-derived progenitor cells (BMDPC) lead to an improved clinical outcome in animal sepsis models. In the present study we evaluated the ability of granulocyte macrophage-colony stimulating factor (GM-CSF) to mobilize BMDPC in a lipopolysaccharide (LPS)-induced sepsis model and thereby its potential as a novel treatment strategy. METHODS: Male Wistar rats received LPS (25µg/kg/h for 4 days) intravenously and were subsequently treated with GM-CSF 12.5µg/kg (0h,24h,48h,72h). As control groups, rats were infused with sodium chloride or GM-CSF only. Clinical and laboratory parameters, proinflammatory plasma cytokines as well as BMDPC counts were analyzed. Cytokine release by isolated peripheral blood mononuclear cells from rat spleen upon incubation with LPS, GM-CSF and a combination of both were investigated in vitro. RESULTS: In vivo, rats receiving both LPS and GM-CSF, showed a reduced weight loss and increased mobilization of BMDPC. At the same time, this regime resulted in an increased release of proinflammatory cytokines (IL-6, IL-8) and a significantly increased mortality. In vitro, the combination of LPS and GM-CSF showed a significantly increased IL-6 release upon incubation compared to incubation with LPS or GM-CSF alone. CONCLUSIONS: GM-CSF did not have a beneficial effect on the clinical course in our LPS-induced sepsis model. It synergistically promoted inflammation with LPS and probably thereby impaired survival.

Perioperative systemic magnesium sulphate to minimize acute and chronic post-thoracotomy pain: a prospective observational study.

BACKGROUND: Thoracotomy leads to acute and chronic post-thoracotomy pain (CPTP). The purpose of this study was to investigate the effect of magnesium sulphate (MgSO4) administered perioperatively on acute postoperative and CPTP syndrome. METHODS: One hundred patients were enrolled in this prospective, observational study. Analgesic medication was provided according to the World Health Organization pain relief ladder (control group). The study group received additionally MgSO4 (40 mg/kg over 10 minutes) during induction of anesthesia followed by an infusion over 24 hours (10 mg/kg/h). The presence and severity of pain were assessed before surgery, on postsurgical days 1-8, 30 and 90, respectively. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) was used pre- and postoperatively for documentation of neuropathic pain. The incidence and severity of CPTP were assessed by a telephone survey 30 and 90 days after surgery. RESULTS: Numerical rating scale (NRS) pain scores at rest were significantly lower in the study group receiving MgSO4 at days 1 to 8 (P<0.05). Thirty days after surgery, 2.1% of the MgSO4-patients had a LANSS score ≥12 compared to 14.3% in the control group (P=0.031). No patient had a LANSS score ≥12 in the study group compared to the control group (0% vs. 12.2%, P<0.05) 90 days following surgery. CONCLUSIONS: MgSO4 administration reduces postoperative pain at rest according to the NRS pain scores and is effective in preventing chronic neuropathic post-thoracotomy pain measured by LANSS score. Prospective-randomized trials are needed to confirm the results of the present study.

CXCR-4 expression by circulating endothelial progenitor cells and SDF-1 serum levels are elevated in septic patients.

BACKGROUND: Endothelial progenitor cell (EPC) numbers are increased in septic patients and correlate with survival. In this study, we investigated, whether surface expression of chemokine receptors and other receptors important for EPC homing is upregulated by EPC from septic patients and if this is associated with clinical outcome. METHODS: Peripheral blood mononuclear cells from septic patients (n = 30), ICU control patients (n = 11) and healthy volunteers (n = 15) were isolated by Ficoll density gradient centrifugation. FACS-analysis was used to measure the expression of the CXC motif chemokine receptors (CXCR)-2 and - 4, the receptor for advanced glycation endproducts (RAGE) and the stem cell factor receptor c-Kit. Disease severity was assessed via the Simplified Acute Physiology Score (SAPS) II. The serum concentrations of vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF)-1α and angiopoietin (Ang)-2 were determined with Enzyme linked Immunosorbent Assays. RESULTS: EPC from septic patients expressed significantly more CXCR-4, c-Kit and RAGE compared to controls and were associated with survival-probability. Significantly higher serum concentrations of VEGF, SDF-1α and Ang-2 were found in septic patients. SDF-1α showed a significant association with survival. CONCLUSIONS: Our data suggest that SDF-1α and CXCR-4 signaling could play a crucial role in EPC homing in the course of sepsis.

VCAM-1 expression is upregulated by CD34+/CD133+-stem cells derived from septic patients.

