Timely Cessation of Proton Pump Inhibitors in Critically Ill Patients Impacts Morbidity and Mortality: A Propensity Score-Matched Cohort Study.

OBJECTIVE: Proton pump inhibitors (PPIs) are among the drugs most commonly used in critically ill patients. Although mainly applied temporarily for stress ulcer prophylaxis, their application is frequently not terminated. Potential adverse effects of PPI treatment could impact the outcome in case of unnecessary and, therefore, avoidable long-term continuation. We tested the hypotheses that nonindicated PPI therapy continued beyond hospital discharge is associated with increased morbidity, rehospitalization rate, and mortality. DESIGN: Nationwide retrospective cohort study considering critically ill patients treated on German ICUs between January, 2017, and December, 2018 with a 2-year follow-up. SETTING: A total of 591,207 patient datasets of a German healthcare insurer were screened. PATIENTS: We identified 11,576 ICU patients who received PPI therapy for the first time during their index ICU stay without having an indication for its continuation. INTERVENTIONS: The cohort was stratified into two groups: 1) patients without further PPI therapy and 2) patients with continuation of PPI therapy beyond 8 weeks after hospital discharge. MEASUREMENTS AND MAIN RESULTS: Frequency of predescribed adverse events associated with PPI therapy, 1-year rehospitalization rate, and 2-year mortality were determined. The proportion of patients with continued PPI therapy without an objectifiable indication was 41.7% (4,825 of 11,576 patients). These patients had a 27% greater risk of pneumonia (odds ratio [OR] 1.27; 95% CI, 1.15-1.39; p < 0.001) and a 17% greater risk of cardiovascular events (OR 1.17; 95% CI, 1.08-1.26; p < 0.001). Continued PPI therapy was associated with a 34% greater risk of rehospitalization (OR 1.34; 95% CI, 1.23-1.47) and a nearly 20% greater 2-year mortality risk (hazard ratio 1.17; 95% CI, 1.08-1.27; p = 0.006). CONCLUSIONS: These data demonstrate that an unnecessary continuation of PPI therapy after hospital discharge may significantly impact morbidity and mortality. To avoid potentially harmful overuse of a PPIs, intensivists should ensure timely cessation of a temporarily indicated PPI therapy.

Quantification of left ventricular ejection fraction and cardiac output using a novel semi-automated echocardiographic method: a prospective observational study in coronary artery bypass patients.

BACKGROUND: Echocardiographic quantification of ejection fraction (EF) by manual endocardial tracing requires training, is time-consuming and potentially user-dependent, whereas determination of cardiac output by pulmonary artery catheterization (PAC) is invasive and carries a risk of complications. Recently, a novel software for semi-automated EF and CO assessment (AutoEF) using transthoracic echocardiography (TTE) has been introduced. We hypothesized that AutoEF would provide EF values different from those obtained by the modified Simpson's method in transoesophageal echocardiography (TOE) and that AutoEF CO measurements would not agree with those obtained via VTILVOT in TOE and by thermodilution using PAC. METHODS: In 167 patients undergoing coronary artery bypass graft surgery (CABG), TTE cine loops of apical 4- and 2-chamber views were recorded after anaesthesia induction under steady-state conditions. Subsequently, TOE was performed following a standardized protocol, and CO was determined by thermodilution. EF and CO were assessed by TTE AutoEF as well as TOE, using the modified Simpson's method, and Doppler measurements via velocity time integral in the LV outflow tract (VTILVOT). We determined Pearson's correlation coefficients r and carried out Bland-Altman analyses. The primary endpoints were differences in EF and CO. The secondary endpoints were differences in left ventricular volumes at end diastole (LVEDV) and end systole (LVESV). RESULTS: AutoEF and the modified Simpson's method in TOE showed moderate EF correlation (r = 0.38, p < 0.01) with a bias of -12.6% (95% limits of agreement (95%LOA): -36.6 - 11.3%). AutoEF CO correlated poorly both with VTILVOT in TOE (r = 0.19, p < 0.01) and thermodilution (r = 0.28, p < 0.01). The CO bias between AutoEF and VTILVOT was 1.33 l min-1 (95%LOA: -1.72 - 4.38 l min-1) and 1.39 l min-1 (95%LOA -1.34 - 4.12 l min-1) between AutoEF and thermodilution, respectively. AutoEF yielded both significantly lower EF (EFAutoEF: 42.0% (IQR 29.0 - 55.0%) vs. EFTOE Simpson: 55.2% (IQR 40.1 - 70.3%), p < 0.01) and CO values than the reference methods (COAutoEF biplane: 2.30 l min-1 (IQR 1.30 - 3.30 l min-1) vs. COVTI LVOT: 3.64 l min-1 (IQR 2.05 - 5.23 l min-1) and COPAC: 3.90 l min-1 (IQR 2.30 - 5.50 l min-1), p < 0.01)). CONCLUSIONS: AutoEF correlated moderately with TOE EF determined by the modified Simpson's method but poorly both with VTILVOT and thermodilution CO. A systematic bias was detected overestimating LV volumes and underestimating both EF and CO compared to the reference methods. TRIAL REGISTRATION: German Register for Clinical Trials (DRKS-ID DRKS00010666, date of registration: 08/07/2016).

