Comparison of endoscopic ultrasound-guided fine-needle aspiration and fine-needle biopsy to generate pancreatic cancer organoids: Randomized trial.

Background and study aims The prognosis for pancreatic cancer remains poor. Molecular diagnostics and customized therapies are becoming increasingly important in clinical routine. Patient-derived, predictive model systems such as organoids have the potential to substantially increase the depth of information from biopsy material by functional and molecular characterization. We compared the extent to which the use of fine-needle aspiration needles (FNA, 22G) or fine-needle biopsy needles (FNB, 22G) influences the generation of pancreatic cancer patient-derived organoids (PDOs) to establish endoscopic standards of organoid technology. Patients and methods Endoscopic ultrasound (EUS)-guided punctures by EUS-FNA and EUS-FNB of pancreatic masses highly suspicious for adenocarcinoma (detected by computed tomography and/or magnetic resonance imaging) were prospectively evaluated. Consecutive patients received EUS-FNA and EUS-FNB in a randomized order without the need to exchange the needle shaft (only the inner needle type (FNA/-B) was exchanged) between the passes. With each needle type, the specimens for histological analysis and for PDOs were obtained separately. Results Fifty patients were enrolled in the study. Histology revealed malignancy in 42 of 50 cases (84%). In total PDOs were generated from 17 patients (34%). Of these, nine were established by FNB only, two by FNA only, and six by both FNA and FNB. Histology revealed malignancy in 13 of 17 PDO cases (76%). In two histologically false-negative cases, PDOs could be established. Conclusions EUS-FNB was superior to EUS-FNA in terms of successful generation of PDOs, although it failed to show statistical significance.

Efficacy and Safety of Cold Snare Polypectomy of Colorectal Polyps 10-15 mm with a Hybrid Snare: A Prospective Observational Pilot Study.

INTRODUCTION: Cold snare polypectomy (CSP) is a safe and effective procedure for small colorectal polyps ≤9 mm. There are only limited data regarding CSP of larger neoplastic lesions. This study evaluated the efficacy and safety of CSP for polyps between 10 and 15 mm in size. METHODS: In this prospective single-arm observational pilot study, patients with a least one polyp 10-15 mm were included. These polyps were preferably removed by CSP using a dedicated hybrid snare. The primary outcome was the histological complete resection rate (CRR) determined by pathologically negative margins of the specimen and no neoplastic tissue obtained from biopsies of the resection site margin. Secondary outcomes were en bloc resection rate, failure of CSP, and incidence of adverse events. RESULTS: A total of 61 neoplastic polyps were removed from 39 patients. Overall CRR was 80.3% (49/61). CSP was feasible in 78.7% (48/61) of polyps and the CRR in this group was 85.4% (41/48). When CSP failed (13/61; 21.3%), lesions were successfully resected by immediate HSP using the same snare with a CRR of 61.5% (8/13) in this group. One patient presented delayed hemorrhage after HSP of a polyp but successful hemostasis was achieved with two hemoclips. No other adverse events occurred. No recurrence was seen on follow-up colonoscopy in cases with incomplete resected polyps. CONCLUSION: CSP seems to be efficient and safe in removing colorectal polyps up to 15 mm. A hybrid snare seems to be particularly advantageous for these polyps as it allows immediate conversion to HSP if CSP might fail in larger polyps. This trial is registered at ClinicalTrials.gov (NCT04464837).

Adjunctive Hydrocortisone Improves Hemodynamics in Critically Ill Patients with Septic Shock: An Observational Study Using Transpulmonary Thermodilution.

Introduction: Septic shock is associated with high mortality and hemodynamic impairment. The use of corticoids is a common therapeutic tool in critically ill patients. However, data on the mechanisms and prognostic ability of hemodynamic improvement by adjunctive steroids are rare. This study primarily aimed to evaluate short-term effects of hydrocortisone therapy on catecholamine requirement and hemodynamics derived from transpulmonary thermodilution (TPTD) in 30 critically ill patients with septic shock and a 28 days mortality rate of 50%. Methods: Hydrocortisone was administered with an intravenous bolus of 200 mg, followed by a continuous infusion of 200 mg per 24 h. Hemodynamic assessment was performed immediately before as well as 2, 8, 16, and 24 h after the initiation of corticoids. For primary endpoint analysis, we evaluated the impact of hydrocortisone on vasopressor dependency index (VDI) and cardiac power index (CPI). Results: Adjunctive hydrocortisone induced significant decreases of VDI from 0.41 (0.29-0.49) mmHg-1 at baseline to 0.35 (0.25-0.46) after 2 h (P < .001), 0.24 (0.12-0.35) after 8 h (P < .001), 0.18 (0.09-0.24) after 16 h (P < .001) and 0.11 (0.06-0.20) mmHg-1 after 24 h (P < .001). In parallel, we found an improvement in CPI from 0.63 (0.50-0.83) W/m2 at baseline to 0.68 (0.54-0.85) after 2 h (P = .208), 0.71 (0.60-0.90) after 8 h (P = .033), 0.82 (0.6-0.98) after 16 h (P = .004) and 0.90 (0.67-1.07) W/m2 after 24 h (P < .001). Our analyses revealed a significant reduction in noradrenaline requirement in parallel with a moderate increase in mean arterial pressure, systemic vascular resistance index, and cardiac index. As a secondary endpoint, our results showed a significant decrease in lung water parameters. Moreover, changes in CPI (ΔCPI) and VDI (ΔVDI) after 24 h of hydrocortisone therapy revealed accurate prognostic ability to predict 28 days mortality (AUC = 0.802 vs 0.769). Conclusion: Adjunctive hydrocortisone leads to a rapid decrease in catecholamine requirement and a substantial circulatory improvement in critically ill patients with septic shock.

