[Intensive care monitoring]. / Intensivmedizinisches Monitoring.

Monitoring the function of essential organ systems is a hallmark of critical care. In combination with the medical history, physical examination and selective diagnostic tests. Monitoring facilitates the bed-side diagnosis of many diseases in critical care and guides therapeutic management while providing optimal patient safety. The availability of monitoring compensates in the very often complex and multimorbid patients and the very dynamic course of their diseases the lack of universally applicable treatment protocols, that are based on the results of randomized critical care trials. In the future clinical decision support systems based on artificial intelligence might support intensivists in the analysis of monitoring data in terms of individual prognosis assessment and choice of therapy.

Course of lactate, pH and base excess for prediction of mortality in medical intensive care patients.

INTRODUCTION: As base excess had shown superiority over lactate as a prognostic parameter in intensive care unit (ICU) surgical patients we aimed to evaluate course of lactate, base excess and pH for prediction of mortality of medical ICU patients. MATERIALS AND METHODS: For lactate, pH and base excess, values at the admission to ICU, at 24 ± 4 hours, maximum or minimum in the first 24 hours and in 24-48 hours after admission were collected from all patients admitted to the Medical ICU of the University Hospital Tübingen between January 2016 until December 2018 (N = 4067 at admission, N = 1715 with ICU treatment > 48 h) and investigated for prediction of in-hospital-mortality. RESULTS: Mortality was 22% and significantly correlated with all evaluated parameters. Strongest predictors of mortality determined by ROC were maximum lactate in 24 h (AUROC 0.74, cut off 2.7 mmol/L, hazard ratio of risk group with value > cut off 3.20) and minimum pH in 24 h (AUROC 0.71, cut off 7.31, hazard ratio for risk group 2.94). Kaplan Meier Curves stratified across these cut offs showed early and clear separation. Hazard ratios per standard deviation increase were highest for maximum lactate in 24 h (HR 1.65), minimum base excess in 24 h (HR 1.56) and minimum pH in 24 h (HR 0.75). CONCLUSION: Lactate, pH and base excess were all suitable predictors of mortality in internal ICU patients, with maximum / minimum values in 24 and 24-48 h after admission altogether stronger predictors than values at admission. Base excess and pH were not superior to lactate for prediction of mortality.

Impact of an interdisciplinary nutrition support team (NST) on the clinical outcome of critically ill patients. A pre/post NST intervention study.

BACKGROUND: Intensive care unit (ICU) patients are at particular risk for malnutrition with major impact for outcome and prognosis. Nutrition support teams (NST) have been proposed to improve nutrition care in ICU patients. OBJECTIVE: To assess the effectiveness of an interdisciplinary NST on anthropometry and clinical outcome of ICU patients. METHODS: Before NST implementation, we assessed 120 patients (before NST group; SAPS II score 44 ± 16), afterwards 60 patients (after NST group), of whom 29 received NST guidance (after NST + group; SAPS II 65 ± 19) and 31 not (after NST - group; SAPS II, 54 ± 16). The primary outcome parameter was length of stay in the hospital (hospital-LOS). Severity of disease was assessed by the APACHE II score and the nutritional risk (NUTRIC) score. RESULTS: NST intervention resulted in a more pronounced improvement of disease severity (APACHE II, from 27 ± 8 to 18 ± 6, p < 0.001; NUTRIC, from 7 ± 2 to 4 ± 2, p < 0.001) compared to no NST intervention (APACHE II from 24 ± 7 to 21 ± 7, p < 0.05; NUTRIC from 6 ± 2 to 5 ± 2, p < 0.01). The mean hospital-LOS was not reduced, neither in the NST intervention group nor in the control group without NST intervention. NST intervention failed to improve nutritional status or mortality compared to no NST intervention. CONCLUSION: In our study the NST intervention had a positive effect on disease severity, but failed to improve mortality, hospital-LOS or nutritional status in ICU patients, likely because of a large patient heterogeneity. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02200874).

Effect of an intensified individual nutrition therapy on serum metabolites in critically ill patients - A targeted metabolomics analysis of the ONCA study.

