Assessing SOFA score trajectories in sepsis using machine learning: A pragmatic approach to improve the accuracy of mortality prediction.

INTRODUCTION: An increasing amount of longitudinal health data is available on critically ill septic patients in the age of digital medicine, including daily sequential organ failure assessment (SOFA) score measurements. Thus, the assessment in sepsis focuses increasingly on the evaluation of the individual disease's trajectory. Machine learning (ML) algorithms may provide a promising approach here to improve the evaluation of daily SOFA score dynamics. We tested whether ML algorithms can outperform the conventional ΔSOFA score regarding the accuracy of 30-day mortality prediction. METHODS: We used the multicentric SepsisDataNet.NRW study cohort that prospectively enrolled 252 sepsis patients between 03/2018 and 09/2019 for training ML algorithms, i.e. support vector machine (SVM) with polynomial kernel and artificial neural network (aNN). We used the Amsterdam UMC database covering 1,790 sepsis patients for external and independent validation. RESULTS: Both SVM (AUC 0.84; 95% CI: 0.71-0.96) and aNN (AUC 0.82; 95% CI: 0.69-0.95) assessing the SOFA scores of the first seven days led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score between day 1 and 7 (AUC 0.73; 95% CI: 0.65-0.80; p = 0.02 and p = 0.05, respectively). These differences were even more prominent the shorter the time interval considered. Using the SOFA scores of day 1 to 3 SVM (AUC 0.82; 95% CI: 0.68 0.95) and aNN (AUC 0.80; 95% CI: 0.660.93) led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score (AUC 0.66; 95% CI: 0.58-0.74; p < 0.01 and p < 0.01, respectively). Strikingly, all these findings could be confirmed in the independent external validation cohort. CONCLUSIONS: The ML-based algorithms using daily SOFA scores markedly improved the accuracy of mortality compared to the conventional ΔSOFA score. Therefore, this approach could provide a promising and automated approach to assess the individual disease trajectory in sepsis. These findings reflect the potential of incorporating ML algorithms as robust and generalizable support tools on intensive care units.

Hypoxemia of the lower limbs during robot-assisted radical prostatectomy in Trendelenburg position.

Objectives: The objective of this study is to assess frequency and risk factors for intraoperative hypoxemia of the lower limbs during robot-assisted radical prostatectomy (RARP). Trendelenburg position during RARP may contribute to hypoxemia and compartment syndrome (CS) of the lower limbs as a major but rare complication. Patients and methods: This prospective study included patients undergoing RARP for prostate cancer. Preoperative calculation of the ankle-brachial-index (ABI) was performed. Peripheral oxygen saturation (SpO2) at the toes was routinely measured. Occurrence of SpO2 levels of <90% was defined as hypoxemic events and treated immediately. Blood pressure, intraabdominal pressure, SpO2 of the upper limb and surgery time were monitored in case of hypoxemia. A multivariable logistic regression model was performed with age, BMI, nicotine abuse, MAP, comorbidities as covariates and hypoxemia of the lower limbs as the outcome. Results: A total of 207 patients were included. Among these, 126 patients had ABI measurements with 10.6% having an abnormal ABI value. One, two or at least three events of lower limb hypoxemia occurred intraoperatively in 19.7%, 14.8% and 16.9%, respectively. In 20 events, surgical instruments were affecting vascular perfusion by compression. None of the covariates were statistically significant associated with lower limb hypoxemia. No patient developed a compartment syndrome. Conclusion: Decrease in oxygen saturation of the lower extremities was observed frequently during RARP, without revealing any risk factors for its occurrence. Routine oximetry leads to an early detection of hypoxemia of the lower extremities, giving the anaesthesiologist and surgeon the opportunity to make adequate adjustments (increasing blood pressure and ending iliac vessel compression).

The Aquaporin 3 Polymorphism (rs17553719) Is Associated with Sepsis Survival and Correlated with IL-33 Secretion.