B-Lines Scores Derived From Lung Ultrasound Provide Accurate Prediction of Extravascular Lung Water Index: An Observational Study in Critically Ill Patients.

INTRODUCTION: Visualization of B-lines via lung ultrasound provides a non-invasive estimation of pulmonary hydration. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) assessed by transpulmonary thermodilution (TPTD) represent the most validated parameters of lung water and alveolocapillary permeability, but measurement is invasive and expensive. This study aimed to compare the correlations of B-lines scores from extensive 28-sector and simplified 4-sector chest scan with EVLWI and PVPI derived from TPTD in the setting of intensive care unit (primary endpoint). METHODS: We performed scoring of 28-sector and 4-sector B-Lines in 50 critically ill patients. TPTD was carried out with the PiCCO-2-device (Pulsion Medical Systems SE, Maquet Getinge Group). Median time exposure for ultrasound procedure was 12 minutes for 28-sector and 4 minutes for 4-sector scan. RESULTS: Primarily, we found close correlations of 28-sector as well as 4-sector B-Lines scores with EVLWI (R2 = 0.895 vs. R2 = 0.880) and PVPI (R2 = 0.760 vs. R2 = 0.742). Both B-lines scores showed high accuracy to identify patients with specific levels of EVLWI and PVPI. The extensive 28-sector B-lines score revealed a moderate advantage compared to simplified 4-sector scan in detecting a normal EVLWI ≤ 7 (28-sector scan: sensitivity = 81.8%, specificity = 94.9%, AUC = 0.939 versus 4-sector scan: sensitivity = 81.8%, specificity = 82.1%, AUC = 0.902). Both protocols were approximately equivalent in prediction of lung edema with EVLWI ≥ 10 (28-sector scan: sensitivity = 88.9%, specificity = 95.7%, AUC = 0.977 versus 4-sector scan: sensitivity = 81.5%, specificity = 91.3%, AUC = 0.958) or severe pulmonary edema with EVLWI ≥ 15 (28-sector scan: sensitivity = 91.7%, specificity = 97.4%, AUC = 0.995 versus 4-sector scan: sensitivity = 91.7%, specificity = 92.1%, AUC = 0.978). As secondary endpoints, our evaluations resulted in significant associations of 28-sector as well as simplified 4-sector B-Lines score with parameters of respiratory function. CONCLUSION: Both B-line protocols provide accurate non-invasive evaluation of lung water in critically ill patients. The 28-sector scan offers a marginal advantage in prediction of pulmonary edema, but needs substantially more time than 4-sector scan.

Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS.

Nearly 5% of patients suffering from COVID-19 develop acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study, we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to COVID-19 negative, ventilated patients with ARDS and whether EVLWI has the potential to monitor disease progression. EVLWI and cardiac function were monitored by transpulmonary thermodilution in 25 patients with COVID-19 ARDS subsequent to intubation and compared to a control group of 49 non-COVID-19 ARDS patients. At intubation, EVLWI was noticeably elevated and significantly higher in COVID-19 patients than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p < 0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p = 0.003) suggested a non-cardiogenic pulmonary oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable in both cohorts. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and in-hospital mortality (23.2 ± 6.7% vs. 30.3 ± 6.0%, p = 0.025). Also, EVLWI showed a significant between-subjects (r = - 0.60; p = 0.001) and within-subjects correlation (r = - 0.27; p = 0.028) to Horowitz index. Compared to non COVID-19 ARDS, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. High EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 ARDS and could serve as parameter to monitor ARDS progression on ICU.

SARS-CoV-2 serology increases diagnostic accuracy in CT-suspected, PCR-negative COVID-19 patients during pandemic.

