[Ocular sarcoidosis : Diagnosis and therapy]. / Okulare Sarkoidose : Diagnose und Therapie.

Sarcoidosis is a multisystem disorder of unknown cause. Ophthalmic involvement occurs in up to 60% of all patients, often as the first manifestation of sarcoidosis. Because of the heterogeneous clinical presentation diagnosis can be difficult; therefore the International Workshop on Ocular Sarcoidosis (IWOS 2009) diagnostic criteria based on clinical presentation, laboratory investigations and imaging techniques enable establishment of the diagnosis. Patients suffering from sarcoidosis should be treated by both ophthalmologists and internal physicians. Corticosteroids are commonly used for treatment, although in some patients the therapy has to be escalated by further immunosuppressants. Finally, a good cooperation between ophthalmologists and internal physicians results in a mostly good prognosis.

Moraxella catarrhalis induces ERK- and NF-kappaB-dependent COX-2 and prostaglandin E2 in lung epithelium.

Moraxella catarrhalis is a major cause of infectious exacerbations of chronic obstructive lung disease. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E(2) (PGE(2)), are considered to be important regulators of lung function. The present authors tested the hypothesis that M. catarrhalis induces COX-2-dependent PGE(2) production in pulmonary epithelial cells. In the present study, the authors demonstrate that M. catarrhalis specifically induces COX-2 expression and subsequent PGE(2) release in pulmonary epithelial cells. Furthermore, the prostanoid receptor subtypes EP2 and EP4 were also upregulated in these cells. The M. catarrhalis-specific ubiquitous cell surface protein A1 was important for the induction of COX-2 and PGE(2). Moreover, M. catarrhalis-induced COX-2 and PGE(2) expression was dependent on extracellular signal-regulated kinase 1/2-driven activation of nuclear factor-kappaB, but not on the activation of p38 mitogen-activated protein kinase. In conclusion, the present data suggest that ubiquitous cell surface protein A1 of Moraxella catarrhalis, extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB control cyclooxygenase-2 expression and subsequent prostaglandin E(2) release by lung epithelial cells. Moraxella catarrhalis-induced prostaglandin E(2) expression might counteract lung inflammation promoting colonisation of the respiratory tract in chronic obstructive pulmonary disease patients.

Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial.

BACKGROUND: Most patients (pts) with metastatic non-small cell lung cancer (NSCLC) receive either single agents or chemotherapy doublets. Recent studies have demonstrated that triple-agent therapies may improve the response rate, but are associated with significant toxicity, and frequently do not prolong survival. A sequential triple-agent schedule may combine acceptable tolerability and good efficacy. We therefore conducted a multicentre, prospectively randomized study that evaluates a sequential three-drug schedule and a platinum-free doublet regimen. PATIENTS AND METHODS: The pts with union international contre le cancer (UICC) stage IV NSCLC were randomized to one of two schedules: in arm Doc-Gem, they received gemcitabine (900 mg/m(2), 30 min infusion) on days 1 and 8, and docetaxel (75 mg/m(2), 1 h infusion) on day 1, repeated every 3 weeks up to six cycles. In arm Cis-Gem-->Doc, gemcitabine (900 mg/m(2), days 1 and 8) and cisplatin (70 mg/m(2), 1 h infusion, day 1) were given for three cycles, followed by three cycles of docetaxel (100 mg/m(2), day 1, repeated every 3 weeks). RESULTS: One hundred and thirteen pts were randomized to arms Doc-Gem (55 pts) and Cis-Gem-->Doc (58 pts). With Doc-Gem, 20.4% of pts responded to the treatment whereas 31.0% responded in arm Cis-Gem-->Doc (overall response, intent-to-treat, difference not significant). The median time to progression was 3.6 months in arm Doc-Gem [95% confidence interval (CI) 1.4, 5.9] and 5.2 months in arm Cis-Gem-->Doc (95% CI 3.1, 7.3). The median survival was 8.7 months with treatment Doc-Gem (95% CI 5.7, 11.6) and 9.4 months with treatment Cis-Gem-->Doc (95% CI 7.8, 11.0). The 1-year survival rates were 34 and 35%, respectively. Mild to moderate leukopenia was frequently seen with both schedules. Other common adverse events (AE) were nausea/vomiting, thrombocytopenia, anaemia, diarrhoea, and infections. No significant differences in AEs were observed between the schedules except for nausea/vomiting, which occurred more frequently with Cis-Gem-->Doc. CONCLUSION: The sequential therapy comprising cisplatin, gemcitabine, and docetaxel demonstrated promising tumour control whereas the platinum-free combination (docetaxel/gemcitabine) was very well tolerated. However, the schedules resulted in comparable survival to recent large trials in pts with advanced NSCLC. The present results do not justify further phase III investigation.