PURPOSE: The effect of medical nutrition on serum metabolomics has been poorly explored. The aim of the study was to investigate the relation between energy supply and metabolic profiles in critically ill patients. MATERIALS AND METHODS: Twenty mechanically ventilated patients on enteral nutrition (EN) or enteral/parenteral nutrition (EN/PN) were randomized into two groups. One group received an individual energy supply based on indirect calorimetry (IC group, n = 9), the other group received a standard energy supply based on a formula, the standard care group (SC group, n = 11). Targeted metabolomics was performed in early-, late- and post-acute metabolic phase. RESULTS: Individual versus standard care energy supply resulted in a metabolite class separation between the IC and the SC group (P < 0.001). In the SC group concentrations of four glucogenic amino acids and three biogenic amines increased between the early- and late-acute metabolic phase (P < 0.05). The metabolomics pattern differed between the routes of nutrition administration (P < 0.01). CONCLUSIONS: The amount of energy supply by EN or PN, besides other factors, seems to modulate serum metabolites. Nutrition therapy based on individualized energy supply is associated with a reduction of metabolites reflecting catabolism. Therefore, metabolomics could be a new tool to determine metabolic phases in critically ill patients.

[Rational therapeutic decisions in intensive care patients]. / Rationale Therapieentscheidungen bei Intensivpatienten.

Decisions about the initiation, continuation and termination of life-supporting treatments are a permanent challenge in intensive care units (ICUs). Decisions should be based on patient preferences and the medical indication. The medical indication is mainly the result of an assessment of the patient's prognosis and the applicable therapeutic options. Factors influencing the short term prognosis are mostly the severity of the acute leading disease, the number and severity of other organ failures and the response to initial treatment. Long term prognosis is dominated by the severity and number of comorbidities, age and the resulting frailty. Because in many patients all these informations are not available at the time of admission, in these cases a time-limited trial is often justified to gather all this information before a decision is made. These principles of decision making can also applied to situations in which ICU-capacities are limited (e. g. COVID-19 pandemic).

Life-threatening pneumonitis after first-line treatment with osimertinib for primary T790M mutated non-small cell lung cancer.

Epithelial growth factor receptor (EGFR) directed tyrosine kinase inhibitor (TKI) treatment is the standard approach in patients with advanced, EGFR-mutated non-small cell lung cancer (NSCLC). Although benefit/risk ratio is favorable for these TKI and side effects are manageable in the vast majority of patients, severe and even life-threatening side effects have been reported. TKI-induced interstitial lung disease (ILD) has been reported for single cases in modest severity, predominantly in EGFR-TKI pretreated patients. Here, we report a case of successful stabilization of a life-threatening ILD in a de novo T790M mutated NSCLC during first-line treatment with osimertinib. As osimertinib will be used more often in many EGFR-positive NSCLC patients in the future, this potentially life-threatening side effect should receive special attention, especially in first-line treatment.

A novel flow cytometry-based assay to measure compromised B cell receptor signaling as a prognostic factor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. In the past years, new therapeutic approaches (e.g., ibrutinib or venetoclax) have been established and greatly improved treatment of CLL. However, complete control or cure of the disease have not been reached so far. Thus, reliable prognostic markers are an imperative for treatment decisions. Recent studies have revealed an essential role for B cell receptor (BCR) signaling in the pathogenesis, prognosis, and therapy of CLL. A heterogeneous response to receptor stimulation with anti-IgM treatment culminating in different calcium flux capabilities has been demonstrated by several authors. However, the methods employed have not reached clinical application. Here, we report on a flow cytometry-based assay to evaluate calcium flux capabilities in CLL and demonstrate that compromised BCR signaling with diminished calcium flux is associated with a significantly better clinical outcome and progression free survival. In summary, our data strongly support the role of compromised BCR signaling as an important prognostic marker in CLL and establish a novel diagnostic tool for its assessment in clinical settings.

Elimination of Contrast Agent Gadobutrol with Sustained Low Efficiency Daily Dialysis Compared to Intermittent Hemodialysis.