BACKGROUND: In the absence of PCR detection of SARS-CoV-2 RNA, accurate diagnosis of COVID-19 is challenging. Low-dose computed tomography (CT) detects pulmonary infiltrates with high sensitivity, but findings may be non-specific. This study assesses the diagnostic value of SARS-CoV-2 serology for patients with distinct CT features but negative PCR. METHODS: IgM/IgG chemiluminescent immunoassay was performed for 107 patients with confirmed (group A: PCR + ; CT ±) and 46 patients with suspected (group B: repetitive PCR-; CT +) COVID-19, admitted to a German university hospital during the pandemic's first wave. A standardized, in-house CT classification of radiological signs of a viral pneumonia was used to assess the probability of COVID-19. RESULTS: Seroconversion rates (SR) determined on day 5, 10, 15, 20 and 25 after symptom onset (SO) were 8%, 25%, 65%, 76% and 91% for group A, and 0%, 10%, 19%, 37% and 46% for group B, respectively; (p < 0.01). Compared to hospitalized patients with a non-complicated course (non-ICU patients), seroconversion tended to occur at lower frequency and delayed in patients on intensive care units. SR of patients with CT findings classified as high certainty for COVID-19 were 8%, 22%, 68%, 79% and 93% in group A, compared with 0%, 15%, 28%, 50% and 50% in group B (p < 0.01). SARS-CoV-2 serology established a definite diagnosis in 12/46 group B patients. In 88% (8/9) of patients with negative serology > 14 days after symptom onset (group B), clinico-radiological consensus reassessment revealed probable diagnoses other than COVID-19. Sensitivity of SARS-CoV-2 serology was superior to PCR > 17d after symptom onset. CONCLUSIONS: Approximately one-third of patients with distinct COVID-19 CT findings are tested negative for SARS-CoV-2 RNA by PCR rendering correct diagnosis difficult. Implementation of SARS-CoV-2 serology testing alongside current CT/PCR-based diagnostic algorithms improves discrimination between COVID-19-related and non-related pulmonary infiltrates in PCR negative patients. However, sensitivity of SARS-CoV-2 serology strongly depends on the time of testing and becomes superior to PCR after the 2nd week following symptom onset.

Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: Results from the prospective AspCOVID-19 study.

BACKGROUND: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia. METHODS: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls. FINDINGS: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA. INTERPRETATION: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.

High lipasemia is frequent in Covid-19 associated acute respiratory distress syndrome.

BACKGROUND: Covid-19 is a rapidly spreading viral disease that can cause severe acute respiratory distress syndrome (ARDS). Besides the lungs it can also affect other organs like the heart or the liver. Whether there is a pancreatic manifestation as well is currently unclear. METHODS: and aims: We prospectively collected patient information of patients with Covid-19 associated ARDS in a registry (COvid Registry REChts der Isar intensive care Trial - CORRECT) and analyzed this patient cohort for signs of acute pancreatitis (e.g. lipase activity >3 times the upper limit). RESULTS: 12/38 (31.6%) patients with Covid-19 associated ARDS had a serum lipase activity >180 U/l. Median lipase activity was 422 U/l (186-1127). No patient showed typical findings of acute pancreatitis on imaging studies. On hemodynamic monitoring no patient had signs of intravascular fluid demand regarding MAP, GEDVI and therapy with vasopressors. To avoid worsening respiratory function no treatment with crystalloids was initiated. Lipasemia was not explained by gastroenteritis or renal insufficiency, occurred before as well as after viral clearance and 16.1 ± 6.0 days after the first symptoms. No patient developed severe acute pancreatitis during the follow up period of 35.8 ± 8.3 days. CONCLUSION: High lipasemia without typical signs of acute pancreatitis is a frequent finding in severe Covid-19 associated ARDS. Considering the markedly high levels of serum lipase activity, we think impaired microcirculation in severely ill patients can explain this finding rather than extra-pancreatic co-morbidities (UTN: DRKS00021612).

Comparison of global end-diastolic volume index derived from jugular and femoral indicator injection: a prospective observational study in patients equipped with both a PiCCO-2 and an EV-1000-device.