[Brain metastases of lung cancer]. / Hirnmetastasen beim Lungenkarzinom.

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

[Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to pulmonary fibrosis]. / Inhaliertes Prostazyklin und Iloprost bei schwerer sekundärer pulmonaler Hypertonie durch Lungenfibrose.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p < 0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome.

Changes in the alveolar hemostatic balance in severe pneumonia were compared with those in the acute respiratory distress syndrome (ARDS). Analysis was performed in bronchoalveolar lavage fluids (BALF) of patients with ARDS triggered by nonpulmonary underlying events in the absence of lung infection (ARDS; n = 25), pneumonia demanding mechanical ventilation (PNEU-vent; n = 114), spontaneously breathing patients with pneumonia (PNEU-spon; n = 40), and ARDS in combination with lung infection (ARDS+PNEU; n = 43); comparison with healthy control subjects (n = 35) was performed. In all groups of patients, BALF total procoagulant activity was increased by nearly two orders of magnitude, being largely attributable to the tissue factor pathway of coagulation. Concomitantly, markedly reduced overall fibrinolytic capacity (fibrin plate assay) was noted in the lavage fluids of all patients. BALF levels of urokinase-type plasminogen activator were significantly reduced throughout, whereas the lavage concentrations of tissue-type plasminogen activator did not differ from those in control subjects. In addition, markedly enhanced levels of plasminogen activator- inhibitor I and alpha(2)-antiplasmin were noted in ARDS, ARDS+PNEU, and PNEU-vent, but not in PNEU-spon. In all groups of patients, the changes in the lavage enzymatic activities were paralleled by manifold increased BALF concentrations of fibrinopeptide A and D-dimer, reflecting in vivo coagulation processes. Within the overall number of patients with pneumonia, changes in the alveolar hemostatic balance were more prominent in alveolar and interstitial pneumonia than in bronchopneumonia. Acute inflammatory lung injury, whether triggered by nonpulmonary systemic events or primary lung infection, is thus consistently characterized by both enhanced procoagulant and depressed fibrinolytic activities in the alveolar lining layer, with the appearance of fibrin formation in this compartment. Profile and extent of changes in severe pneumonia demanding respirator therapy are virtually identical to those in ARDS, whereas somewhat less prominent alterations of the alveolar hemostatic balance are noted in spontaneously breathing patients with pneumonia.

Severe microcirculatory abnormalities elicited by E. coli hemolysin in the rabbit ileum mucosa.

Decreased capillary flow and heterogeneity of microvascular perfusion are hallmarks of septic circulatory disturbances, and the gastrointestinal mucosa is considered to be particularly prone to such abnormalities. We investigated the impact of Escherichia coli hemolysin (HlyA), a medically relevant pore-forming bacterial toxin, on the mucosal microvasculature in a constant-flow blood-perfused rabbit ileum model. Microsensor techniques were employed to assess spatial distribution of mucosal hemoglobin oxygenation and relative mucosal hemoglobin content, as well as mucosal-arterial PCO(2) gap. Administration of low doses of HlyA (0.005 to 0.1 hemolytic units [HU]/ml) into the mesenteric artery provoked a transient vasoconstrictor response. Whereas physiological mucosal oxygenation is homogeneous, severe heterogeneity in capillary blood flow distribution appeared, paralleled by a marked increase in the mucosal-arterial PCO(2) gap. In addition, HlyA provoked a dose-dependent increase in relative hemoglobin concentration (rel Hb(conc)) values and edema formation, suggesting postcapillary vasoconstriction and capillary leakage. The observed changes occurred while fully maintaining mesenteric oxygen delivery. We conclude that low doses of HlyA may elicit severe mucosal microcirculatory disturbances in the rabbit ileum under maintenance of global hemodynamics, reminiscent of septic perfusion abnormalities. Pore-forming bacterial toxins may thus be considered as contributors to splanchnic mucosal damage under conditions of severe infection and sepsis.