Polymorphic Variants in the GRK5 Gene Promoter Are Associated With Diastolic Dysfunction in Coronary Artery Bypass Graft Surgery Patients.

BACKGROUND: The G-protein-coupled receptor kinase 5 (GRK5) is a mediator of cardiovascular homeostasis and participates in inflammation and cardiac fibrosis, both being involved in the development of diastolic dysfunction (DD). While mechanisms of transcriptional regulation of the GRK5 promoter are unclear, we tested the hypotheses, that (1) GRK5 expression varies depending on functional single nucleotide polymorphisms (SNPs) in the GRK5 promoter and (2) this is associated with DD in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: We amplified and sequenced the GRK5 promoter followed by cloning, reporter assays, and electrophoretic mobility shift assays (EMSA). GRK5 messenger ribonucleic acid (mRNA) expression was determined in right atrial tissue sampled from 50 patients undergoing CABG surgery. In another prospective study, GRK5 genotypes were associated with determinants of diastolic function using transesophageal echocardiography in 255 patients with CABG with normal systolic left ventricular (LV) function. Specifically, we measured ejection fraction (EF), transmitral Doppler early filling velocity (E), tissue Doppler early diastolic lateral mitral annular velocity (E' lateral), and calculated E/E', E' norm and the difference of E' lateral and E' norm to account for age-related changes in diastolic function. RESULTS: We identified 6 SNPs creating 3 novel haplotypes with the greatest promoter activation in haplotype tagging (ht) SNP T(-678)C T-allele constructs (P < .001). EMSAs showed allele-specific transcription factor binding proving functional activity. GRK5 mRNA expression was greatest in TT genotypes (TT: 131 fg/µg [95% CI, 108-154]; CT: 109 [95% confidence interval {CI}, 93-124]; CC: 83 [95% CI, 54-112]; P = .012). Moreover, GRK5 genotypes were significantly associated with determinants of diastolic function. Grading of DD revealed more grade 3 patients in TT compared to CT and CC genotypes (58% vs 38% vs 4%; P = .023). E´ lateral was lowest in TT genotypes (P = .007) and corresponding E/E' measurements showed 1.27-fold increased values in TT versus CC genotypes (P = .01), respectively. While E' norm values were not different between genotypes (P = .182), the difference between E' lateral and E' norm was significantly higher in TT genotypes compared to CC and CT genotypes (-1.2 [interquartile range {IQR}, 2.7], -0.5 [IQR, 3.4], and -0.4 [IQR, 4.2; P = .035], respectively). CONCLUSIONS: A functional GRK5 SNP results in allele-dependent differences in GRK5 promoter activity and mRNA expression. This is associated with altered echocardiographic determinants of diastolic function. Thus, SNPs in the GRK5 promoter are associated with altered perioperative diastolic cardiac function. In the future, preoperative testing for these and other SNPs might allow to initiate more specific diagnostic and perioperative pathways to benefit patients at risk.

Glycocalyx components affect platelet function, whole blood coagulation, and fibrinolysis: an in vitro study suggesting a link to trauma-induced coagulopathy.

BACKGROUND: The mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial. Amongst others, however, shedding of the endothelial glycocalyx resulting in increased concentrations of glycocalyx fragments in plasma might also play a role. Thus, we hypothesized that shedded glycocalyx components affect coagulation and may act as humoral mediators of TIC. METHODS: To investigate effects of heparan sulfate, chondroitin sulfate, syndecan-1, versican, and thrombomodulin we added these fragments to in vitro assays of whole blood from healthy volunteers to yield concentrations observed in trauma patients. Platelet function, whole blood coagulation, and fibrinolysis were measured by standard coagulation tests, impedance aggregometry (IA), and viscoelastic tests (VET). To assess dose-response relationships, we performed IA with increasing concentrations of versican and VET with increasing concentrations of thrombomodulin. RESULTS: Intrinsically activated clotting times (i.e., activated partial thromboplastin time and intrinsically activated VET with and without heparinase) were unaffected by any glycocalyx fragment. Thrombomodulin, however, significantly and dose-dependently diminished fibrinolysis as assessed by VET with exogenously added rt-PA, and increased rt-PA-induced lysis Indices after 30 (up to 108% of control, p <  0,0001), 45 (up to 368% of control, p <  0,0001), and 60 min (up to 950% of control, p <  0,0001) in VET. Versican impaired platelet aggregation in response to arachidonic acid (up to - 37,6%, p <  0,0001), ADP (up to - 14,5%, p <  0,0001), and collagen (up to - 31,8%, p <  0,0001) in a dose-dependent manner, but did not affect TRAP-6 induced platelet aggregation. Clotting time in extrinsically activated VET was shortened by heparan sulfate (- 7,2%, p = 0,024), chondroitin sulfate (- 11,6%, p = 0,016), versican (- 13%, p = 0,012%), and when combined (- 7,2%, p = 0,007). CONCLUSIONS: Glycocalyx components exert distinct inhibitory effects on platelet function, coagulation, and fibrinolysis. These data do not support a 'heparin-like auto-anticoagulation' by shed glycosaminoglycans but suggest a possible role of versican in trauma-induced thrombocytopathy and of thrombomodulin in trauma-associated impairment of endogenous fibrinolysis.