Transpulmonary thermodilution (TPTD)-derived global end-diastolic volume index (GEDVI) is a static marker of preload which better predicted volume responsiveness compared to filling pressures in several studies. GEDVI can be generated with at least two devices: PiCCO and EV-1000. Several studies showed that uncorrected indicator injection into a femoral central venous catheter (CVC) results in a significant overestimation of GEDVI by the PiCCO-device. Therefore, the most recent PiCCO-algorithm corrects for femoral indicator injection. However, there are no systematic data on the impact of femoral indicator injection for the EV-1000 device. Furthermore, the correction algorithm of the PiCCO is poorly validated. Therefore, we prospectively analyzed 14 datasets from 10 patients with TPTD-monitoring undergoing central venous catheter (CVC)- and arterial line exchange. PiCCO was replaced by EV-1000, femoral CVCs were replaced by jugular/subclavian CVCs and vice-versa. For PiCCO, jugular and femoral indicator injection derived GEDVI was comparable when the correct information about femoral catheter site was given (p = 0.251). By contrast, GEDVI derived from femoral indicator injection using the EV-1000 was obviously not corrected and was substantially higher than jugular GEDVI measured by the EV-1000 (846 ± 250 vs. 712 ± 227 ml/m2; p = 0.001). Furthermore, measurements of GEDVI were not comparable between PiCCO and EV-1000 even in case of jugular indicator injection (p = 0.003). This is most probably due to different indexations of the raw value GEDV. EV-1000 could not be recommended to measure GEDVI in case of a femoral CVC. Furthermore, different indexations used by EV-1000 and PiCCO should be considered even in case of a jugular CVC when comparing GEDVI derived from PiCCO and EV-1000.

NUTRIC and Modified NUTRIC are Accurate Predictors of Outcome in End-Stage Liver Disease: A Validation in Critically Ill Patients with Liver Cirrhosis.

Malnutrition in critically ill patients with cirrhosis is a frequent but often overlooked complication with high prognostic relevance. The Nutrition Risk in Critically ill (NUTRIC) score and its modified variant (mNUTRIC) were established to assess the nutrition risk of intensive care unit patients. Considering the high mortality of cirrhosis in critically ill patients, this study aims to evaluate the discriminative ability of NUTRIC and mNUTRIC to predict outcome. We performed a retro-prospective evaluation in 150 Caucasian cirrhotic patients admitted to our ICU. Comparative prognostic analyses between NUTRIC and mNUTRIC were assessed in 114 patients. On ICU admission, a large proportion of 65% were classified as high NUTRIC (6-10) and 75% were categorized as high mNUTRIC (5-9). High nutritional risk was linked to disease severity and poor outcome. NUTRIC was moderately superior to mNUTRIC in prediction of 28-day mortality (area under curve 0.806 vs. 0.788) as well as 3-month mortality (area under curve 0.839 vs. 0.819). We found a significant association of NUTRIC and mNUTRIC with MELD, CHILD, renal function, interleukin 6 and albumin, but not with body mass index. NUTRIC and mNUTRIC are characterized by high prognostic accuracy in critically ill patients with cirrhosis. NUTRIC revealed a moderate advantage in prognostic ability compared to mNUTRIC.

Implementing cell-free DNA of pancreatic cancer patient-derived organoids for personalized oncology.

One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for endoscopic ultrasound-guided fine-needle aspiration biopsies, typically resulting in specimens with limited tumor cell yield. Here, we tested conditioned media of individual PDOs for cell-free DNA to detect driver mutations already early on during the expansion process to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72 hours after biopsy, recapitulate the mutational profile of the primary tumor, indicating suitability of this approach to subject PDOs to drug testing in a reduced time frame. In addition, we demonstrated that this workflow was practicable, even in patients for whom the amount of tumor material was not sufficient for molecular characterization by established means. Together, our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach, this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.

Prediction of outcome in patients with ARDS: A prospective cohort study comparing ARDS-definitions and other ARDS-associated parameters, ratios and scores at intubation and over time.

BACKGROUND: Early recognition of high-risk-patients with acute respiratory distress syndrome (ARDS) might improve their outcome by less protracted allocation to intensified therapy including extracorporeal membrane oxygenation (ECMO). Among numerous predictors and classifications, the American European Consensus Conferenece (AECC)- and Berlin-definitions as well as the oxygenation index (OI) and the Murray-/Lung Injury Score are the most common. Most studies compared the prediction of mortality by these parameters on the day of intubation and/or diagnosis of ARDS. However, only few studies investigated prediction over time, in particular for more than three days. OBJECTIVE: Therefore, our study aimed at characterization of the best predictor and the best day(s) to predict 28-days-mortality within four days after intubation of patients with ARDS. METHODS: In 100 consecutive patients with ARDS severity according to OI (mean airway pressure*FiO2/paO2), modified Murray-score without radiological points (Murray_mod), AECC- and Berlin-definition, were daily documented for four days after intubation. In the subgroup of 49 patients with transpulmonary thermodilution (TPTD) monitoring (PiCCO), extravascular lung water index (EVLWI) was measured daily. PRIMARY ENDPOINT: Prediction of 28-days-mortality (Area under the receiver-operating-characteristic curve (ROC-AUC)); IBM SPSS 26. RESULTS: In the totality of patients the best prediction of 28-days-mortality was found on day-1 and day-2 (mean ROC-AUCs for all predictors/scores: 0.632 and 0.620). OI was the best predictor among the ARDS-scores (AUC=0.689 on day-1; 4-day-mean AUC = 0.625). AECC and Murray_mod had 4-day-means AUCs below 0.6. Among the 49 patients with TPTD, EVLWI (4-day-mean AUC=0.696) and OI (4-day-mean AUC=0.695) were the best predictors. AUCs were 0.789 for OI on day-1, and 0.786 for EVLWI on day-2. In binary regression analysis of patients with TPTD, EVLWI (B=-0.105; Wald=7.294; p=0.007) and OI (B=0.124; Wald=7.435; p=0.006) were independently associated with 28-days-mortality. Combining of EVLWI and OI provided ROC-AUCs of 0.801 (day-1) and 0.824 (day-2). Among the totality of patients, the use of TPTD-monitoring "per se" and a lower SOFA-score were independently associated with a lower 28-days-mortality. CONCLUSIONS: Prognosis of ARDS-patients can be estblished within two days after intubation. The best predictors were EVLWI and OI and their combination. TPTD-monitoring "per se" was independently associated with reduced mortality.

