Impact of Therapeutic Plasma Exchange on Hemodynamic Parameters in Medical Intensive Care Unit Patients: An Observational Study.

Therapeutic plasma exchange (TPE) is an extracorporeal treatment with reported beneficial as well as detrimental effects on circulation. However, there is a lack of data using advanced hemodynamic monitoring during TPE. Therefore, we investigated the effects of TPE on hemodynamic parameters derived from transpulmonary thermodilution (TPTD) as well as the risk for transfusion-related acute lung injury (TRALI). We compared hemodynamic parameters obtained before and after a total of 30 sessions of TPE treatment in 10 intensive care unit patients. Among standard hemodynamic parameters, heart rate (P < 0.012) and systolic blood pressure (P < 0.008) significantly increase, whereas neither mean arterial pressure nor diastolic blood pressure was altered after TPE. The TPTD-derived cardiac function parameters, cardiac index (CI; P = 0.035), cardiac power index (CPI; P = 0.008), global ejection fraction (GEF; P = 0.002), and stroke volume index (SVI; P = 0.014), were significantly higher after TPE. Furthermore, systemic vascular index significantly increased (P < 0.042). Among the cardiac preload parameters, central venous pressure was significantly lower after TPE (P < 0.001), while the global end-diastolic volume index (GEDVI) did not change. Contractility marker dPmax did not change. Finally, TPE application did not significantly alter the pulmonary hydration and permeability parameters, extravascular lung water index (EVLWI) and pulmonary vascular permeability index. Vasopressor dose was not statistically significantly altered. Considering increases in SVI, CI, GEF, and CPI and stable values for GEDVI, EVLWI, and dPmax, our data do not give any hint for hemodynamic impairment or TRALI.

Pseudallescheria boydii with Aspergillus fumigatus and Aspergillus terreus in a Critically Ill Hematopoietic Stem Cell Recipient with ARDS.

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

Influence of echinocandin administration on hemodynamic parameters in medical intensive care unit patients: a single center prospective study.

PURPOSE: Fungal infections present a constant risk to critically ill and immunocompromised patients. Therefore, treatment guidelines recommend echinocandins as first-line antifungals in critically ill patients to improve patient outcomes. Echinocandins are usually well tolerated; nevertheless, rare adverse events can occur. There are reports of temporary deterioration of hemodynamic parameters during loading doses, especially in critically ill patients. The objective of this study is to analyze the hemodynamic changes during administration of the echinocandin antifungals, caspofungin and anidulafungin, in medical intensive care unit patients. METHODS: A prospective study in medical ICU patients receiving echinocandins was monitored using single-indicator transpulmonary thermodilution (TPTD). TPTD measurements were performed immediately before, directly after, and 4 h after echinocandins on two following days. RESULTS: Mean arterial pressure and also diastolic blood pressure showed significant changes (p < 0.042 and p < 0.007) after echinocandin application in the measurement immediately after application, but not after 4 h. Basic hemodynamic parameters as well as the TPTD-derived cardiac function parameters did not significantly change after echinocandin application at all. In patients with the need for norepinephrine therapy, the vasopressor dose was not statistically significantly altered. CONCLUSION: To conclude, administration of echinocandins in this observed study population is safe, even in severely critically ill patients if application rules of these agents are followed. However, adverse effects could be observed and practitioners should be cognizant of these effects. These observations can be optimized by high-level assessments, such as the pulse contour cardiac output monitoring, and clinicians should continue to be vigilant with cardiac monitoring of patients receiving echinocandin antifungals.

Fungal "colonisation" is associated with increased mortality in medical intensive care unit patients with liver cirrhosis.

OBJECTIVES: Patients with liver cirrhosis are at increased risk for fungal infections. However, distinction of fungal colonisation (FC) and invasive mycoses is difficult. Aim of this study was to analyse the impact of FC on mortality of cirrhotic ICU-patients. METHODS: Retrospective mortality analysis of a prospectively maintained database on 120 cirrhotic patients with and without FC. Comparison to 120 noncirrhotic controls matched for APACHE-II (24.9 ± 3.7 vs. 25.0 ± 2.6; p = 0.263). RESULTS: About 69/120 (58%) of patients with cirrhosis had FC. These patients had significantly higher APACHE-II score and mortality compared to cirrhotic patients without FC (27 ± 3 vs. 23 ± 4, p < 0.001; 78 vs. 35%, p < 0.001). In multivariate analysis, FC was independently (p = 0.047) associated to mortality. Mortality of noncirrhotic patients with FC (14/31; 45.2%) was not different to noncirrhotic controls without FC [28/89 (31.2%; p = 0.168)]. Similarly, in multivariate analysis of noncirrhotics, APACHE-II (p < 0.001), but not FC, was independently associated to mortality. Multiple regression analysis of all 240 cirrhotic and noncirrhotic patients demonstrated that APACHE-II (p < 0.001), cirrhosis (p = 0.001) and FC (p = 0.049) were independently associated with mortality. CONCLUSION: Fungal "colonisation" is independently associated to mortality in cirrhotic ICU-patients. Early antimycotic therapy should be considered in critically ill cirrhotic patients with FC.

