Intraoperative haemodynamic monitoring and management of adults having non-cardiac surgery: Guidelines of the German Society of Anaesthesiology and Intensive Care Medicine in collaboration with the German Association of the Scientific Medical Societies.

Haemodynamic monitoring and management are cornerstones of perioperative care. The goal of haemodynamic management is to maintain organ function by ensuring adequate perfusion pressure, blood flow, and oxygen delivery. We here present guidelines on "Intraoperative haemodynamic monitoring and management of adults having non-cardiac surgery" that were prepared by 18 experts on behalf of the German Society of Anaesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und lntensivmedizin; DGAI).

Noninvasive Assessment of Arterial Pulse-Pressure Variation During General Anesthesia: Clinical Evaluation of a New High-Fidelity Upper Arm Cuff.

OBJECTIVES: To compare noninvasive pulse-pressure variation (PPV) measurements obtained from a new high-fidelity upper arm cuff using a hydraulic coupling technique to corresponding intraarterial PPV measurements. DESIGN: The authors used prospective multicenter comparison and development studies for the new high-fidelity upper arm cuff. SETTING: The study was performed in the departments of Anesthesiology at the Ludwig-Maximilians-Universität München Hospital, the University Hospital of Bonn, and the RoMed Hospital in Rosenheim (all Germany). PARTICIPANTS: A total of 153 patients were enrolled, undergoing major abdominal surgery or neurosurgery with mechanical ventilation. For the evaluation of PPV, 1,467 paired measurements in 107 patients were available after exclusion due to predefined quality criteria. INTERVENTIONS: Simultaneous measurements of PPV were performed from a reference femoral arterial catheter (PPVref) and the high-fidelity upper arm cuff (PPVcuff). The new device uses a semirigid conical shell. It incorporates a hydraulic sensor pad with a pressure transducer, leading to a tissue pressure-pulse contour with all characteristics of an arterial- pulse contour. MEASUREMENTS AND MAIN RESULTS: The comparative analysis of the included measurements showed that PPVref and PPVcuff were closely correlated (r = 0.92). The mean of the differences between PPVref and PPVcuff was 0.1 ± 2.0%, with 95% limits of agreement between -4.1% and 3.9%. To track absolute changes in PPV >2%, the concordance rate between the 2 methods was 93%. CONCLUSIONS: The new high-fidelity upper arm cuff method provided a clinically reliable estimate of PPV.

Do higher alarm thresholds for arterial blood pressure lead to less perioperative hypotension? A retrospective, observational cohort study.

Arterial blood pressure is one of the vital signs monitored mandatory in anaesthetised patients. Even short episodes of intraoperative hypotension are associated with increased risk for postoperative organ dysfunction such as acute kidney injury and myocardial injury. Since there is little evidence whether higher alarm thresholds in patient monitors can help prevent intraoperative hypotension, we analysed the blood pressure data before (group 1) and after (group 2) the implementation of altered hypotension alarm settings. The study was conducted as a retrospective observational cohort study in a large surgical centre with 32 operating theatres. Alarm thresholds for hypotension alarm for mean arterial pressure (MAP) were altered from 60 (before) to 65 mmHg for invasive measurement and 70 mmHg for noninvasive measurement. Blood pressure data from electronic anaesthesia records of 4222 patients (1982 and 2240 in group 1 and 2, respectively) with 406,623 blood pressure values undergoing noncardiac surgery were included. We analysed (A) the proportion of blood pressure measurements below the threshold among all measurements by quasi-binomial regression and (B) whether at least one blood pressure measurement below the threshold occurred by logistic regression. Hypotension was defined as MAP < 65 mmHg. There was no significant difference in overall proportions of hypotensive episodes for mean arterial pressure before and after the adjustment of alarm settings (mean proportion of values below 65 mmHg were 6.05% in group 1 and 5.99% in group 2). The risk of ever experiencing a hypotensive episode during anaesthesia was significantly lower in group 2 with an odds ratio of 0.84 (p = 0.029). In conclusion, higher alarm thresholds do not generally lead to less hypotensive episodes perioperatively. There was a slight but significant reduction of the occurrence of intraoperative hypotension in the presence of higher thresholds for blood pressure alarms. However, this reduction only seems to be present in patients with very few hypotensive episodes.

Intraoperative Blood Pressure Monitoring in Obese Patients.