Sepsis is a common life-threatening disease caused by dysregulated immune response and metabolic acidosis which lead to organ failure. An abnormal expression of aquaporins plays an important role in organ failure. Additionally, genetic variants in aquaporins impact on the outcome in sepsis. Thus, we investigated the polymorphism (rs17553719) and expression of aquaporin-3 (AQP3) and correlated these measurements with the survival of sepsis patients. Accordingly, we collected blood samples on several days (plus clinical data) from 265 sepsis patients who stayed in different ICUs in Germany. Serum plasma, DNA, and RNA were then separated to detect the promotor genotypes of AQP3 mRNA expression of AQP3 and several cytokines. The results showed that the homozygote CC genotype exhibited a significant decrease in 30-day survival (38.9%) compared to the CT (66.15%) and TT genotypes (76.3%) (p = 0.003). Moreover, AQP3 mRNA expression was significantly higher and nearly doubled in the CC compared to the CT (p = 0.0044) and TT genotypes (p = 0.018) on the day of study inclusion. This was accompanied by an increased IL-33 concentration in the CC genotype (day 0: p = 0.0026 and day 3: p = 0.008). In summary, the C allele of the AQP3 polymorphism (rs17553719) shows an association with increased AQP3 expression and IL-33 concentration accompanied by decreased survival in patients with sepsis.

Turn down your thermostats - A contribution to overcoming the European gas crisis? The example of Germany.

Europe's current gas crisis requires rapid government intervention to curtail natural gas consumption and mitigate expenses for consumers. This study aims to comprehensively assess the impact of adjusting thermostats, with single-family houses in Germany serving as a case study. A unique bottom-up approach for approximating gas consumption at the level of building archetypes reveals that decreasing temperature setpoints from 21 °C to 19 °C and 17 °C can save about 14 and 30 TWh/a of gas, respectively. This corresponds to 3-6 % of gas imports from Russia to Germany in 2020. The largest absolute savings can be realized in older and larger buildings. Additionally, our findings suggest that the adjustment of thermostats may decrease residential CO2 emissions by 3-6 Mt/a, achieved through a reduction of 2-4 °C in the setpoint. Therefore, the measure shows great promise regardless of the present crisis. From the consumer's perspective, a 1 °C temperature reduction can lead to a gas bill reduction of 4-9 %, contingent upon building type. Nevertheless, the cost burden associated with rising gas prices surpasses these savings. Residents of older buildings suffer more severe financial impacts than those in newer ones. Our research suggests that policymakers should consider implementing adjustments to residential thermostats. Furthermore, consumer financial assistance programs should factor in building type when designing relief mechanisms.

AQP3 and AQP9-Contrary Players in Sepsis?

Sepsis involves an immunological systemic response to a microbial pathogenic insult, leading to a cascade of interconnected biochemical, cellular, and organ-organ interaction networks. Potential drug targets can depict aquaporins, as they are involved in immunological processes. In immune cells, AQP3 and AQP9 are of special interest. In this study, we tested the hypothesis that these aquaporins are expressed in the blood cells of septic patients and impact sepsis survival. Clinical data, routine laboratory parameters, and blood samples from septic patients were analyzed on day 1 and day 8 after sepsis diagnosis. AQP expression and cytokine serum concentrations were measured. AQP3 mRNA expression increased over the duration of sepsis and was correlated with lymphocyte count. High AQP3 expression was associated with increased survival. In contrast, AQP9 expression was not altered during sepsis and was correlated with neutrophil count, and low levels of AQP9 were associated with increased survival. Furthermore, AQP9 expression was an independent risk factor for sepsis lethality. In conclusion, AQP3 and AQP9 may play contrary roles in the pathophysiology of sepsis, and these results suggest that AQP9 may be a novel drug target in sepsis and, concurrently, a valuable biomarker of the disease.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial.

Importance: The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. Objective: To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. Design, Setting, and Participants: This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Interventions: Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. Main Outcomes and Measures: The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Results: Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. Conclusion and Relevance: A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03052660.

Influence of the Anesthetic Technique on Circulating Extracellular Vesicles in Bladder Cancer Patients Undergoing Radical Cystectomy: A Prospective, Randomized Trial.