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I(2) caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mm Hg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn. s. cm(-)(5) (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn. s. cm(-)(5). In contrast, both intravenous PGI(2) and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI(2) infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI(2) analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI(2) or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost.

OBJECTIVE: The treatment of decompensated right ventricular failure with vasodilators is difficult due to reduced systemic pressure and/or ventilation/perfusion (V/Q) mismatch with hypoxemia. In a recent study we demonstrated that inhaled vasodilatory prostanoids may offer a new strategy to achieve pulmonary selective vasodilatation and improvement of right ventricular function. We applied this new approach to a patient with circulatory shock due to primary pulmonary hypertension (PPH), complicated by a pulmonary infiltrate, who did not tolerate intravenous prostacyclin. DESIGN: Case report. SETTING: Intensive Care Unit (ICU), Medizinische Klinik Giessen, Germany. PATIENT: A 45-year-old woman with PPH presenting with decompensated right heart failure (ascites, pleural effusion), circulatory shock and commencing renal and hepatic failure, despite maximum therapy including the use of catecholamines. INTERVENTION: Intermittent inhalation of aerosolized iloprost, the stable analogue of prostacyclin, and comparison to inhaled nitric oxide (NO). Subsequent long-term therapy with aerosolized iloprost, 150 microg/day. MEASUREMENTS AND RESULTS: In response to inhaled iloprost, pulmonary arterial pressure (PAP) decreased from 65 to 61 mmHg, cardiac index (CI) increased from 1.25 to 1.85 l/min per m2, and pulmonary vascular resistance (PVR) decreased from 2416 to 1549 dyn/s per cm5 while inhaled NO decreased the PVR from 2280 to 1920 dyn/s per cm5 without a decrease in PAP. Both of these interventions increased the arterial pO2 but did not change the systemic arterial pressure. In contrast, intravenous prostacyclin was not tolerated, due to systemic side effects. During repeated inhalations with iloprost, the baseline hemodynamics and gas exchange improved dramatically and renal and liver functions normalized. During 1 year of continued therapy, the clinical status improved very much, concomitant with improved hemodynamics, and the patient has been taken off the transplantation list. CONCLUSIONS: Inhalation of aerosolized iloprost may offer a new life-saving strategy in near desperate cases of pulmonary hypertension in which intravenous prostacyclin cannot be applied due to severe side effects.

Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine.

Splanchnic mucosal perfusion abnormalities have been implicated in the development of sepsis and multiorgan failure. We employed reflectance spectrophotometry for direct assessment of the microvascular hemoglobin oxygen saturation (HbiO2) and hemoglobin concentration (rel Hb(conc)) in the mucosa of the upper gastrointestinal tract. Owing to the high recording frequency together with a small catchment volume, assessment of spatial heterogeneity is enabled. Results were as follows: In healthy controls (n = 7), mean HbiO2 was 70.3 +/- 2.1%, with narrow dispersion and near-Gaussian distribution of the histogram. In patients presenting with hyperdynamic septic shock (n = 15) mean HbiO2 was reduced to 51.0 +/- 1.6% in spite of high normal whole-body oxygen delivery, with tailing of the histogram to severely hypoxic values (18.4 % of data < 40%). In parallel, markedly reduced rel Hb(conc) values were recorded and the standardized intramucosal pH (pHi) was lowered to 7.25 +/- 0.01. Short-term infusion of dopexamine (2 microg/kg/min) caused a significant rise in HbiO2 and rel Hb(conc), whereas whole-body oxygen uptake and standardized pHi values were not altered. In conclusion, decreased oxygenation and tissue hemoglobin concentration, with the appearance of severely hypoxic microdomains, were noted in patients with hyperdynamic sepsis, strongly suggesting pronounced microcirculatory disturbances in this compartment. The partial responsiveness of these abnormalities to dopexamine warrants further elucidation.

Advantage of buffered solutions or automated capnometry in air-filled balloons for use in gastric tonometry.