BACKGROUND: In patients with renal failure, gadolinium-based contrast agents (GBCA) can be removed by intermittent hemodialysis (iHD) to prevent possible toxic effects. There is no data on the efficacy of GBCA removal via sustained low efficiency daily dialysis (SLEDD) which is mainly used in intensive care unit (ICU) patients. METHODS: We compared the elimination of the GBCA gadobutrol in 6 ICU patients treated with SLEDD (6-12 h, 90 L dialysate) with 7 normal ward inpatients treated with iHD (4 h, dialysate flow 500 mL/min). Both groups received 3 dialysis sessions on 3 consecutive days starting after the application of gadobutrol. Blood samples were drawn before and after each session and total dialysate, as well as urine was collected. Gadolinium (Gd) concentrations were measured using mass spectrometry and eliminated Gd was calculated from dialysate and urine. RESULTS: The initial mean plasma Gd concentration was 385 ± 183 µM for the iHD and 270 ± 97 µM for the SLEDD group, respectively (p > 0.05). The Gd-reduction rate after the first dialysis session was 83 ± 9 and 67 ± 9% for the iHD and the SLEDD groups, respectively (p = 0.0083). The Gd-reduction rate after the second and third dialysis was 94-98 and 89-96% for the iHD and the SLEDD groups (p > 0.05). The total eliminated Gd was 89 ± 14 and 91 ± 4% of the dose in the iHD and the SLEDD groups, respectively (p > 0.05). Gd dialyzer clearance was 95 ± 22 mL/min and 79 ± 19 mL/min for iHD and SLEDD, respectively (p > 0.05). CONCLUSIONS: Gd-elimination with SLEDD is equally effective as iHD and can be safely used to remove GBCA in ICU patients.

Association Between Urinary Catecholamine Excretion and Urine Volume.

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients' age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume.

Potential role of CT-textural features for differentiation between viral interstitial pneumonias, pneumocystis jirovecii pneumonia and diffuse alveolar hemorrhage in early stages of disease: a proof of principle.

BACKGROUND: Pulmonary involvement is common in several infectious and non-infectious diagnostic settings. Imaging findings consistently overlap and are therefore difficult to differentiate by chest-CT. The aim of this study was to evaluate the role of CT-textural features(CTTA) for discrimination between atypical viral (respiratory-syncitial-virus(RSV) and herpes-simplex-1-virus (HSV1)), fungal (pneumocystis-jirovecii-pneumonia(PJP)) interstitial pneumonias and alveolar hemorrhage. METHODS: By retrospective single-centre analysis we identified 46 consecutive patients (29 m) with RSV(n = 5), HSV1(n = 6), PJP(n = 21) and lung hemorrhage(n = 14) who underwent unenhanced chest CTs in early stages of the disease between 01/2016 and 02/2017. All cases were confirmed by microbiologic direct analysis of bronchial lavage. On chest-CT-scans, the presence of imaging features like ground-glass opacity(GGO), crazy-paving, air-space consolidation, reticulation, bronchial wall thickening and centrilobular nodules were described. A representative large area was chosen in both lungs and used for CTTA-parameters (included heterogeneity, intensity, average, deviation, skewness). RESULTS: Discriminatory CTTA-features were found between alveolar hemorrhage and PJP consisting of differences in mean heterogeneity(p < 0.015) and uniformity of skewness(p < 0.006). There was no difference between CT-textural features of diffuse alveolar hemorrhage and viral pneumonia or PJP and viral pneumonia. Visual HRCT-assessment yielded great overlap of imaging findings with predominance of GGO for PJP and airspace consolidation for pneumonia/alveolar hemorrhage. Significant correlations between HRCT-based imaging findings and CT-textural features were found for all three disease groups. CONCLUSION: CT-textural features showed significant differences in mean heterogeneity and uniformity of skewness. HRCT-based imaging findings correlated with certain CT-textural features showing that the latter have the potential to characterize structural properties of lung parenchyma and related abnormalities.

Optimization of Nutrition Therapy with the Use of Calorimetry to Determine and Control Energy Needs in Mechanically Ventilated Critically Ill Patients: The ONCA Study, a Randomized, Prospective Pilot Study.