Methylation in HT22 cells and primary hippocampal neurons with and without isoflurane exposurewhether isoflurane causes.

BACKGROUND: Epigenetic modulation may play a role in anesthesia related phenotypes, such as cognitive impairment or memory loss, especially with exposure to anesthetics in the vulnerable phase of brain development. While isoflurane anesthesia can evoke neuroinflammation and neuroapoptosis in young animals, we investigated in a permanent hippocampal cell line (HT22) and in primary hippocampal neurons in an a priori in vitro analysis, whether isoflurane exposure 1) evokes DNA methylation changes in genes involved in apoptosis and inflammation, and 2) results observed in a permanent hippocampal cell line are comparable to primary hippocampal neurons. In case of methylation changes in specific genes, (3) mRNA analysis was performed to assess possible effects on gene expression. METHODS: HT22 cells and primary mouse hippocampal neurons were exposed to 3% isoflurane for 4 h and DNA (each 6 single experiments) and RNA (3 single independent experiments) were extracted. Methylation analysis (EpiTect Methyl II PCR Array Systems, Qiagen) included the methylation status of 66 genes involved in apoptosis, cytokine production, inflammatory response, and autoimmunity. Quantitative Real-Time PCR was performed using the Quantitect SYBR Green Kit on a Step One Plus. RESULTS: Methylation status was markedly different between immortalized HT22 cells and cultured primary hippocampal neurons without isoflurane exposure. Of 66 genes investigated, 29 were methylated to a significantly greater degree in HT22 cells compared to primary hippocampal neurons. In cultured primary hippocampal neurons, in contrast, there was a greater methylation in several genes involved in inflammation, accompanied with significant downregulation of C-X-C motif chemokine 12 with isoflurane exposure (p = 0.023). CONCLUSIONS: We demonstrate marked differences in gene methylation between HT22 cells and cultured primary hippocampal neurons without isoflurane exposure, with a greater methylation of several genes involved in inflammation upon isoflurane exposure and significant downregulation of Cxcl12 mRNA expression in primary hippocampal neurons. Accordingly, further investigations of anesthesia related DNA methylation should be performed with special consideration being given to the choice of cells targeted for such investigations.

Correction to: Methylation in HT22 cells and primary hippocampal neurons with and without isoflurane exposure.

Following publication of the original article [1], it was brought to our attention of an error in the article title.

Neutrophil extracellular trap formation and nuclease activity in septic patients.

BACKGROUND: There is little knowledge, whether in patients with sepsis neutrophil extracellular trap (NET) formation and NET degrading nuclease activity are altered. Thus, we tested the hypotheses that 1) NET formation from neutrophils of septic patients is increased compared to healthy volunteers, both without stimulation and following incubation with mitochondrial DNA (mtDNA), a damage-associated molecular pattern, or phorbol 12-myristate 13-acetate (PMA; positive control) and 2) that serum nuclease activities are increased as well. METHODS: Following ethic committee approval, we included 18 septic patients and 27 volunteers in this prospective observational trial. Blood was withdrawn and NET formation from neutrophils was analyzed in vitro without stimulation and following incubation with mtDNA (10 µg/well) or PMA (25 nmol). Furthermore, serum nuclease activity was assessed using gel electrophoresis. RESULTS: In contrast to our hypothesis, in septic patients, unstimulated NET release from neutrophils was decreased by 46.3% (4.3% ± 1.8 SD vs. 8.2% ± 2.9, p ≤ 0.0001) and 48.1% (4.9% ± 2.5 vs. 9.4% ± 5.2, p = 0.002) after 2 and 4 h compared to volunteers. mtDNA further decreased NET formation in neutrophils from septic patients (4.7% ± 1.2 to 2.8% ± 0,8; p = 0.03), but did not alter NET formation in neutrophils from volunteers. Of note, using PMA, as positive control, we ensured that neutrophils were still able to form NETs, with NET formation increasing to 73.2% (±29.6) in septic patients and 91.7% (±7.1) in volunteers (p = 0.22). Additionally, we show that serum nuclease activity (range: 0-6) was decreased in septic patients by 39.6% (3 ± 2 vs 5 ± 0, median and ICR, p = 0.0001) compared to volunteers. CONCLUSIONS: Unstimulated NET formation and nuclease activity are decreased in septic patients. mtDNA can further reduce NET formation in sepsis. Thus, neutrophils from septic patients show decreased NET formation in vitro despite diminished nuclease activity in vivo. TRIAL REGISTRATION: DRKS00007694, german clinical trials database (DRKS). Retrospectively registered 06.02.2015.