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC.

Invasive mycosis in medical intensive care unit patients with severe alcoholic hepatitis.

BACKGROUND: Severe alcoholic hepatitis (AH) has a poor short-term prognosis often caused by infections. However, the incidence of invasive mycosis in patients with AH treated with corticosteroids and its impact still remains unknown. METHODS: Retrospective analyses of twelve medical ICU patients (out of 120 patients with liver cirrhosis) with histological proven AH. RESULTS: Twelve patients were diagnosed with histological proven AH during there stay at the ICU. All patients were treated with corticosteroids; three patients were treated with corticosteroids and pentoxifylline. Five patients had invasive aspergillosis (IA); three patients had candidemia; and two had fungal colonization with candida species. Only two patients had no evidence for fungals. IA was associated with death in all cases. Death occured in most cases shortly after diagnosis despite antifungal medication. Two patients with candidemia died; one patient died in the group with fungal colonization. Overall, the mortality rate was 100% in patients with IA and 70% in the group with candidemia. CONCLUSIONS: Patients with severe AH have an increased susceptibility to invasive mycosis associated with high mortality. A high level of suspicion of invasive mycosis in AH patients and prophylactic strategies are needed in those patients.

E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex.

BACKGROUND & AIMS: Early metastasis is a hallmark of pancreatic ductal adenocarcinoma and responsible for >90% of pancreatic cancer death. Because little is known about the biology and genetics of the metastatic process, we desired to elucidate molecular pathways mediating pancreatic cancer metastasis in vivo by an unbiased forward genetic approach. METHODS: Highly metastatic pancreatic cancer cell populations were selected by serial in vivo passaging of parental cells with low metastatic potential and characterized by global gene expression profiling, chromatin immunoprecipitation, and in vivo metastatic assay. RESULTS: In vivo selection of highly metastatic pancreatic cancer cells induced epithelial-mesenchymal transition (EMT), loss of E-cadherin expression, and up-regulation of mesenchymal genes such as Snail. Genetic inactivation of E-cadherin in parental cells induced EMT and increased metastasis in vivo. Silencing of E-cadherin in highly metastatic cells is mediated by a transcriptional repressor complex containing Snail and histone deacetylase 1 (HDAC1) and HDAC2. In line, mesenchymal pancreatic cancer specimens and primary cell lines from genetically engineered Kras(G12D) mice showed HDAC-dependent down-regulation of E-cadherin and high metastatic potential. Finally, transforming growth factor beta-driven E-cadherin silencing and EMT of human pancreatic cancer cells depends on HDAC activity. CONCLUSIONS: We provide the first in vivo evidence that HDACs and Snail play an essential role in silencing E-cadherin during the metastatic process of pancreatic cancer cells. These data link the epigenetic HDAC machinery to EMT and metastasis and provide preclinical evidence that HDACs are promising targets for antimetastatic therapy.

Sustained low-efficiency dialysis with regional citrate anticoagulation in medical intensive care unit patients with liver failure: A prospective study.

PURPOSE: Patients with liver failure requiring dialysis are at increased risk for citrate accumulation during sustained low-efficiency dialysis (SLED). The aim of this study was to evaluate the feasibilty of citrate SLED in critical ill patients with liver failure and investigate predictive parameters regarding citrate accumulation. MATERIALS AND METHODS: This is a prospective study in 24 medical intensive care unit patients with liver failure and a total of 43 SLED runs (maximum of 3 runs per patient) using citrate anticoagulation. Liver function was characterized before SLED using not only laboratory parameters but also determination of the plasma disappearance rate of indocyanine green. In addition, blood gas parameters as well total calcium and citrate in serum were measured at baseline and defined time points during SLED. RESULTS: Accumulation of citrate could be observed in all SLED runs, which were nearly normalized until the end of SLED and 24 hours after SLED, respectively. However, the critical threshold of total calcium/ionized calcium on ratio of greater than 2.5 was exceeded in only 1 patient. Equalization of initial metabolic acidosis was possible without major disturbances of acid base and electrolyte status. Liver function parameters showed poor predicitve capabilities regarding citrate accumulation. CONCLUSIONS: Despite substantial accumulation of citrate in serum, SLED is save and feasible in patients with liver failure using a citrate anticoagulation. Careful monitoring of electrolytes and acid base status is mandatory to ensure patient safety.