Anesthetics have been shown to alter tumor progression and seem to influence surgical cancer outcome. Circulating extracellular vesicles as mediators of intercellular communication are involved in cancer progression and may be influenced by anesthetics. In this prospective, randomized study, effects of anesthetics on extracellular vesicles and associated micro-RNAs in bladder cancer patients undergoing radical cystectomy were tested. Extracellular vesicles from 51 patients at four perioperative time points receiving Propofol or Sevoflurane were extracted with polymer-based methods and quantified with a nanoparticle-tracking analysis. Vesicle-associated micro-RNAs were analyzed with a real-time polymerase chain reaction using array cards and single assays for tumor-associated miR-21-5p, miR-15a-5p, miR-17-5p and miR-451a. Plasma extracellular vesicle concentration (suture: fold change (fc) in Propofol at 4.1 ± 3.9 vs. Sevoflurane at 0.8 ± 0.5; p = 0.003) and associated miRNAs increased significantly (+30% post induction, +9% 30 Min surgery) in the Propofol group. Tumor-associated miRNAs increased during surgery in both groups (fc in miR-21-5p: 24.3 ± 10.2, p = 0.029; fc in miR-15a-5p: 9.7 ± 3.8, p = 0.027; fc in miR-17-5p: 5.4 ± 1.7, p = 0.014), whereas antitumor miR-451a increased in the Propofol group only (fc: 2.5 ± 0.6 vs. 1.0 ± 0.2; p = 0.022). Anesthetics influence extracellular vesicles and associated micro-RNAs of bladder cancer patients during surgery. Increased expression of antitumor micro-RNA may be an explanatory approach for decreased tumor cell viability after Propofol.

Hypotension Prediction Index and Incidence of Perioperative Hypotension: A Single-Center Propensity-Score-Matched Analysis.

(1) Background: Intraoperative hypotension is common and is associated with increased morbidity and mortality. The Hypotension Prediction Index (HPI) is an advancement of arterial waveform analysis and allows preventive treatments. We used a propensity-score-matched study design to test whether application of the HPI reduces hypotensive events in non-cardiac surgery patients; (2) Methods: 769 patients were selected for propensity score matching. After matching, both HPI and non-HPI groups together comprised n = 136 patients. A goal-directed treatment protocol was applied in both groups. The primary endpoint was the incidence and duration of hypotensive events defined as MAP < 65 mmHg, evaluated by the time-weighted average (TWA) of hypotension. (3) Results: The median TWA of hypotension below 65 mmHg in the matched cohort was 0.180 mmHg (IQR 0.060, 0.410) in the non-HPI group vs. 0.070 mmHg (IQR 0.020, 0.240) in the HPI group (p < 0.001). TWA was higher in patients with ASA classification III/IV (0.170 mmHg; IQR 0.035, 0.365) than in patients with ASA status II (0.100; IQR 0.020, 0.250; p = 0.02). Stratification by intervention group showed no differences in the HPI group while TWA values in the non-HPI group were more than twice as high in patients with ASA status III/IV (p = 0.01); (4) Conclusions: HPI reduces intraoperative hypotension in a matched cohort seen for TWA below 65 mmHg and relative time in hypotension. In addition, non-HPI patients with ASA status III/IV showed a higher TWA compared with HPI-patients, indicating an advantageous effect of using HPI in patients at higher risk.

Intraoperative hypotension when using hypotension prediction index software during major noncardiac surgery: a European multicentre prospective observational registry (EU HYPROTECT).

Background: Intraoperative hypotension is associated with organ injury. Current intraoperative arterial pressure management is mainly reactive. Predictive haemodynamic monitoring may help clinicians reduce intraoperative hypotension. The Acumen™ Hypotension Prediction Index software (HPI-software) (Edwards Lifesciences, Irvine, CA, USA) was developed to predict hypotension. We built up the European multicentre, prospective, observational EU HYPROTECT Registry to describe the incidence, duration, and severity of intraoperative hypotension when using HPI-software monitoring in patients having noncardiac surgery. Methods: We enrolled 749 patients having elective major noncardiac surgery in 12 medical centres in five European countries. Patients were monitored using the HPI-software. We quantified hypotension using the time-weighted average MAP <65 mm Hg (primary endpoint), the proportion of patients with at least one ≥1 min episode of a MAP <65 mm Hg, the number of ≥1 min episodes of a MAP <65 mm Hg, and duration patients spent below a MAP of 65 mm Hg. Results: We included 702 patients in the final analysis. The median time-weighted average MAP <65 mm Hg was 0.03 (0.00-0.20) mm Hg. In addition, 285 patients (41%) had no ≥1 min episode of a MAP <65 mm Hg; 417 patients (59%) had at least one. The median number of ≥1 min episodes of a MAP <65 mm Hg was 1 (0-3). Patients spent a median of 2 (0-9) min below a MAP of 65 mm Hg. Conclusions: The median time-weighted average MAP <65 mm Hg was very low in patients in this registry. This suggests that using HPI-software monitoring may help reduce the duration and severity of intraoperative hypotension in patients having noncardiac surgery.