Aquaporin 5 -1364A/C Promoter Polymorphism Is Associated with Pulmonary Inflammation and Survival in Acute Respiratory Distress Syndrome.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Acute respiratory distress syndrome is defined according to clinical criteria, but lack of precise characterization may contribute to negative trials and impede personalized care. Polymorphisms of aquaporin-5, a key mediator of inflammation, may impact outcome. WHAT THIS ARTICLE TELLS US THAT IS NEW: In acute respiratory distress syndrome attributable to bacterial pneumonia, the C-allele of the aquaporin-5 -1364A/C promoter polymorphism is associated with less pulmonary inflammation and greater survival. This may improve characterization of acute respiratory distress syndrome and ultimately facilitate individualized care. BACKGROUND: The aquaporin-5 (AQP5) -1364A/C promoter single-nucleotide polymorphism is associated with an altered AQP5 expression and mortality in sepsis. Because AQP5 expression alters neutrophil cell migration, it could affect pulmonary inflammation and survival in bacterially evoked acute respiratory distress syndrome. Accordingly, the authors tested the hypotheses that the AC/CC genotype in patients with bacterially evoked pneumonia resulting in acute respiratory distress syndrome is associated with (1) attenuated pulmonary inflammation and (2) higher 30-day survival. METHODS: In this prospective, observational study, bronchoalveolar lavage and blood sampling were performed within 24 h of intensive care unit admission. In 136 Caucasian patients with bacterially evoked acute respiratory distress syndrome, genotype of the AQP5 -1364A/C promoter polymorphism, bronchoalveolar lavage total protein, albumin, white cell concentrations, and lactate dehydrogenase activity were measured to evaluate the relationship between genotypes and survival. RESULTS: AC/CC patients as well as survivors showed lower bronchoalveolar lavage protein (0.9 mg/ml vs. 2.3 mg/ml, P < 0.001 and 1.6 mg/ml vs. 2.6 mg/ml, P = 0.035), albumin (0.2 mg/ml vs. 0.6 mg/ml, P = 0.019 and 0.3 mg/ml vs. 0.6 mg/ml, P = 0.028), leukocytes (424 /ml vs. 1,430/ml; P = 0.016 and 768 /ml vs. 1,826/ml; P = 0.025), and lactate dehydrogenase activity (82 U/l vs. 232 U/l; P = 0.006 and 123 U/l vs. 303 U/l; P = 0.020). Thirty-day survival was associated with AQP5 -1364A/C genotypes (P = 0.005), with survival of 62% for AA genotypes (58 of 93) but 86% for C-allele carriers (37 of 43). Furthermore, multiple proportional hazard analysis revealed the AA genotype was at high risk for death within 30 days (hazard ratio, 3.53; 95% CI, 1.38 to 9.07; P = 0.009). CONCLUSIONS: In acute respiratory distress syndrome attributable to bacterial pneumonia, the C-allele of the AQP5 -1364A/C promoter polymorphism is associated with an attenuated pulmonary inflammation and higher 30-day survival. Thus, the AQP5 genotype impacts on inflammation and prognosis in acute respiratory distress syndrome.

Remote ischaemic preconditioning increases serum extracellular vesicle concentrations with altered micro-RNA signature in CABG patients.

BACKGROUND: Remote ischaemic preconditioning (RIPC) can attenuate myocardial ischaemia/reperfusion injury but its underlying mechanisms remain largely unknown. Recently, extracellular vesicles (EVs) containing microRNAs (miRNAs) were shown to mediate distant intercellular communication that may be involved in cardioprotection. We tested the hypothesis that RIPC in anaesthetized patients undergoing coronary artery bypass (CABG) surgery results in the release of EVs from the ischaemic/reperfused arm into the blood stream harbouring cardioprotective miRNAs. METHODS: In 58 patients randomised to RIPC (three 5/5 minutes episodes of left arm ischaemia/reperfusion by suprasystolic blood pressure cuff inflations/deflations) or Sham, a subprotocol comprising of parallel right radial artery and regional (left subclavian) venous blood sampling before (awake) and 5 and 60 minutes after RIPC/Sham during isoflurane/sufentanil anaesthesia could be completed. EVs were extracted by polymer-based precipitation methods, their concentrations measured, and their miRNA signature analysed. RESULTS: Five minutes after RIPC, regional venous EV concentrations downstream from the cuff increased and arterial concentrations increased after 60 minutes (fold change [fc]: RIPC: 1.33 ± 0.5, Sham: 0.91 ± 0.31; P = 0.003 for interaction). Already 5 minutes after RIPC, expression of 26 miRNAs (threshold fc: 3.0, P < 0.05) isolated from EVs including the cardioprotective miR-21 had increased. RIPC also decreased postoperative Troponin I concentrations (AUC RIPC: 336 ng/mL × 72 hours ± 306 vs Sham: 713 ± 1013; P  = â€Š0.041). CONCLUSIONS: Remote ischaemic preconditioning increases serum EV concentrations, most likely by early EV release from the patients' left (RIPC) arm, alters their miRNA signature, and is associated with myocardial protection. Thus, an increased EV concentration with an altered miR-signature may mediate the RIPC effect.