BACKGROUND: The optimal method for blood pressure monitoring in obese surgical patients remains unknown. Arterial catheters can cause potential complications, and noninvasive oscillometry provides only intermittent values. Finger cuff methods allow continuous noninvasive monitoring. The authors tested the hypothesis that the agreement between finger cuff and intraarterial measurements is better than the agreement between oscillometric and intraarterial measurements. METHODS: This prospective study compared intraarterial (reference method), finger cuff, and oscillometric (upper arm, forearm, and lower leg) blood pressure measurements in 90 obese patients having bariatric surgery using Bland-Altman analysis, four-quadrant plot and concordance analysis (to assess the ability of monitoring methods to follow blood pressure changes), and error grid analysis (to describe the clinical relevance of measurement differences). RESULTS: The difference (mean ± SD) between finger cuff and intraarterial measurements was -1 mmHg (± 11 mmHg) for mean arterial pressure, -7 mmHg (± 14 mmHg) for systolic blood pressure, and 0 mmHg (± 11 mmHg) for diastolic blood pressure. Concordance between changes in finger cuff and intraarterial measurements was 88% (mean arterial pressure), 85% (systolic blood pressure), and 81% (diastolic blood pressure). In error grid analysis comparing finger cuff and intraarterial measurements, the proportions of measurements in risk zones A to E were 77.1%, 21.6%, 0.9%, 0.4%, and 0.0% for mean arterial pressure, respectively, and 89.5%, 9.8%, 0.2%, 0.4%, and 0.2%, respectively, for systolic blood pressure. For mean arterial pressure and diastolic blood pressure, absolute agreement and trending agreement between finger cuff and intraarterial measurements were better than between oscillometric (at each of the three measurement sites) and intraarterial measurements. Forearm performed better than upper arm and lower leg monitoring with regard to absolute agreement and trending agreement with intraarterial monitoring. CONCLUSIONS: The agreement between finger cuff and intraarterial measurements was better than the agreement between oscillometric and intraarterial measurements for mean arterial pressure and diastolic blood pressure in obese patients during surgery. Forearm oscillometry exhibits better measurement performance than upper arm or lower leg oscillometry.

Oscillometric versus invasive blood pressure measurement in patients with shock: a prospective observational study in the emergency department.

In emergency medicine, blood pressure is often measured by an oscillometric device using an upper arm cuff. However, measurement accuracy of this technique in patients suffering from hypotensive shock has not been sufficiently evaluated. We designed a prospective observational study investigating the accuracy of an oscillometric device in hypotensive patients admitted to the resuscitation area of the emergency department. Patients admitted to the resuscitation area of a university hospital, who were equipped with an arterial catheter and found to be hypotensive (mean arterial pressure (MAP) < 60 mmHg) were eligible for the study. Blood pressure was measured simultaneously via upper arm cuff and invasively under routine clinical conditions. After data extraction, Bland-Altman analysis, correlation coefficient and percentage error of mean and systolic blood pressure pairs were performed. We analysed 75 simultaneously obtained blood pressure measurements of 30 patients in hypotension, 11 (37%) were female, median age was 76.5 years (IQR 63-82). Oscillometric MAP was markedly higher than invasive MAP with a mean of the differences of 13 ± 15 mmHg (oscillometric-invasive), 95% limits of agreement - 16 to 41 mmHg, percentage error was 76%. In 64% of readings, values obtained by the upper arm cuff were not able to detect hypotension. Oscillometric blood pressure measurement is not able to reliably detect hypotension in emergency patients. Therefore, direct measurement of blood pressure should be established as soon as possible in patients suffering from shock.

Clinical Evaluation of a High-fidelity Upper Arm Cuff to Measure Arterial Blood Pressure during Noncardiac Surgery.

BACKGROUND: In most patients having noncardiac surgery, blood pressure is measured with the oscillometric upper arm cuff method. Although the method is noninvasive and practical, it is known to overestimate intraarterial pressure in hypotension and to underestimate it in hypertension. A high-fidelity upper arm cuff incorporating a hydraulic sensor pad was recently developed. The aim of the present study was to investigate whether noninvasive blood pressure measurements with the new high-fidelity cuff correspond to invasive measurements with a femoral artery catheter, especially at low blood pressure. METHODS: Simultaneous measurements of blood pressure recorded from a femoral arterial catheter and from the high-fidelity upper arm cuff were compared in 110 patients having major abdominal surgery or neurosurgery. RESULTS: 550 pairs of blood pressure measurements (5 pairs per patient) were considered for analysis. For mean arterial pressure measurements, the average bias was 0 mmHg, and the precision was 3 mmHg. The Pearson correlation coefficient was 0.96 (P < 0.0001; 95% CI, 0.96 to 0.97), and the percentage error was 9%. Error grid analysis showed that the proportions of mean arterial pressure measurements done with the high-fidelity cuff method were 98.4% in zone A (no risk), 1.6% in zone B (low risk) and 0% in zones C, D, and E (moderate, significant, and dangerous risk, respectively). The high-fidelity cuff method detected mean arterial pressure values less than 65 mmHg with a sensitivity of 84% (95% CI, 74 to 92%) and a specificity of 97% (95% CI, 95% to 98%). To detect changes in mean arterial pressure of more than 5 mmHg, the concordance rate between the two methods was 99.7%. Comparable accuracy and precision were observed for systolic and diastolic blood pressure measurements. CONCLUSIONS: The new high-fidelity upper arm cuff method met the current international standards in terms of accuracy and precision. It was also very accurate to track changes in blood pressure and reliably detect severe hypotension during noncardiac surgery.