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).

Mortality rates of severe COVID-19-related respiratory failure with and without extracorporeal membrane oxygenation in the Middle Ruhr Region of Germany.

The use of extracorporeal membrane oxygenation (ECMO) is discussed to improve patients' outcome in severe COVID-19 with respiratory failure, but data on ECMO remains controversial. The aim of the study was to determine the characteristics of patients under invasive mechanical ventilation (IMV) with or without veno-venous ECMO support and to evaluate outcome parameters. Ventilated patients with COVID-19 with and without additional ECMO support were analyzed in a retrospective multicenter study regarding clinical characteristics, respiratory and laboratory parameters in day-to-day follow-up. Recruitment of patients was conducted during the first three COVID-19 waves at four German university hospitals of the Ruhr University Bochum, located in the Middle Ruhr Region. From March 1, 2020 to August 31, 2021, the charts of 149 patients who were ventilated for COVID-19 infection, were included (63.8% male, median age 67 years). Fifty patients (33.6%) received additional ECMO support. On average, ECMO therapy was initiated 15.6 ± 9.4 days after symptom onset, 10.6 ± 7.1 days after hospital admission, and 4.8 ± 6.4 days after the start of IMV. Male sex and higher SOFA and RESP scores were observed significantly more often in the high-volume ECMO center. Pre-medication with antidepressants was more often detected in survivors (22.0% vs. 6.5%; p = 0.006). ECMO patients were 14 years younger and presented a lower rate of concomitant cardiovascular diseases (18.0% vs. 47.5%; p = 0.0004). Additionally, cytokine-adsorption (46.0% vs. 13.1%; p < 0.0001) and renal replacement therapy (76.0% vs. 43.4%; p = 0.0001) were carried out more frequently; in ECMO patients thrombocytes were transfused 12-fold more often related to more than fourfold higher bleeding complications. Undulating C-reactive protein (CRP) and massive increase in bilirubin levels (at terminal stage) could be observed in deceased ECMO patients. In-hospital mortality was high (Overall: 72.5%, ECMO: 80.0%, ns). Regardless of ECMO therapy half of the study population deceased within 30 days after hospital admission. Despite being younger and with less comorbidities ECMO therapy did not improve survival in severely ill COVID-19 patients. Undulating CRP levels, a massive increase of bilirubin level and a high use of cytokine-adsorption were associated with worse outcomes. In conclusion, ECMO support might be helpful in selected severe cases of COVID-19.

The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain.

The G protein-coupled receptor kinase 6 is associated with inflammation and pathological pain. Impairment of GRK6 expression was described in chronic inflammatory diseases such as rheumatoid arthritis and this was shown to be accompanied by an imbalance of downstream signaling pathways. Here, we discuss novel aspects of GRK6 interaction and its impact upon hyperalgesia and inflammatory processes. In this review, we compile important findings concerning GRK6 regulation for a better pathophysiological understanding of the intracellular interaction in the context of inflammation and show clinical implications-for example, the identification of possible therapy goals in the treatment of chronic inflammatory hyperalgesia.

Hypotension Prediction Index Software to Prevent Intraoperative Hypotension during Major Non-Cardiac Surgery: Protocol for a European Multicenter Prospective Observational Registry (EU-HYPROTECT).