Point-of-care measurement of activated clotting time for cardiac surgery as measured by the Hemochron signature elite and the Abbott i-STAT: agreement, concordance, and clinical reliability.

BACKGROUND: Since inadequate heparin anticoagulation and insufficient reversal can result in complications during cardiopulmonary bypass (CPB) surgery, heparin anticoagulation monitoring by point-of-care (POC) activated clotting time (ACT) measurements is essential for CPB initiation, maintainance, and anticoagulant reversal. However, concerns exist regarding reproducibility of ACT assays and comparability of devices. METHODS: We evaluated the agreement of ACT assays using four parallel measurements performed on two commonly used devices each (i.e., two Hemochron Signature Elite (Hemochron) and two Abbott i-STAT (i-STAT) devices, respectively). Blood samples from 30 patients undergoing cardiac surgery on CPB were assayed at specified steps (baseline, after heparin administration, after protamine administration) with four parallel measurements (two of each device type) using commercial Kaolin activated assays provided by the respective manufactures. Measurements were compared between identical and different device types using linear regression, Bland-Altman analyses, and calculation of Cohen's kappa coefficient. RESULTS: Parallel i-STAT ACTs demonstrated a good linear correlation (r = 0.985). Bias, as determined by Bland-Altman analysis, was low (- 3.8 s; 95% limits of agreement (LOA): - 77.8 -70.2 s), and Cohen's Kappa demonstrated good agreement (kappa = 0.809). Hemochron derived ACTs demonstrated worse linear correlation (r = 0.782), larger bias with considerably broader LOA (- 13.14 s; 95%LOA:-316.3-290 s), and lesser concordance between parallel assays (kappa = 0.554). Although demonstrating a fair linear correlation (r = 0.815), parallel measurements on different ACT-devices showed large bias (-20s; 95% LOA: - 290-250 s) and little concordance (kappa = 0.368). Overall, disconcordant results according to clinically predefined target values were more frequent with the Hemochron than i-STAT. Furthermore, while discrepancies in ACT between two parallel iSTAT assays showed little or no clinical relevance, deviations from parallel Hemochron assays and iSTAT versus Hemochron measurements revealed marked and sometimes clinically critical deviations. CONCLUSION: Currently used ACT point-of-care devices cannot be used interchangeably. Furthermore, our data question the reliability of the Hemochron in assessing adequacy of heparin anticoagulation monitoring for CPB.

Impact of baseline left ventricular ejection fraction on outcome after transfemoral transcatheter aortic valve implantation in patients with and without low-gradient aortic stenosis.

OBJECTIVES: To evaluate the impact of baseline left ventricular ejection fraction (LVEF) and its interaction with low-gradient aortic stenosis (LGAS) on all-cause mortality after transfemoral aortic valve implantation (TF-TAVI). METHODS: We reviewed mortality data of 624 consecutive single center TF-TAVI patients and categorized LVEF according to current ASE/EACVI recommendations (normal, mildly-, moderately-, and severely abnormal). RESULTS: Baseline LVEF was normal in 336 (53.8%), mildly abnormal in 160 (25.6%), moderately abnormal in 91 (14.6%), and severely abnormal in 37 (5.9%) patients, and 1-year mortality was 19%, 17%, 23%, and 43% (P = 0.002), respectively. Patients with LGAS had a similar 1-year mortality compared to those without LGAS in groups with normal (19% vs 19%, P = 0.899) and mildly abnormal LVEF (16% vs 17%, P = 0.898). One-year mortality of patients with LGAS was significantly greater than in those without LGAS in presence of moderately abnormal LVEF (31% vs 11%, P = 0.022), and it was numerically greater than in those without LGAS in presence of severely abnormal LVEF (48% vs 25%, P = 0.219). In multivariate analysis, only the combination of moderately/severely abnormal LVEF and LGAS predicted increased 1-year mortality (HR: 2.12, 95% CI: 1.4-3.2, P < 0.001). Other variables, including EuroSCORE I did not affect this result. CONCLUSIONS: Moderately/severely abnormal LVEF (≤40%) at baseline is associated with increased mortality after TF-TAVI, especially when the mean transvalvular aortic gradient is <40 mm Hg (LGAS), while outcomes in patients with normal and mildly abnormal LVEF are comparable regardless of the pressure gradient across the native aortic valve. (DRKS00013729).

Validation of a photoplethysmography device for detection of obstructive sleep apnea in the perioperative setting.