CD34+/CD133+- cells are a bone marrow derived stem cell population, which presumably contain vascular progenitor cells and are associated with improved vascular repair. In this study, we investigated whether the adhesion molecules ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular adhesion molecule-1), E-selectin und L-selectin, which are involved in homing of vascular stem cells, are upregulated by CD34+/CD133+-stem cells from septic patients and would be associated with improved clinical outcome. Peripheral blood mononuclear cells from intensive care unit (ICU) patients with (n = 30) and without sepsis (n = 10), and healthy volunteers (n = 15) were isolated using Ficoll density gradient centrifugation. The expression of VCAM-1, ICAM-1, E-selectin and L-selectin was detected on CD34+/CD133+-stem cells by flow cytometry. The severity of disease was assessed by the Simplified Acute Physiology Score (SAPS) II. Serum concentrations of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 were determined by Enzyme-linked immunosorbent assay. The expression of VCAM-1, ICAM-1, E-selectin and L-selectin by CD34+/CD133+-stem cells was significantly upregulated in septic patients, and correlated with sepsis severity. Furthermore, high expression of VCAM-1 by CD34+/CD133+-stem cells revealed a positive association with mortalitiy (p<0.05). Furthermore, significantly higher serum concentrations of VEGF and Ang-2 were found in septic patients, however none showed a strong association with survival. Our data suggest, that VCAM-1 upregulation on CD34+/CD133+-stem cells could play a crucial role in their homing in the course of sepsis. An increase in sepsis severity resulted in both and increase in CD34+/CD133+-stem cells and VCAM-1-expression by those cells, which might reflect an increase in need for vascular repair.

Evaluation of pharmacokinetic properties and anaesthetic effects of propofol in a new perfluorohexyloctane (F6H8) emulsion in rats--A comparative study.

Propofol (2,6-diisopropylphenol) is a safe and widely used anaesthetic, but due to low water solubility and high lipophilicity a difficult compound to formulate. The solubility of propofol in the semifluorinated alkane perfluorohexyloctane (F6H8) is very high (>300 mg/ml). In the present work we investigate if a F6H8-based emulsion could be used as a new intravenous drug delivery system for propofol from a pharmacokinetic, pharmacodynamic and safety point of view. The pharmacokinetic parameters were evaluated after an intravenous bolus injection of either Disoprivan(®) or a F6H8-based propofol emulsion in Wistar rats. The onset and end of sedation after multiple dosings (5, 10 and 15 mg/kg bw) were examined. Clinical chemistry and histology were assessed. No significant difference was found for any of the pharmacokinetic parameters. No differences in the onset nor the end of sedation in the tested dosages could be detected. Histology scores revealed no differences. A slightly increased alanine aminotransferase (ALT) was measured after multiple application of the F6H8-propofol emulsion. In conclusion, the F6H8-propofol emulsion showed no significant different pharmacokinetics and sedation properties, compared to a commercial soy-based propofol emulsion. Further, no toxic effects could be detected on the F6H8 emulsion indicating it was a safe excipient in rats.

Comparing Patient Satisfaction and Intubating Conditions Using Succinylcholine or Low-Dose Rocuronium for Rigid Bronchoscopy: A Randomized Study.

INTRODUCTION: Despite its serious side effects, succinylcholine is commonly used for neuromuscular relaxation in short procedures, such as rigid bronchoscopy and tracheobronchial interventions. The application of low-dose rocuronium reversed by low-dose sugammadex might be a modern alternative. The aim of this study was to compare patient satisfaction, incidence of postoperative myalgia (POM) as well as intubating conditions of these two muscle relaxants for rigid bronchoscopy. METHODS AND MATERIALS: A single-center, prospective-randomized, blinded study of 95 patients, scheduled for rigid bronchoscopy and tracheobronchial intervention was conducted. The patients were anesthetized with propofol, remifentanil and either low-dose succinylcholine (S) (0.5 mg/kg) or low-dose rocuronium (0.25 mg/kg) with sugammadex (RS) (0.5 mg/kg). All patients were evaluated on the first and second postinterventional day for their satisfaction with the treatment (rigid bronchoscopy) using a Numeric Analog Rating Scale (NAS 0-10) and the presence and severity of POM (NAS 1-4). Intubating conditions were assessed as excellent, good, or poor on the basis of position of vocal cords and reaction to insertion of the rigid bronchoscope. RESULTS: Patients in the S group were less satisfied with the treatment than patients in RS group (72.7 vs. 93.7%, p = 0.007). The incidence of POM on the first day after intervention was significantly higher in the S group then in the RS group (56.9% vs. 4.3%, p < 0.001). Although the intubation was faster (p < 0.001) and the intubating conditions significantly superior (p < 0.003) with succinylcholine, acceptable conditions were also achieved with low-dose rocuronium in 75% of patients. The anesthetic drug costs were significantly higher in the RS group then in the S group (p < 0.001). CONCLUSION: The results suggest that low-dose rocuronium provided better patient satisfaction and less POM. But with the use of low-dose succinylcholine, the intubating conditions are more comfortable, and it is less expensive than rocuronium/sugammadex.