Background: Intraoperative hypotension is common in patients having non-cardiac surgery and associated with postoperative acute myocardial injury, acute kidney injury, and mortality. Avoiding intraoperative hypotension is a complex task for anesthesiologists. Using artificial intelligence to predict hypotension from clinical and hemodynamic data is an innovative and intriguing approach. The AcumenTM Hypotension Prediction Index (HPI) software (Edwards Lifesciences; Irvine, CA, USA) was developed using artificial intelligence­specifically machine learning­and predicts hypotension from blood pressure waveform features. We aimed to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery. Methods: We built up a European, multicenter, prospective, observational registry including at least 700 evaluable patients from five European countries. The registry includes consenting adults (≥18 years) who were scheduled for elective major non-cardiac surgery under general anesthesia that was expected to last at least 120 min and in whom arterial catheter placement and HPI monitoring was planned. The major objectives are to quantify and characterize intraoperative hypotension (defined as a mean arterial pressure [MAP] < 65 mmHg) when using HPI monitoring. This includes the time-weighted average (TWA) MAP < 65 mmHg, area under a MAP of 65 mmHg, the number of episodes of a MAP < 65 mmHg, the proportion of patients with at least one episode (1 min or more) of a MAP < 65 mmHg, and the absolute maximum decrease below a MAP of 65 mmHg. In addition, we will assess causes of intraoperative hypotension and investigate associations between intraoperative hypotension and postoperative outcomes. Discussion: There are only sparse data on the effect of using HPI monitoring on intraoperative hypotension in patients having elective major non-cardiac surgery. Therefore, we built up a European, multicenter, prospective, observational registry to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery.

Human cooperation in changing groups in a large-scale public goods game.

How people cooperate to provide public goods is an important scientific question and relates to many societal problems. Previous research studied how people cooperate in stable groups in repeated or one-time-only encounters. However, most real-world public good problems occur in groups with a gradually changing composition due to old members leaving and new members arriving. How group changes are related to cooperation in public good provision is not well understood. To address this issue, we analyze a dataset from an online public goods game comprising approximately 1.5 million contribution decisions made by about 135 thousand players in about 11.3 thousand groups with about 234 thousand changes in group composition. We find that changes in group composition negatively relate to cooperation. Our results suggest that this is related to individuals contributing less in the role of newcomers than in the role of incumbents. During the process of moving from newcomer status to incumbent status, individuals cooperate more and more in line with incumbents.

The impact of the COVID-19 pandemic on non-COVID induced sepsis survival.

BACKGROUND: The COVID-19 pandemic has taken a toll on health care systems worldwide, which has led to increased mortality of different diseases like myocardial infarction. This is most likely due to three factors. First, an increased workload per nurse ratio, a factor associated with mortality. Second, patients presenting with COVID-19-like symptoms are isolated, which also decreases survival in cases of emergency. And third, patients hesitate to see a doctor or present themselves at a hospital. To assess if this is also true for sepsis patients, we asked whether non-COVID-19 sepsis patients had an increased 30-day mortality during the COVID-19 pandemic. METHODS: This is a post hoc analysis of the SepsisDataNet.NRW study, a multicentric, prospective study that includes septic patients fulfilling the SEPSIS-3 criteria. Within this study, we compared the 30-day mortality and disease severity of patients recruited pre-pandemic (recruited from March 2018 until February 2020) with non-COVID-19 septic patients recruited during the pandemic (recruited from March 2020 till December 2020). RESULTS: Comparing septic patients recruited before the pandemic to those recruited during the pandemic, we found an increased raw 30-day mortality in sepsis-patients recruited during the pandemic (33% vs. 52%, p = 0.004). We also found a significant difference in the severity of disease at recruitment (SOFA score pre-pandemic: 8 (5 - 11) vs. pandemic: 10 (8 - 13); p < 0.001). When adjusted for this, the 30-day mortality rates were not significantly different between the two groups (52% vs. 52% pre-pandemic and pandemic, p = 0.798). CONCLUSIONS: This led us to believe that the higher mortality of non-COVID19 sepsis patients during the pandemic might be attributed to a more severe septic disease at the time of recruitment. We note that patients may experience a delayed admission, as indicated by elevated SOFA scores. This could explain the higher mortality during the pandemic and we found no evidence for a diminished quality of care for critically ill sepsis patients in German intensive care units.

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.

Hemodynamic monitoring with Hypotension Prediction Index versus arterial waveform analysis alone and incidence of perioperative hypotension.