Obstructive sleep apnea (OSA) is a risk factor for perioperative complications, but many OSA patients present undiagnosed. While polysomnography (PSG) is the "gold standard" for diagnosis, its application is technology-intense, time-consuming, expensive, and requires specialists, often delaying surgery. Thus, miniaturized devices were developed for OSA screening aimed at ruling out major OSA while measuring a lesser number of biological signals. We evaluated the accuracy of a photoplethysmography (PPG)-based device for OSA detection. 48 patients with established or strongly suspected (STOP-Questionnaire) OSA scheduled for surgery underwent in their preoperative nights parallel recordings by PPG and a classic polygraphy (PG) devices (SomnoLab2®). We compared the diagnostic accuracy of the PPG in diagnosing mild [Apnea-/Hypopnea-Index (AHI) 5-14 events/h] and moderate-to-severe OSA (AHI > 15). PPG and PG-derived AHI correlated significantly (r = 0.85, p < 0.0001) and high area under curve (AUC) in receiver operator characteristics (ROC) values were seen for both AHI thresholds (0.93 and 0.95, respectively). For an AHI > 5, sensitivity was 100%, specificity 44%, positive predictive value (PPV) 62%, negative predictive value (NPV) 100%, likelihood ratio (LHR) 1.79, and Cohen κ was 0.43. For an AHI > 15, sensitivity was 92%, specificity 77%, PPV 60%, NPV 96%, LHR 4.04, and Cohen κ was 0.59. In a typical perioperative cohort of confirmed and suspected OSA patients, PPG reliably detected OSA patients while showing some false-positive results. Such devices are helpful for preoperative OSA screening.

Supplemental Carbon Dioxide Stabilizes the Upper Airway in Volunteers Anesthetized with Propofol.

BACKGROUND: Propofol impairs upper airway dilator muscle tone and increases upper airway collapsibility. Preclinical studies show that carbon dioxide decreases propofol-mediated respiratory depression. We studied whether elevation of end-tidal carbon dioxide (PETCO2) via carbon dioxide insufflation reverses the airway collapsibility (primary hypothesis) and impaired genioglossus muscle electromyogram that accompany propofol anesthesia. METHODS: We present a prespecified, secondary analysis of previously published experiments in 12 volunteers breathing via a high-flow respiratory circuit used to control upper airway pressure under propofol anesthesia at two levels, with the deep level titrated to suppression of motor response. Ventilation, mask pressure, negative pharyngeal pressure, upper airway closing pressure, genioglossus electromyogram, bispectral index, and change in end-expiratory lung volume were measured as a function of elevation of PETCO2 above baseline and depth of propofol anesthesia. RESULTS: PETCO2 augmentation dose-dependently lowered upper airway closing pressure with a decrease of 3.1 cm H2O (95% CI, 2.2 to 3.9; P < 0.001) under deep anesthesia, indicating improved upper airway stability. In parallel, the phasic genioglossus electromyogram increased by 28% (23 to 34; P < 0.001). We found that genioglossus electromyogram activity was a significant modifier of the effect of PETCO2 elevation on closing pressure (P = 0.005 for interaction term). CONCLUSIONS: Upper airway collapsibility induced by propofol anesthesia can be reversed in a dose-dependent manner by insufflation of supplemental carbon dioxide. This effect is at least partly mediated by increased genioglossus muscle activity.

Perioperative incidence of airway obstructive and hypoxemic events in patients with confirmed or suspected sleep apnea - a prospective, randomized pilot study comparing propofol/remifentanil and sevoflurane/remifentanil anesthesia.

BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for perioperative complications but data on anesthesia regimen are scarce. METHODS: In patients with established or strongly suspected OSA, we assessed in a prospective, randomized design the effects on nocturnal apnea-hypopnea-index (AHI) and oxygen saturation (SpO2) of propofol/remifentanil or sevoflurane/remifentanil based anesthesia. Patients were selected by a history for OSA and / or a positive STOP - questionnaire and received general anesthesia using remifentanil (12 µg/kg/h) combined either with propofol (4-6 mg/kg/h, n = 27) or sevoflurane (approx. 2.2 vol% endtidal, n = 27). AHI and SpO2 were measured during the nights before and after anesthesia. RESULTS: There were no differences in AHI between anesthetic regimens nor between the pre- and postoperative nights (propofol: 8.6 h- 1 (median, CI: 3.6-21.9) vs. 7.9 h- 1 (1.8-28.8); p = 0.97; sevoflurane: 3.8 h- 1 (1.8-7.3) vs. 2.9 h- 1 (1.2-9.5); p = 0.85). Postoperative minimum SpO2 (propofol: 80.7% ± 4.6, sevoflurane: 81.6 ± 4.6) did not differ from their respective preoperative baselines (propofol: 79.6% ± 6.5; p = 0.26, sevoflurane: 80.8% ± 5.2; p = 0.39). Even in patients with a preanesthetic AHI > 15, nocturnal AHI remained unchanged postoperatively. CONCLUSION: Thus, in a cohort of patients with suspected or confirmed OSA undergoing surgery of moderate duration and severity neither the volatile agent sevoflurane nor the intravenous anesthetic propofol altered nocturnal AHI or oxygen saturation, when combined with the short acting opioid remifentanil. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00005824 retrospectively registered on 03/12/2014.