Correction to: How to measure blood pressure using an arterial catheter: a systematic 5-step approach.

An amendment to this paper has been published and can be accessed via the original article.

How to measure blood pressure using an arterial catheter: a systematic 5-step approach.

Arterial blood pressure (BP) is a fundamental cardiovascular variable, is routinely measured in perioperative and intensive care medicine, and has a significant impact on patient management. The clinical reference method for BP monitoring in high-risk surgical patients and critically ill patients is continuous invasive BP measurement using an arterial catheter. A key prerequisite for correct invasive BP monitoring using an arterial catheter is an in-depth understanding of the measurement principle, of BP waveform quality criteria, and of common pitfalls that can falsify BP readings. Here, we describe how to place an arterial catheter, correctly measure BP, and identify and solve common pitfalls. We focus on 5 important steps, namely (1) how to choose the catheter insertion site, (2) how to choose the type of arterial catheter, (3) how to place the arterial catheter, (4) how to level and zero the transducer, and (5) how to check the quality of the BP waveform.

Exhaled Breath and Oxygenator Sweep Gas Propionaldehyde in Acute Respiratory Distress Syndrome.

BACKGROUND: Oxidative stress-induced lipid peroxidation (LPO) due to neutrophil-derived reactive oxygen species plays a key role in the early stage of the acute respiratory distress syndrome (ARDS). Monitoring of oxidative stress in this patient population is of great interest, and, ideally, this can be done noninvasively. Recently, propionaldehyde, a volatile chemical compound (VOC) released during LPO, was identified in the breath of lung transplant recipients as a marker of oxidative stress. The aim of the present study was to identify if markers of oxidative stress appear in the oxygenator outflow gas of patients with severe ARDS treated with veno-venous extracorporeal membrane oxygenation (ECMO). METHODS: The present study included patients with severe ARDS treated with veno-venous ECMO. Concentrations of acetone, isoprene, and propionaldehyde were measured in inspiratory air, exhaled breath, and oxygenator inflow and outflow gas at corresponding time points. Ion-molecule reaction mass spectrometry was used to measure VOCs in a sequential order within the first 24 h and on day three after ECMO initiation. RESULTS: Nine patients (5 female, 4 male; age = 42.1 ± 12.2 year) with ARDS and already established ECMO therapy (pre-ECMO PaO2/FiO2 = 44.0 ± 11.5 mmHg) were included into analysis. VOCs appeared in comparable amounts in breath and oxygenator outflow gas (acetone: 838 (422-7632) vs. 1114 (501-4916) ppbv; isoprene: 53.7 (19.5-244) vs. 48.7 (37.9-108) ppbv; propionaldehyde: 53.7 (32.1-82.2) vs. 42.9 (24.8-122) ppbv). Concentrations of acetone, isoprene, and propionaldehyde in breath and oxygenator outflow gas showed a parallel course with time. CONCLUSIONS: Acetone, isoprene, and propionaldehyde appear in breath and oxygenator outflow gas in comparable amounts. This allows for the measurement of these VOCs in a critically ill patient population via the ECMO oxygenator outflow gas without the need of ventilator circuit manipulation.

Accuracy of oscillometric noninvasive blood pressure compared with intra-arterial blood pressure in infants and small children during neurosurgical procedures: An observational study.