Vitamin D Deficiency Is Highly Prevalent in Critically Ill Patients and a Risk Factor for Mortality: A Prospective Observational Study Comparing Noncirrhotic Patients and Patients With Cirrhosis.

INTRODUCTION: A 25-hydroxyvitamin D, 25(OH)D, deficiency is common among critically ill patients and correlated with increased mortality. Furthermore, deficiency is associated with advanced liver disease. However, there are no studies available comparing the dimensions and consequences of a 25(OH)D deficiency between patients with and without liver cirrhosis in the setting of intensive care units (ICUs). This study focuses on differences in 25(OH)D status between critically ill noncirrhosis patients and patients with cirrhosis (primary end point), hypothesizing that deficiency and its impact on mortality risk are even more pronounced in patients with cirrhosis. METHODS: We performed a prospective observational study of 176 patients (noncirrhosis patients, N = 114; patients with cirrhosis, N = 62) with a laboratory assessment of 25(OH)D on ICU admission and survival analyses after 180 days. RESULTS: On admission, 55% of patients showed a severe deficiency, 25(OH)D <10 ng/mL, and a further 23% moderate deficiency (10-19 ng/mL). The overall median level of 25(OH)D was 8.0 (5.0-18.0) ng/mL (10.5 [6.0-21.3] in noncirrhosis patients vs 7.0 [4.8-10.0] in patients with cirrhosis; P < .001). We found extremely low levels particularly in patients without prior vitamin D supplementation (6.0 [4.0-7.5] in patients with cirrhosis vs 8.0 [5.0-12.0] ng/mL in noncirrhosis patients; P = .004). Vitamin D status correlated inversely with the sequential organ failure assessment, acute and physiology chronic health evaluation, model of end-stage liver disease, and Child-Pugh scores. Survival analyses categorized 25(OH)D levels <10 ng/mL as a high-risk factor for mortality 180 days after admission (hazard ratio [HR]: 2.45, 95% confidence interval [CI] = 1.60-3.70; P < .001). In patients with cirrhosis, a severe deficiency (<10 ng/mL) involved a significantly higher mortality risk than in noncirrhosis patients (HR: 2.30, 95% CI = 1.39-3.82; P = .001). In cases of admission levels ≥10 ng/mL, however, mortality risk was similar between patients with cirrhosis and noncirrhosis patients (HR: 1.08, 95% CI = 0.43-2.73; P = .873). CONCLUSIONS: Hypovitaminosis D is a highly frequent disorder in critically ill patients admitted to ICU. A severe deficiency with levels <10 ng/mL is a high risk factor for increased mortality, especially in patients with cirrhosis.

Transpulmonary thermodilution before and during veno-venous extra-corporeal membrane oxygenation ECMO: an observational study on a potential loss of indicator into the extra-corporeal circuit.