Increased circulating microRNA-122 is associated with mortality and acute liver injury in the acute respiratory distress syndrome.

BACKGROUND: Acute liver injury in patients with ARDS decreases survival but early stages may be easily missed due to the lack of sufficient biomarkers signalling its onset. Accordingly, we tested in ARDS patients the hypotheses that microRNA-122, the foremost liver-related microRNA (miR), 1) is an sensitive and specific early predictor for potential liver injury and 2) analysed its impact on 30-day-survival. METHODS: We collected clinical data and analysed blood samples from 119 ARDS patients within the first 24 h of ICU admission and from 20 patients undergoing elective abdominal non-liver surgery serving as controls. Total circulating miR was isolated from serum and relative miR-122 expression was measured (using specific probes and spiked-in miR-54), as were liver function and 30-day survival. Acute liver injury was defined as a total bilirubin concentration ≥ 3.0 mg/dl, an ALT activity ≥350 U/l, and an INR ≥2.0. RESULTS: 30-day survival of the entire ARDS-cohort was 69% but differed between patients with normal liver function (77%) and acute liver injury (19% p <  0.001). miR-122 expression was 20fold higher in non-survivors (95%-CI 0.0149-0.0768; p = 0.001) and almost 4fold greater in survivors (95%-CI: 0.0037-0.0122; p = 0.005) compared to controls (95%-CI 0.0008-0.0034) and correlated with markers of liver cell integrity/function [ALT (p <  0.001, r = 0.495), AST (p <  0.001, r = 0.537), total bilirubin (p = 0.025, r = 0.206), INR (p = 0.001, r = 0.308), and GLDH (p <  0.001, r = 0.489)]. miR-122 serum expression discriminated survivors and non-survivors (AUC: 0.78) better than total bilirubin concentration (AUC: 0.66). Multivariable Cox-regression analysis revealed both acute liver injury (HR 7.6, 95%-CI 2.9-19.8, p <  0.001) and miR-122 (HR 4.4, 95%-CI 1.2-16.1, p = 0.02) as independent prognostic factors for 30-day mortality. CONCLUSIONS: Increased miR-122 serum expression is an early and independent risk factor for 30-day mortality in ARDS patients and potentially reveal an acute liver injury earlier than the conventional markers of liver cell integrity.

GNAQ TT(-695/-694)GC Polymorphism Is Associated with Increased Gq Expression, Vascular Reactivity, and Myocardial Injury after Coronary Artery Bypass Surgery.

BACKGROUND: Angiotensin II receptor type 1-mediated activation of the α-subunit of the heterotrimeric Gq protein evokes increased vasoconstriction and may promote hypertrophy-induced myocardial damage. The authors recently identified a TT(-695/-694)GC polymorphism in the human Gq promoter, the GC allele being associated with an increased prevalence of cardiac hypertrophy. In this article, the authors tested whether the TT(-695/-694)GC polymorphism is associated with differences in (1) myocardial Gq protein expression, (2) vascular reactivity, and (3) myocardial damage after coronary artery bypass grafting. METHODS: Gq protein expression was measured in right atrial muscle from 55 patients undergoing coronary artery bypass grafting as were skin perfusion changes (n = 18; laser Doppler imaging), saphenous vein ring vascular reactivity (n = 50, organ bath) in response to angiotensin II, and myocardial damage (227 patients undergoing coronary artery bypass grafting), as assessed by postoperative cardiac troponin I concentration. RESULTS: Myocardial Gq expression was greater in GC/GC genotypes (GC/GC vs. TT/TT: 1.27-fold change; P = 0.006). Skin perfusion after intradermal angiotensin II injection decreased only in GC/GC genotypes (P = 0.0002). Saphenous vein rings exposed to increasing angiotensin II concentrations showed an almost doubled maximum contraction in GC/GC compared with individuals with the TT/TT genotype (P = 0.022). In patients undergoing coronary artery bypass grafting, baseline cardiac ejection fraction was different (GC/GC: 55 ± 13%; GC/TT: 54 ± 14%; TT/TT: 48 ± 15%; P = 0.037) and postoperative peak cardiac troponin I was greater in patients with the GC/GC (11.5 ± 13.8 ng/ml) than in patients with the GC/TT (9.2 ± 9.2 ng/ml) or patients with the TT/TT genotype (6.6 ± 4.8 ng/ml, P = 0.015). CONCLUSIONS: The GC/GC genotype of the TT(-695/-694)GC polymorphism is associated with increased Gq protein expression, augmented angiotensin II receptor type 1-related vasoconstriction, and increased myocardial injury after coronary artery bypass grafting, highlighting the impact of Gq genotype variation.