BACKGROUND: Adequate nutrition therapy in critically ill patients poses a challenge because of the variable energy and substrate needs. The objective was to investigate whether nutrition therapy involving indirect calorimetry (IC), instead of equations for assessment of energy needs, could improve the nutrition status of critically ill patients. METHODS: Forty mechanically ventilated patients were randomized into a group in which energy needs were controlled by calorimetry (IC group) and a group treated with a formula-based approach reflecting standard care (SC group). The primary outcome was change in the phase angle (PhA), a bioelectrical impedance parameter related to nutrition status and prognosis. RESULTS: The mean IC-based energy requirement was lower than the formula-based estimate (21.1 ± 6.4 versus [vs] 25 kcal/kg/d, P < .01). The IC group reached 98% ± 8% of the energy goal, whereas the SC group reached only 79% ± 29% (P < 0.05), although mean intake was similar in both groups. The protein intake goal was better met in the IC group (91% ± 24%) than the SC group (73% ± 33%). The PhA of the IC group did not change during treatment, whereas that of the SC group tended to decrease by 0.36° ± 0.86° (P = .077). A shorter length of stay in intensive care was observed in the IC than in the SC group (13 ± 8 vs 24 ± 20 days, P < .05). CONCLUSION: Intensified individual nutrition therapy involving IC appears to be useful for improving nutrition status in critically ill patients.

Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter's syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter's syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.

A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant B cell clones and represents the most common leukemia in western countries. The majority of CLL patients show an indolent course of the disease as well as an anergic phenotype of their leukemia cells, referring to a B cell receptor unresponsive to external stimulation. We have recently shown that the transcription factor NFAT2 is a crucial regulator of anergy in CLL. A major challenge in the analysis of the role of a transcription factor in different diseases is the identification of its specific target genes. This is of great significance for the elucidation of pathogenetic mechanisms and potential therapeutic interventions. Chromatin immunoprecipitation (ChIP) is a classic technique to demonstrate protein-DNA interactions and can, therefore, be used to identify direct target genes of transcription factors in mammalian cells. Here, ChIP was used to identify LCK as a direct target gene of NFAT2 in human CLL cells. DNA and associated proteins are crosslinked using formaldehyde and subsequently sheared by sonication into DNA fragments of approximately 200-500 base pairs (bp). Cross-linked DNA fragments associated with NFAT2 are then selectively immunoprecipitated from cell debris using an αNFAT2 antibody. After purification, associated DNA fragments are detected via quantitative real-time PCR (qRT-PCR). DNA sequences with evident enrichment represent regions of the genome which are targeted by NFAT2 in vivo. Appropriate shearing of the DNA and the selection of the required antibody are particularly crucial for the successful application of this method. This protocol is ideal for the demonstration of direct interactions of NFAT2 with target genes. Its major limitation is the difficulty to employ ChIP in large-scale assays analyzing the target genes of multiple transcription factors in intact organisms.

[Do Vitamins Play a Role in the Pathogenesis and Therapy of Sepsis?] / Spielen Vitamine bei der Pathogenese und Therapie der Sepsis eine Rolle?

Hospital mortality of severe sepsis and septic shock is still around 40 % according to recent studies. In accordance to the current sepsis definition, sepsis is a life-threatening organ dysfunction caused by a dysregulated response of the organism to infection. Septic shock is defined by vasopressor-dependent circulatory failure and lactic acidosis. Patients with sepsis and septic shock are often old and/or characterized by severe comorbidities, e. g. tumor or liver disease. These factors also predispose to malnutrition and hence to a corresponding deficiency of essential nutritional components e. g. vitamins. A number of recent studies and reviews have addressed the question whether deficiencies in certain vitamins may facilitate the transition from infection to septic shock. In addition, studies have investigated the effect of high-dose vitamin therapies on sepsis mortality and sepsis-associated organ dysfunctions. This article would like to summarize this current discussion with a focus on vitamin B1 (thiamine), vitamin C and vitamin D.

[Quality Management in Intensive Care Units]. / Qualitätsmanagement auf der Intensivstation.

The care of critically ill patients in an intensive care unit is effected by an interprofessional and interdisciplinary team. Quality and success of intensive care is mainly based on the performance of this team. Suitable quality management measures, based on valid indicators, insure an optimal workflow for the benefit of patient safety.