Haemodynamic monitoring before extra-corporeal membrane oxygenation (ECMO) might help to optimize the effectiveness of ECMO. However, there are concerns that pulmonary arterial and trans-pulmonary thermodilution (TPTD) might be confounded by a loss of indicator into the ECMO-circuit, resulting in an overestimation of volumetric parameters. Since there is a lack of data on indicator dilution techniques during ECMO, we compared TPTD-measurements before and during ECMO. TPTD-derived parameters before and after initiation of ECMO were compared in 14 intensive care unit-patients with veno-venous ECMO and TPTD-monitoring (PiCCO®). Eight patients had a jugular and six patients a femoral central venous catheter (CVC). Cardiac index, global end-diastolic volume index (GEDVI) and extra-vascular lung water index (EVLWI) before ECMO as well as the ECMO-flow were comparable in patients with jugular and femoral CVC. Pre-ECMO, cardiac index (CI) was not significantly different compared to values during ECMO (4.5 ± 1.7 vs. 4.4 ± 2.1 L/min/m2; p = 0.43). By contrast, GEDVI (791 ± 179 vs. 974 ± 384 mL/m2; p = 0.04) and EVLWI (21 ± 9 vs. 28 ± 11 mL/kg; p < 0.01) were higher during ECMO than before. Increases in GEDVI (36 ± 210 vs. 378 ± 247 mL/m2; p = 0.02) and EVLWI (3 ± 2 vs. 11 ± 8 mL/kg; p = 0.06) were substantially more pronounced in patients with femoral compared to jugular indicator injection. In multivariate analysis, femoral indicator injection was independently associated with larger increases in GEDVI (p < 0.01) and EVLWI (p = 0.04) during ECMO. However, CI and haemodynamic parameters not derived from TPTD, but from pulse contour analysis (systolic and diastolic arterial pressure, stroke volume variation and pulse pressure variation) were not affected by the start of ECMO. Our study demonstrates marked increases in GEDVI and EVLWI after the onset of ECMO. These increases were more pronounced for femoral compared to jugular indicator injection. CI and haemodynamic parameters not derived from TPTD were not affected by the extra-corporeal circuit.

Comparison of cardiac function index derived from femoral and jugular indicator injection for transpulmonary thermodilution with the PiCCO-device: A prospective observational study.

INTRODUCTION: Cardiac function index (CFI) is a trans-pulmonary thermodilution (TPTD)-derived estimate of systolic function. CFI is defined as the ratio of cardiac output divided by global end-diastolic volume GEDV (CFI = CO/GEDV). Several studies demonstrated that the use of femoral venous access results in a marked overestimation of GEDV, while CFI is underestimated. One study suggested a correction formula for femoral venous access that markedly reduced the bias for GEDVI. Therefore, the last PiCCO-algorithm requires information about the CVC-position which suggests a correction of GEDV for femoral access. However, a recent study demonstrated inconsistencies of the last PiCCO algorithm using incorrected GEDV to calculate CFI despite obvious correction of GEDV. Nevertheless, this study was based on mathematical analyses of data displayed in a total of 15 patients equipped with only a femoral, but not with a jugular CVC. Therefore, this study compared CFI derived from the femoral indicator injection TPTD to data derived from jugular indicator injection in 28 patients with both a jugular and a femoral CVC. METHODS: 28 ICU-patients with PiCCO-monitoring were included. Each dataset consisted of three triplicate TPTDs using the jugular venous gold standard access and the femoral access with and without information about the femoral indicator injection to evaluate, if correction for femoral GEDV also pertains to CFI. (CFI_jug: jugular indicator injection; CFI_fem: femoral indicator injection; CFI_fem_cor: femoral indicator injection with correct information about CVC-position; CFI_fem_uncor: femoral indicator injection with uncorrect information about CVC-position; CFI_fem_uncor_form = CFI_fem_uncor * (GEDVI_fem_uncor/GEDVI_fem_cor)). RESULTS: CFI_fem_uncor was significantly lower than CFI_jug (4.28±1.70 vs. 5.21±1.91 min-1; p<0.001). Similarly, CFI_fem_cor was significantly lower than CFI_jug (4.24±1.62 vs. 5.21±1.91 min-1; p<0.001). This is explained by the finding that CFI_fem_uncor was not different to CFI_fem_cor (4.28±1.70 vs. 4.24±1.62 min-1; p = 0.611). This suggests that correction for femoral CVC does not pertain to CFI. Calculative correction of CFI_fem_uncor by multiplying CFI_fem_uncor by the ratio GEDVI_fem_uncor/GEDVI_jug resulted in CFI_fem_uncor_form which was slightly, but significantly different from the gold standard CFI_jug (5.51±2.00 vs. 5.21±1.91 min-1; p = 0.024). The agreement of measurements classified in the same category of CFI (decreased (<4.5), normal (4.5-6.5) and increased (>6.5 min-1)) was high for CFI_jug and CFI_fem_uncor_form (identical categories in 26 of 28 comparisons; p = 0.49). By contrast, the agreement with CFI_jug was significantly lower for CFI_fem_cor (14 out of 28; p<0.001) and CFI_fem_uncor (15 out of 28; p<0.001). CONCLUSIONS: While the last PiCCO algorithm obviously corrects GEDVI for femoral indicator injection, this correction is not applied to CFI. Therefore, femoral TPTD indicator injection results in substantially lower values for CFI compared to TPTD using a jugular CVC. Necessarily, uncorrected CFI-values derived from femoral TPTD are misleading and have to be corrected.

Large-volume paracentesis effects plasma disappearance rate of indo-cyanine green in critically ill patients with decompensated liver cirrhosis and intraabdominal hypertension.