BACKGROUND: General anaesthesia in children results in a significant decrease of arterial pressure. Hypotension in neonates and infants reduces cerebral perfusion; therefore, an accurate arterial pressure measurement is of utmost importance. Although arterial pressure measured via an arterial catheter is considered to be the gold standard, in most children undergoing anaesthesia, arterial pressure is monitored by an upper arm cuff using an oscillometric technique. Data on the accuracy of these devices in such young patients are rare. OBJECTIVE: The aim of this study was to assess the accuracy of oscillometric blood pressure measurement compared with intra-arterial measurement. DESIGN: An observational comparison study. SETTING: A single-centre study, conducted in a German university hospital from November 2015 to January 2018. PATIENTS: Twenty-five children of 2 years old or less (median age 6 [IQR, 5 to 11]) months undergoing neurosurgical procedures requiring invasive arterial pressure determination. MAIN OUTCOME MEASURES: Arterial pressure was measured invasively and also oscillometrically by an upper arm cuff every 10 min. Simultaneously measured pairs of mean arterial pressures were analysed by the Bland-Altman method; the correlation coefficient, percentage error and concordance were calculated. RESULTS: Data from 21 children were analysed. Mean, (standard deviation) and [range] of invasive and noninvasive mean arterial pressures were 54 (8) [30 to 94] and 57 (8) [40 to 108] mmHg, respectively. The overall bias between invasive and noninvasive arterial pressure was -3 (7) mmHg, with 95% limits of agreement from -17 to +10 mmHg. The correlation coefficient, percentage error and concordance were 0.65, 25% and 0.77, respectively. For hypotensive invasive arterial pressure values below 45 mmHg, the mean bias (invasive arterial pressure - noninvasive arterial pressure) was -9 (5) mmHg. CONCLUSION: Arterial pressure derived by the oscillometric device showed acceptable levels of agreement. However, during hypotension, a clinically relevant overestimation of arterial pressure occurred when measured by an upper arm cuff.

The impact of continuous non-invasive arterial blood pressure monitoring on blood pressure stability during general anaesthesia in orthopaedic patients: A randomised trial.

BACKGROUND: In patients undergoing general anaesthesia, intraoperative hypotension occurs frequently and is associated with adverse outcomes such as postoperative acute kidney failure, myocardial infarction or stroke. A history of chronic hypertension renders patients more susceptible to a decrease in blood pressure (BP) after induction of general anaesthesia. As a patient's BP is generally monitored intermittently via an upper arm cuff, there may be a delay in the detection of hypotension by the anaesthetist. OBJECTIVE: The current study investigates whether the presence of continuous BP monitoring leads to improved BP stability. DESIGN: Randomised, controlled and single-centre study. PATIENTS: A total of 160 orthopaedic patients undergoing general anaesthesia with a history of chronic hypertension. INTERVENTION: The patients were randomised to either a study group (n = 77) that received continuous non-invasive BP monitoring in addition to oscillometric intermittent monitoring, or a control group (n = 83) whose BP was monitored intermittently only. The interval for oscillometric measurements in both groups was set to 3 min. After induction of general anaesthesia, oscillometric BP values of the two groups were compared for the first hour of the procedure. Anaesthetists were blinded to the purpose of the study. MAIN OUTCOME MEASURE: BP stability and hypotensive events. RESULTS: There was no difference in baseline BP between the groups. After adjustment for multiple testing, mean arterial BP in the study group was significantly higher than in the control group at 12 and 15 min. Mean ±â€ŠSD for study and control group, respectively were: 12 min, 102 ±â€Š24 vs. 90 ±â€Š26 mmHg (P = 0.039) and 15 min, 102 ±â€Š21 vs. 90 ±â€Š23 mmHg (P = 0.023). Hypotensive readings below a mean pressure of 55 mmHg occurred more often in the control group (25 vs. 7, P = 0.047). CONCLUSION: Continuous monitoring contributes to BP stability in the studied population. TRIAL REGISTRATION: NCT02519101.

Falsely low values of oxygen saturation measured by pulse oximetry in a boy treated with Chinese herb tea.

An 8-year-old boy suffering from progressive glioblastoma was scheduled for neurosurgery. Prior to induction of anaesthesia pulse oximetry measured 64 % saturation of oxygen (SpO2). Arterial blood gas analysis revealed normal oxygen saturation and normal oxygen partial pressure. After having ruled out technical problems of pulse oximetry the neurosurgical procedure was halted. Meticulous examination of the child's history and medication did not explain a possible interaction of drugs with pulse oximetry. A Chinese herb tea had been given to the child, but was then stopped on the day of admission. The surgical procedure took place the next day without any complications. During the subsequent inpatient stay, repeated blood gas analyses showed normal oxygenation, but pulse oximetry measured initially SpO2 values of 64 %, gradually increasing over 7 days up to 91 % by the time of discharge from hospital. Blood samples were taken and analysed. Absorption spectroscopy from the patient's blood showed an uncommon absorption maximum at 684 nm besides the normal maxima. The normalisation of SpO2 values after stopping Chinese herb tea administration leads to the conclusion that one of its ingredients caused the distorted pulse oximetry measurement.