Evaluation of a dosing regimen for continuous vancomycin infusion in critically ill patients: an observational study in intensive care unit patients.

PURPOSE: We aimed to evaluate a dosing algorithm for continuous vancomycin administration in intensive care unit patients. MATERIALS AND METHODS: This observational study was conducted in a medical intensive care unit (German university hospital; June 2012-February 2013). Following a loading dose of 20 mg per kg actual body weight, vancomycin was administered continuously (20 or 30 mg of vancomycin per kg actual body weight over 24 hours depending on renal function). The vancomycin infusion rate was adjusted to achieve a target serum vancomycin concentration of 20-30 mg/L. RESULTS: Vancomycin was administered for a median (interquartile range) of 7 (5-9) days. The median vancomycin dose given as an initial bolus was 1750 (1400-2000) mg. The median daily vancomycin dose ranged from 480 (180-960) mg (day 6) to 3.120 (2596-3980) mg (day 1). Altogether, the achieved median serum vancomycin concentration was 29.0 (25.2-33.2) mg/L. On treatment days 1 to 7, we observed target serum vancomycin levels (20-30 mg/L) in 48%, 39%, 33%, 26%, 43%, 57%, and 69% of patients. Supra-therapeutic serum vancomycin concentrations (>30 mg/L) were observed in 36%, 52%, 61%, 63%, 39%, 19%, and 15% of patients on treatment days 1 to 7. CONCLUSIONS: The evaluated vancomycin dosing regimen for continuous infusion allowed rapid achievement of sufficient vancomycin serum levels. However, we frequently observed supra-therapeutic serum vancomycin concentrations in the first days of vancomycin treatment.

The effects of transjugular intrahepatic portosystemic stent shunt on systemic cardiocirculatory parameters.

PURPOSE: We aimed to evaluate the effects of transjugular intrahepatic portosystemic stent shunt (TIPS) on systemic cardiocirculatory parameters in patients treated with TIPS for portal hypertension-associated complications. MATERIALS AND METHODS: This prospective study was conducted in an intensive care unit of a German university hospital (October 2010-July 2013). We assessed hemodynamic parameters before and after TIPS placement using single-indicator transpulmonary thermodilution and pulse contour analysis. After exclusion of 5 patients treated with vasoactive agents during study measurements, 15 patients were included in the final statistical analysis. RESULTS: Transjugular intrahepatic portosystemic stent shunt induced a statistically significant decrease in portal pressure (median, 29 [25%-75% percentile range, 23-37] mm Hg before TIPS vs 21 [18-27] mm Hg after TIPS; P<.01) in parallel with a statistically significant increase in central venous pressure (10 [6-15] mm Hg before TIPS vs 13 [9-16] mm Hg after TIPS; P=.01), cardiac index (3.8 [2.9-4.6] L min(-1) m(-2) before TIPS vs 4.5 [3.8-5.4] L min(-1) m(-2) 14 hours after TIPS; P=.01), and stroke volume index (54 [42-60] mL/m2 before TIPS vs 60 [47-63] mL/m2 14 hours after TIPS; P=.03). Arterial blood pressure and systemic vascular resistance index were statistically significantly lower after TIPS. CONCLUSIONS: Transjugular intrahepatic portosystemic stent shunt placement is associated with an increase in central venous pressure and an improvement of global blood flow (cardiac index and stroke volume index) in patients with portal hypertension.

Impact of large-volume thoracentesis on transpulmonary thermodilution-derived extravascular lung water in medical intensive care unit patients.