Bone marrow-derived progenitor cells attenuate inflammation in lipopolysaccharide-induced acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the most common cause of respiratory failure among critically ill patients. Novel treatment strategies are required to address this common clinical problem. The application of exogenous adult stem cells was associated with a beneficial outcome in various pre-clinical models of ARDS. In the present study we evaluated the functional capacity and homing ability of bone marrow-derived progenitor cells (BMDPC) in vitro and investigated their potential as a treatment strategy in lipopolysaccharide (LPS)-induced ARDS. RESULTS: Evaluation of the BMDPC showed functional capacity to form endothelial outgrowth cell colonies, which stained positive for CD133 and CD31. Furthermore, DiI-stained BMDPC were demonstrated to home to injured lung tissue. Rats treated with BMDPC showed significantly reduced histopathological changes, a reduced expression of ICAM-1 and VCAM-1 by the lung tissue, an inhibition of proinflammatory cytokine synthesis, a reduced weight loss and a reduced mortality (p < 0.03) compared to rats treated with LPS alone. CONCLUSIONS: These findings suggest that the application of exogenous BMDPC can attenuate inflammation in LPS-induced ARDS and thereby reduce the severity of septic organ damage. Cell therapy strategies using adult stem cells might therefore become a novel and alternative option in ARDS therapy.

Catecholamines reduce dose-dependent oedema formation and inflammatory reaction in an isolated rat lung model.

AIM: Since we detected that donor dopamine pre-treatment ameliorates lung function after hypothermia and ischaemia/reperfusion in an isolated rat lung model we studied, whether other catecholamines have beneficial effects on lungs. MATERIALS AND METHODS: Rats were treated with noradrenaline, adrenaline or dobutamine in different doses. Thereafter lungs were explanted, flushed with Perfadex® solution and stored at 4°C for different time periods. Oedema production was measured and inflammatory mediators were analysed after reperfusion and ventilation. RESULTS: Low-dose noradrenaline or dobutamine did not reduce tissue oedema after eight hours of hypothermia, whereas higher doses significantly reduced oedema formation. Low-dose catecholamines did not prevent the inflammatory response, whereas higher doses of beta-receptor-stimulating catecholamines significantly blunted inflammatory reaction. CONCLUSION: This study demonstrates that adrenergic-receptor-stimulating catecholamines have a protective dose-dependent effect on lungs after hypothermia and ischaemia/reperfusion. Although noradrenaline and dobutamine have similar dose-dependent organ-protective effects to dopamine, they have more side-effects.

Alterations of circulating bone marrow-derived VEGFR-2+ progenitor cells in isolated limb perfusion with or without rhTNF-α.

BACKGROUND: Circulating endothelial progenitor cells (cEPCs) as recruited to the angiogenic vascular system of malignant tumors have been proposed as a biomarker in malignancies. The effect of antitumor chemotherapy on cEPCs is not fully understood. We examined the level of cEPCs, vascular endothelial growth factor (VEGF), and angiopoietin-2 in the blood of sarcoma and melanoma patients before and after isolated limb perfusion (ILP) with or without recombinant human tumor necrosis factor-α (rhTNF-α). METHODS: Twenty-two patients, 11 each with soft tissue sarcoma or recurrent melanoma of the limb, were recruited. ILP was performed with rhTNF-α/melphalan (TNF) or melphalan only (no TNF). Fifteen healthy volunteers served as control subjects. Blood was sampled before and up to 6 weeks after ILP. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, and annexin V-negative cells were characterized as cEPCs by triple staining for CD133(+), CD34, and VEGFR-2(+). RESULTS: Before treatment, cEPC numbers were significantly increased in sarcoma (0.179 ± 0.190 %) and melanoma patients (0.110 ± 0.073 %) versus healthy controls (0.025 ± 0.018 %; P < 0.01), but did not differ significantly between sarcoma and melanoma patients. cEPC decreased significantly after ILP in patients with no TNF compared to pretreatment values (P < 0.05) and were significantly lower at 4 h, 48 h, and 1 week compared to ILP with TNF (P < 0.05). Values 6 weeks after ILP were significantly lower than before ILP in both investigated groups (P < 0.01). CONCLUSIONS: ILP with TNF results in activation of bone marrow-derived EPCs compared to ILP without TNF. Alteration of cEPCs and angiopoietin-2 by rhTNF-α might account for the cytotoxicity and hemorrhagic effects on tumor vessels during limb perfusion procedures.

Endothelial progenitor cells in regeneration after acute lung injury: do they play a role?

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common disorders in patients requiring critical care. The clinical management of these disorders is difficult and unrewarding, and thus they are among the most common causes of death in intensive care units. The activation and damage of pulmonary endothelium comprise the hallmark of ALI/ARDS. Therefore, the recruitment of circulating endothelial progenitor cells (EPCs) to these lesions may exert a beneficial effect on the clinical course of ALI/ARDS. Consequently, cell-based therapies using stem cells to regenerate lung tissue have emerged as potential novel treatment strategies. Although initial studies suggested implantations of exogenously administered bone marrow-derived progenitor cells into damaged vessel walls, recent evidence indicates that this is rather a rare occurrence with uncertain physiologic significance. In the past few years, different populations of progenitor cells were identified, with different functional capacities. This review (1) highlights the different populations of EPCs identified or administered in different models of ALI/ARDS, (2) reports on whether beneficial effects of EPCs could be demonstrated, and (3) puts the conflicting results of different studies into perspective.