BACKGROUND: Ascites is a major complication of decompensated liver cirrhosis. Intraabdominal hypertension and structural alterations of parenchyma involve decisive changes in hepatosplanchnic blood flow. Clearance of indo-cyanine green (ICG) is mainly dependent on hepatic perfusion and hepatocellular function. As a consequence, plasma disappearance rate of ICG (ICG-PDR) is rated as a useful dynamic parameter of liver function. This study primarily evaluates the impact of large-volume paracentesis (LVP) on ICG-PDR in critically ill patients with decompensated cirrhosis. Additionally, it describes influences on intraabdominal pressure (IAP), abdominal perfusion pressure (APP), hepatic blood flow, hemodynamic and respiratory function. METHODS: We analyzed LVP in 22 patients with decompensated liver cirrhosis. ICG-PDR was assessed by using noninvasive LiMON technology (Pulsion® Medical Systems; Maquet Getinge Group), and hepatic blood flow was analyzed by color-coded duplex sonography. RESULTS: Paracentesis of a median volume of 3450 mL ascites evoked significant increases of ICG-PDR from 3.6 (2.8-4.6) to 5.1 (3.9-6.2)%/min (p < 0.001). Concomitantly, we observed a raise in "ICG-Clearance" from 99 (73.5-124.5) to 104 (91-143.5) mL/min/m2 (p = 0.005), while circulating blood volume index was unchanged [2412 (1983-3025) before paracentesis vs. 2409 (1997-2805) mL/m2, p = 0.734]. Sonography revealed a significant impact of paracentesis on hepatic blood flow: Hepatic artery resistance index dropped from 0.74 (0.68-0.75) to 0.68 (0.65-0.71) (p < 0.001) and maximum flow velocity in hepatic vein increased from 24 (17-30) to 30 (22-36) cm/s (p < 0.001). Consistent with previous studies, paracentesis caused significant decreases in IAP from 19.0 (15.0-20.3) to 11.0 (8.8-12.3) mmHg (p < 0.001) and central venous pressure from 22.5 (17.8-29.0) to 17.5 (12.8-24.0) mmHg (p < 0.001) with inverse increases in APP from 63.0 (56.8-69.5) to 71.0 (65.5-78.5) mmHg (p < 0.001). Changes in ICG-PDR were concomitant with changes in IAP (r = - 0.602) and APP (r = 0.576). Moreover, we found a substantial improvement in respiratory function. By contrast, hemodynamic parameters assessed by transpulmonary thermodilution, serum bilirubin and international normalized ratio did not change after paracentesis. CONCLUSION: Critically ill patients with decompensated cirrhosis and elevated IAP showed dramatically impaired ICG-PDR. Paracentesis evoked an improvement in ICG-PDR in parallel with a decreased IAP and an increased APP, while conventional parameters of liver function did not change. This effect on ICG-PDR is mainly referable to a relief of intraabdominal hypertension and changes in hepatosplanchnic blood flow.

Accuracy and precision of ScvO2 measured with the CeVOX-device: A prospective study in patients with a wide variation of ScvO2-values.

INTRODUCTION: Central-venous oxygen saturation (ScvO2) is a key parameter of hemodynamic monitoring and has been suggested as therapeutic goal for resuscitation. Several devices offer continuous monitoring features. The CeVOX-device (Pulsion Medical Systems) uses a fibre-optic probe inserted through a conventional central-venous catheter (CVC) to obtain continuous ScvO2. OBJECTIVES: Since there is a lack of studies validating the CeVOX, we prospectively analyzed data from 24 patients with CeVOX-monitoring. To increase the yield of lower ScvO2-values, 12 patients were equipped with a femoral CVC. METHODS: During the 8h study period ScvO2_CeVOX was documented immediately before withdrawal of blood to measure ScvO2 by blood gas analysis (ScvO2_BGA) 6min, 1h, 4h, 5h and 8h after the initial calibration. No further calibrations were performed. RESULTS: In patients with jugular CVC (primary endpoint; 60 measurements), bias, lower and upper limits of agreement (LLOA; ULOA) and percentage error (PE) of the estimate of ScvO2 (ScvO2_CeVOX_jug) were acceptable with 0.45%, -13.0%, 13.9% and 16.6%, respectively. As supposed, ScvO2 was lower in the femoral compared to the jugular measurements (69.5±10.7 vs. 79.4±5.8%; p<0.001). While the bias (0.64%) was still acceptable, LLOA (-23.8%), ULOA (25.0%) and PE (34.5%) were substantially higher for femoral assessment of ScvO2 by the CeVOX (ScvO2_CeVOX_fem). Analysis of the entire data-pool with jugular as well as femoral CVCs allowed for a multivariate analysis which demonstrated that the position of the CVC per se was not independently associated with the bias ScvO2_CeVOX-ScvO2_BGA. The amount of the bias |ScvO2_CeVOX-ScvO2_BGA| was independently associated with the amount of the change of ScvO2_CeVOX compared to the initial calibration to ScvO2_BGA_baseline (|ScvO2_CeVOX-ScvO2_BGA_baseline|) as well as with low values of ScvO2_BGA_baseline. Furthermore, increasing time to the initial calibration was associated to the amount of the bias with borderline significance. A statistical model based on |ScvO2_CeVOX-ScvO2_BGA_baseline| and "time to last calibration" derived from an evaluation dataset (80 of 120 datasets, 16 of 24) provided a ROC-AUC of 0.903 to predict an amount of the bias |ScvO2_CeVOX-ScvO2_BGA| ≥5% in an independent validation group (40 datasets of 8 patients). CONCLUSION: These findings suggest that the CeVOX device is capable to detect stability or instability of ScvO2_BGA. ScvO2_CeVOX accurately estimates ScvO2_BGA in case of stable values. However, intermittent measurement of ScvO2_BGA and re-calibration should be performed in case of substantial changes in ScvO2_CeVOX compared to baseline. Therefore, continuous measurement of ScvO2 with the CeVOX cannot replace ScvO2_BGA in instable patients. On the other hand, CeVOX might be useful for the monitoring of stable patients as a pre-test tool for more differentiated monitoring in case of changes in ScvO2_CeVOX.