Comparison of mortality prediction models in acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation and development of a novel prediction score: the PREdiction of Survival on ECMO Therapy-Score (PRESET-Score).

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy in acute respiratory distress syndrome (ARDS) patients but is associated with complications and costs. Here, we validate various scores supposed to predict mortality and develop an optimized categorical model. METHODS: In a derivation cohort, 108 ARDS patients (2010-2015) on veno-venous ECMO were retrospectively analysed to assess four established risk scores (ECMOnet-Score, RESP-Score, PRESERVE-Score, Roch-Score) for mortality prediction (receiver operating characteristic analysis) and to identify by multivariable logistic regression analysis independent variables for mortality to yield the new PRESET-Score (PREdiction of Survival on ECMO Therapy-Score). This new score was then validated both in independent internal (n = 82) and external (n = 59) cohorts. RESULTS: The median (25%; 75% quartile) Sequential Organ Failure Assessment score was 14 (12; 16), Simplified Acute Physiology Score II was 62.5 (57; 72.8), median intensive care unit stay was 17 days (range 1-124), and mortality was 62%. Only the ECMOnet-Score (area under curve (AUC) 0.69) and the RESP-Score (AUC 0.64) discriminated survivors and non-survivors. Admission pHa, mean arterial pressure, lactate, platelet concentrations, and pre-ECMO hospital stay were independent predictors of death and were used to build the PRESET-Score. The score's internal (AUC 0.845; 95% CI 0.76-0.93; p < 0.001) and external (AUC 0.70; 95% CI 0.56-0.84; p = 0.008) validation revealed excellent discrimination. CONCLUSIONS: While our data confirm that both the ECMOnet-Score and the RESP-Score predict mortality in ECMO-treated ARDS patients, we propose a novel model also incorporating extrapulmonary variables, the PRESET-Score. This score predicts mortality much better than previous scores and therefore is a more precise choice for decision support in ARDS patients to be placed on ECMO.

Moxifloxacin monotherapy versus combination therapy in patients with severe community-acquired pneumonia evoked ARDS.

BACKGROUND: We tested the hypothesis that moxifloxacin monotherapy is equally effective and safe as a betalactam antibiotic based combination therapy in patients with acute respiratory distress syndrome (ARDS) evoked by severe community acquired pneumonia (CAP). METHODS: In a retrospective chart review study of 229 patients with adult respiratory distress syndrome (ARDS) admitted to our intensive care unit between 2001 and 2011, 169 well-characterized patients were identified to suffer from severe CAP. Patients were treated with moxifloxacin alone, moxifloxacin in combination with ß-lactam antibiotics, or with another antibiotic regimen based on ß-lactam antibiotics, at the discretion of the admitting attending physician. The primary endpoint was 30-day survival. To assess potential drug-induced liver injury, we also analyzed biomarkers of liver cell integrity. RESULTS: 30-day survival (69% overall) did not differ (p = 0.89) between moxifloxacin monotherapy (n = 42), moxifloxacin combination therapy (n = 44), and other antibiotic treatments (n = 83). We found significantly greater maximum activity of aspartate transaminase (p = 0.048), alanine aminotransferase (p = 0.003), and direct bilirubin concentration (p = 0.01) in the moxifloxacin treated groups over the first 10-20 days. However, these in-between group differences faded over time, and no differences remained during the last 10 days of observation. CONCLUSIONS: In CAP evoked ARDS, moxifloxacin monotherapy and moxifloxacin combination therapy was not different to a betalactam based antibiotic regimen with respect to 30-day mortality, and temporarily increased markers of liver cell integrity had no apparent clinical impact. Thus, in contrast to the current S3 guidelines, moxifloxacin may also be safe and effective even in patients with severe CAP evoked ARDS while providing coverage of an extended spectrum of severe CAP evoking bacteria. However, further prospective studies are needed for definite recommendations.

Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS).

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs' prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09-10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.

[How Much Alarm Can the Human Being Tolerate?] / Alarm-Fatigue ­ wieviel Alarm verträgt der Mensch?

Due to growing technisation of intensive care the number of devices with integrated alarm systems is steadily increasing. However, most of the sounding alarms are false alarms causing high levels of frustration, aggression and inappropriate behaviour amongst the medical personnel. All this jeopardises patient care. The high number of alarms also disturb the patients interrupting their sleep and provokes anxiety, and also increases the already high noise level in intensive care units and the operating theatre alike. In the interest of the medical staff and our patients, we should reduce the high frequency of false alarms by using modern alarm algorithms techniques, lower both noise exposure and stress load with the help of modern individualized alarm systems and by increasing awareness on the dangers of alarm fatigue through training and by using individualized patient-related alarm limits. Despite economic challenges hospitals and intensive care units should optimize staffing, thereby lowering the risk to patients and improving employee satisfaction.