BACKGROUND: Intraoperative hypotension is associated with increased morbidity and mortality. The Hypotension Prediction Index (HPI) is an advancement of the arterial waveform analysis to predict intraoperative hypotension minutes before episodes occur enabling preventive treatments. We tested the hypothesis that the HPI combined with a personalized treatment protocol reduces intraoperative hypotension when compared to arterial waveform analysis alone. METHODS: We conducted a retrospective analysis of 100 adult consecutive patients undergoing moderate- or high-risk noncardiac surgery with invasive arterial pressure monitoring using either index guidance (HPI) or arterial waveform analysis (FloTrac) depending on availability (FloTrac, n = 50; HPI, n = 50). A personalized treatment protocol was applied in both groups. The primary endpoint was the incidence and duration of hypotensive events defined as MAP <65 mmHg evaluated by time-weighted average of hypotension. RESULTS: In the FloTrac group, 42 patients (84%) experienced a hypotension while in the HPI group 26 patients (52%) were hypotensive (p = 0.001). The median (IQR) time-weighted average of hypotension in the FloTrac group was 0.27 (0.42) mmHg versus 0.10 (0.19) mmHg in the HPI group (p = 0.001). Finally, the median duration of each hypotensive event (IQR) was 2.75 (2.40) min in the FloTrac group compared to 1.00 (2.06) min in the HPI group (p = 0.002). CONCLUSIONS: The application of the HPI combined with a personalized treatment protocol can reduce incidence and duration of hypotension when compared to arterial waveform analysis alone. This study therefore provides further evidence of the transition from prediction to actual prevention of hypotension using HPI.

Agony of choice: How anesthetics affect the composition and function of extracellular vesicles.

The choice of the anesthetic regime is suggested to affect clinical outcomes following major surgery. Propofol was shown to exert beneficial effects on different cancer outcomes, while volatile anesthetics may be favorable in cardiac surgery. Recently, extracellular vesicles (EVs) were discovered as essential signal mediators in physiological and pathophysiological processes including carcinogenesis and metastasis. Furthermore, depending on their cell source, EVs fulfill therapeutic functions. In addition to extracorporally produced EVs, appropriate systemic intervention such as remote ischemic preconditioning (RIPC) is considered to promote endogenous release of therapeutically active EVs to mediate cardioprotective effects. EVs are assembled in cell-type specific manners and the composition of EVs is not only affected by the disease, but also by the applied anesthetic of anesthetized patients. Here, we compare known impacts of anesthetic agents on outcomes in cancer surgery and cardioprotection and link these effects to the composition and therapeutic potential of EVs.

Characterization of the G protein-coupled receptor kinase 6 promoter reveals a functional CREB binding site.

BACKGROUND: G protein-coupled receptor kinase 6 (GRK6) is part of the G protein-coupled receptor kinase family, whose members act as key regulators of seven-transmembrane receptor signalling. GRK6 seems to play a role in regulation of inflammatory processes, but mechanisms of transcriptional regulation of GRK6 expression in inflammatory cell lines have not been characterized. Protein kinase C (PKC) signalling is also involved in inflammatory regulation and an impact of PKC activation on GRK6 protein expression was described previously. Thus, the aim of this study was to 1) characterize the GRK6 promoter, and 2) investigate a potential influence of PKC on GRK6 expression. METHODS: Five deletion constructs of the GRK6 promoter were cloned. After transient transfection into a human T cell line, promoter activity was assessed using luciferase reporter gene assays. Putative transcription factor binding sites were identified, mutated, and binding was investigated using electrophoretic mobility shift assays (EMSA). Following stimulation with a PKC activator, GRK6 expression on mRNA and protein levels was assessed by reverse transcriptase qPCR and Western blots. RESULTS: Investigation of the GRK6 promoter revealed a putative cAMP responsive element (CRE), whose mutation led to decreased promoter activity (p = 0.0006). Functionality of the CRE binding protein (CREB) binding site was verified in EMSA blots. Stimulation with a PKC activator resulted in decreased GRK6 promoter activity (p = 0.0027), mRNA (p = 0.04) and protein expression. CONCLUSION: We characterized the human GRK6 promoter and identified promoter activity to be influenced by a CREB binding site. PKC might be one determinant contributing to altered GRK6 expression.