PURPOSE: The purpose of this study was to investigate the impact of large-volume thoracentesis (>1000 mL) on transpulmonary thermodilution (TPTD)-derived cardiopulmonary parameters with special regard to extravascular lung water index (EVLWI). MATERIALS AND METHODS: Retrospective analysis of a prospectively maintained database including TPTD measurements of patients treated in a medical intensive care unit of a German university hospital between January 2009 and September 2010. Data of 17 patients treated with large-volume thoracentesis were analyzed. RESULTS: A median of 1350 (25%-75% interquartile range [IQR], 1200-1590) mL of pleural fluid was removed. Extravascular lung water index was statistically significantly higher after thoracentesis compared with baseline (9.0 [IQR, 8.0-13.0] vs 8.0 [IQR, 7.0-13.0] mL/kg) (P = .039). Pulmonary vascular permeability index (PVPI) also increased significantly after thoracentesis (1.7 [IQR, 1.3-2.4] vs 1.4 [IQR, 1.1-2.1]) (P = .019). When determined 2 and 6 hours after thoracentesis, EVLWI and PVPI even further increased. Six hours after removal of pleural fluid, we observed a median EVLWI of 11.0 (IQR, 8.0-15.0) mL/kg (P = .048 compared with baseline) and a median PVPI of 2.0 (IQR, 1.5-2.7) (P = .040 compared with baseline). CONCLUSIONS: Large-volume thoracentesis results in a statistically significant increase in TPTD-derived EVLWI. Because EVLWI was higher after removal of pleural fluid, we conclude that pleural effusions do not take part in single-indicator TPTD as a part of the pulmonary thermovolume and do not increase TPTD-derived EVLWI.

Effects of red blood cell transfusion on hemodynamic parameters: a prospective study in intensive care unit patients.

BACKGROUND: The aim of the study was to investigate the effect of red blood cell (RBC) transfusion on hemodynamic parameters including transpulmonary thermodilution (TPTD)-derived variables. METHODS: We compared hemodynamic parameters obtained before and after RBC transfusion (2 RBC units) in 34 intensive care unit (ICU) patients. RESULTS: Directly after RBC transfusion, we observed a significant increase in hematocrit (28 ± 3 vs. 22 ± 2%, p < 0.001), hemoglobin (9.4 ± 0.9 vs. 7.6 ± 0.8 g/dL, p < 0.001), arterial oxygen content (CaO2) (12.2 ± 1.2 vs. 9.9 ± 1.0 mL/dL, p < 0.001), and oxygen delivery (DO2) (1073 ± 369 vs. 934 ± 288 mL/min, p < 0.001) compared with baseline. Cardiac output (CO) (8.89 ± 3.06 vs. 9.42 ± 2.75 L/min, p = 0.020), cardiac index (CI) (4.53 ± 1.36 vs. 4.82 ± 1.21 L/min/m², p = 0.016), and heart rate (91 ± 16 vs. 95 ± 14 bpm, p = 0.007) were significantly lower following RBC transfusion while no significant change in stroke volume (SV) was observed. Mean arterial pressure (MAP) (median 87 vs. 78 mmHg, p < 0.001) and systemic vascular resistance index (SVRI) (median 1212 vs. 1103 dyn*s*cm⁻5*m², p = 0.001) significantly increased directly after RBC transfusion. Global end-diastolic volume index (GEDVI), extravascular lung water index (EVLWI), and pulmonary vascular permeability index (PVPI) did not significantly change. CONCLUSIONS: In ICU patients, the transfusion of 2 RBC units induces a significant decrease in CO and CI because of a significant decrease in heart rate (while SV remains unchanged). Despite the decrease in CO, DO2 significantly increases because of a significant increase in CaO2. In addition, RBC transfusion results in a significant increase in MAP and SVRI. No significant changes in TPTD-parameters reflecting cardiac preload (GEDVI), pulmonary edema (EVLWI), and pulmonary vascular permeability (PVPI) are observed following RBC transfusion.

Efemp1 and p27(Kip1) modulate responsiveness of pancreatic cancer cells towards a dual PI3K/mTOR inhibitor in preclinical models.

Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease with a poor prognosis and targeted therapies have failed in the clinic so far. Several evidences point to the phosphatidylinositol 3-kinase (PI3K)-mTOR pathway as a promising signaling node for targeted therapeutic intervention. Markers, which predict responsiveness of PDAC cells towards PI3K inhibitors are unknown. However, such markers are needed and critical to better stratify patients in clinical trials. We used a large murine Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3K-mTOR inhibitor Bez235. In contrast to other tumor models, we show that Kras(G12D)- and PI3K (p110α(H1047R))-driven PDAC cell lines are equally sensitive towards Bez235. In an unbiased approach we found that the extracellular matrix protein Efemp1 controls sensitivity of murine PDAC cells towards Bez235. We show that Efemp1 expression is connected to the cyclin-dependent kinase inhibitor p27(Kip1). In a murine Kras(G12D)-driven PDAC model, p27(Kip1) haploinsufficiency accelerates cancer development in vivo. Furthermore, p27(Kip1) controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27(Kip1) decreases Bez235 responsiveness in murine PDAC models. Together, we define the Efemp1-p27(Kip1) axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors, which might help to better stratify patients in clinical trials.

Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer.

Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.