Comparison of pulmonary vascular permeability index PVPI and global ejection fraction GEF derived from jugular and femoral indicator injection using the PiCCO-2 device: A prospective observational study.

BACKGROUND: Transpulmonary thermodilution (TPTD) is used to derive cardiac output CO, global end-diastolic volume GEDV and extravascular lung water EVLW. To facilitate interpretation of these data, several ratios have been developed, including pulmonary vascular permeability index (defined as EVLW/(0.25*GEDV)) and global ejection fraction ((4*stroke volume)/GEDV). PVPI and GEF have been associated to the aetiology of pulmonary oedema and systolic cardiac function, respectively. Several studies demonstrated that the use of femoral venous access results in a marked overestimation of GEDV. This also falsely reduces PVPI and GEF. One of these studies suggested a correction formula for femoral venous access that markedly reduced the bias for GEDV. Consequently, the last PiCCO-algorithm requires information about the CVC, and correction for femoral access has been shown. However, two recent studies demonstrated inconsistencies of the last PiCCO algorithm using incorrected GEDV for PVPI, but corrected GEDV for GEF. Nevertheless, these studies were based on mathematical analyses of data displayed in a total of 15 patients equipped with only a femoral, but not with a jugular CVC. Therefore, this study compared PVPI_fem and GEF_fem derived from femoral TPTD to values derived from jugular indicator injection in 25 patients with both jugular and femoral CVCs. METHODS: 54 datasets in 25 patients were recorded. Each dataset consisted of three triplicate TPTDs using the jugular venous access as the gold standard and the femoral access with (PVPI_fem_cor) and without (PVPI_fem_uncor) information about the femoral indicator injection to evaluate, if correction for femoral GEDV pertains to PVPI_fem and GEF_fem. RESULTS: PVPI_fem_uncor was significantly lower than PVPI_jug (1.48±0.47 vs. 1.84±0.53; p<0.001). Similarly, PVPI_fem_cor was significantly lower than PVPI_jug (1.49±0.46 vs. 1.84±0.53; p<0.001). This is explained by the finding that PVPI_fem_uncor was not different to PVPI_fem_cor (1.48±0.47 vs. 1.49±0.46; n.s.). This clearly suggests that correction for femoral CVC does not pertain to PVPI. GEF_fem_uncor was significantly lower than GEF_jug (20.6±5.1% vs. 25.0±6.1%; p<0.001). By contrast, GEF_fem_cor was not different to GEF_jug (25.6±5.8% vs. 25.0±6.1%; n.s.). Furthermore, GEF_fem_cor was significantly higher than GEF_fem_uncor (25.6±5.8% vs. 20.6±5.1%; p<0.001). This finding emphasizes that an appropriate correction for femoral CVC is applied to GEF_fem_cor. The extent of the correction (25.5/20.6; 124%) for GEF and the relation of PVPI_jug/PVPI_fem_uncor (1.84/1.48; 124%) are in the same range as the ratio of GEDVI_fem_uncor/GEDVI_fem_cor (1056ml/m2/821mL/m2; 129%). This further emphasizes that GEF, but not PVPI is corrected in case of femoral indicator injection. CONCLUSIONS: Femoral indicator injection for TPTD results in significantly lower values for PVPI and GEF. While the last PiCCO algorithm appropriately corrects GEF, the correction is not applied to PVPI. Therefore, GEF-values can be used in case of femoral CVC, but PVPI-values are substantially underestimated.

Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. ©2016 AACR.

Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.