OBJECTIVE: To test accuracy, reproducibility and time constants of pCO2 measurement with the tonometric technique, using different media for filling the silastic balloon (saline, phosphate buffer, citrate buffer, air) and employing different analyzer devices (ABL3, ABL330, Nova Stat 5, automated capnometry). DESIGN: Comparative laboratory study of different tonometric techniques, measuring test solutions with known pCO2 values due to pre-equilibration with three different pCO2 concentrations. SETTING: Clinical laboratory of a university hospital intensive care unit. MEASUREMENTS AND RESULTS: The use of saline, as suggested for routine tonometry, led to negative bias values throughout, i.e. underestimation of pCO2 values, the extent of which depended on the blood gas analyzer device employed. Registration of the equilibration kinetics showed that full equilibration demanded 90 min regardless of the environmental pCO2 level. Replacing saline by buffered electrolyte solutions resulted in a significant improvement of bias, but did not change the kinetics of pCO2 equilibration. The employment of air-filled balloons, combined with automated capnometry, led to very low bias values, approaching zero, for all pCO2 levels, along with excellent precision. Time constants of equilibration were dramatically reduced, with full equilibration being achieved within 12.5 min. CONCLUSIONS: Buffered electrolyte solutions are preferable to saline for achieving reliable pCO2 measurements in gastric tonometry. Air-filled balloons, combined with automated capnometry, present excellent accuracy and reproducibility together with short equilibration times, thus offering "on-line" monitoring of even rapid changes in environmental pCO2.

Prevention and therapy of the adult respiratory distress syndrome.

The complex pathophysiology of adult respiratory distress syndrome (ARDS) makes preventive and therapeutic concepts difficult. Ample experimental evidence indicates that ARDS can be prevented by blocking systemic inflammatory agents. Clinically, only heparin, for inhibition of coagulation phenomena, is presently used among this array of approaches. Corticosteroids have not proven to be beneficial in ARDS. Alternative antiinflammatory agents are being proposed and are under current clinical investigation (e.g. indomethacin, acetylcysteine, alpha 1-proteinase inhibitor, antitumor necrosis factor, interleukin 1 receptor antagonist, platelet-activating factor antagonists). Symptomatic therapeutic strategies in early ARDS include selective pulmonary vasodilation (preferably by inhaled vasorelaxant agents) and optimal fluid balance. Transbronchial surfactant application, presently tested in pilot studies, may be available for ARDS patients in the near future and may have acute beneficial effects on gas exchange, pulmonary mechanics, and lung hemodynamics; its impact on survival cannot be predicted at the present time. Strong efforts should be taken to reduce secondary nosocomial pneumonia in ARDS patients and thus avoid the vicious circle of pneumonia, sepsis from lung infection, and perpetuation of multiple organ dysfunction syndrome. Optimal respirator therapy should be directed to ameliorate gas-exchange conditions acutely but at the same time should aim at minimizing potentially aggravating side effects of artificial ventilation (barotrauma, O2 toxicity). Several new techniques of mechanical ventilation and the concept of permissive hypercapnia address these aspects. Approaches with extracorporeal CO2 removal and oxygenation are being used in specialized centers.

[Three cases of a fulminant course of idiopathic pulmonary fibrosis (Hamman-Rich syndrome)]. / Drei Fälle von foudroyant verlaufender idiopathischer Lungenfibrose (Hamman-Rich-Syndrom).

The Hamman-Rich syndrome is defined as an acute pulmonary disease of unclear aetiology that takes a rapid and prognostically unfavourable, usually fatal course. We report on three patients admitted to the intensive-care ward during a period of 6 months in a state of mandatory artificial respiration, each patient dying within 3 weeks after admission. Basing on clinical and histological criteria these patients were diagnosed as suffering from Hamman-Rich syndrome. At the time of the clinically identifiable onset of the disease all the patients had fever (> 39 X), leucocytosis (> 20 x 10(3)/microliters) and dyspnoea. These signs and symptoms were at first, in conjunction with the radiological identification of diffuse pulmonary infiltrations, misdiagnosed as pneumonia. The patients had to be artificially respirated after a short time because of the foundroyant course of the disease. Despite optimised respiratory parameters it was already initially apparent that there was a severe disturbance of the gas exchange function (paO2/FiO2 < 150) and high respiratory pressures (> 40 mmHg). Polymorphonuclear neutrophilics dominated in the bronchoalveolar lavage. Lung biopsy showed marked fibrosing that was a decisive factor in diagnosing. An infectious agent as triggering cause of the disease could not be identified in any of the patients. Treatment was effected with antibiotics, steroids and cyclophosphamide. The patients died after 14, 17 and 21 days, respectively, from intractable respiratory insufficiency with increasing loss of compliance of the lungs (compliance of lungs and thorax < 20 ml/mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)