Continuous noninvasive arterial pressure measurement using the volume clamp method: an evaluation of the CNAP device in intensive care unit patients.

The CNAP system allows continuous noninvasive arterial pressure measurement based on the volume clamp method using a finger cuff. We aimed to evaluate the agreement between arterial pressure measurements noninvasively obtained using the CNAP device and arterial catheter-derived arterial pressure measurements in intensive care unit patients. In 55 intensive care unit patients, we simultaneously recorded arterial pressure values obtained by an arterial catheter placed in the abdominal aorta through the femoral artery (criterion standard) and arterial pressure values determined noninvasively using CNAP. We performed Bland-Altman analysis and calculated the percentage error. The mean difference (±standard deviation, 95% limits of agreement, percentage error) between noninvasive (CNAP) and invasively assessed arterial pressure was for mean arterial pressure +1 mmHg (±9 mmHg, -16 to +19 mmHg, 22%), for systolic arterial pressure -10 mmHg (±16 mmHg, -42 to +21 mmHg, 27%), and for diastolic arterial pressure +7 mmHg (±9 mmHg, -10 to +24 mmHg, 28%). Our results indicate a reasonable accuracy and precision for the determination of mean and diastolic arterial pressure by noninvasive continuous arterial pressure measurements using the volume clamp method compared with the criterion standard (invasive arterial catheter). Systolic arterial pressure is determined less accurately and precisely.

An autocalibrating algorithm for non-invasive cardiac output determination based on the analysis of an arterial pressure waveform recorded with radial artery applanation tonometry: a proof of concept pilot analysis.

We aimed to describe and evaluate an autocalibrating algorithm for determination of cardiac output (CO) based on the analysis of an arterial pressure (AP) waveform recorded using radial artery applanation tonometry (AT) in a continuous non-invasive manner. To exemplarily describe and evaluate the CO algorithm, we deliberately selected 22 intensive care unit patients with impeccable AP waveforms from a database including AP data obtained with AT (T-Line system; Tensys Medical Inc.). When recording AP data for this prospectively maintained database, we had simultaneously noted CO measurements obtained from just calibrated pulse contour analysis (PiCCO system; Pulsion Medical Systems) every minute. We applied the autocalibrating CO algorithm to the AT-derived AP waveforms and noted the computed CO values every minute during a total of 15 min of data recording per patient (3 × 5-min intervals). These 330 AT-derived CO (AT-CO) values were then statistically compared to the corresponding pulse contour CO (PC-CO) values. Mean ± standard deviation for PC-CO and AT-CO was 7.0 ± 2.0 and 6.9 ± 2.1 L/min, respectively. The coefficient of variation for PC-CO and AT-CO was 0.280 and 0.299, respectively. Bland-Altman analysis demonstrated a bias of +0.1 L/min (standard deviation 0.8 L/min; 95% limits of agreement -1.5 to 1.7 L/min, percentage error 23%). CO can be computed based on the analysis of the AP waveform recorded with AT. In the selected patients included in this pilot analysis, a percentage error of 23% indicates clinically acceptable agreement between AT-CO and PC-CO.

A pipeline for the development and analysis of extracellular vesicle-based transcriptomic biomarkers in molecular diagnostics.

Extracellular vesicles are shed by every cell type and can be found in any biofluid. They contain different molecules that can be utilized as biomarkers, including several RNA species which they protect from degradation. Here, we present a pipeline for the development and analysis of extracellular vesicle-associated transcriptomic biomarkers that our group has successfully applied multiple times. We highlight the key steps of the pipeline and give particular emphasis to the necessary quality control checkpoints, which are linked to numerous available guidelines that should be considered along the workflow. Our pipeline starts with patient recruitment and continues with blood sampling and processing. The purification and characterization of extracellular vesicles is explained in detail, as well as the isolation and quality control of extracellular vesicle-associated RNA. We point out the possible pitfalls during library preparation and RNA sequencing and present multiple bioinformatic tools to pinpoint biomarker signature candidates from the sequencing data. Finally, considerations and pitfalls during the validation of the biomarker signature using RT-qPCR will be elaborated.

Identification of microRNA biomarkers simultaneously expressed in circulating extracellular vesicles and atherosclerotic plaques.

Background: Atherosclerosis is a widespread disorder of the cardiovascular system. The early detection of plaques by circulating biomarkers is highly clinically relevant to prevent the occurrence of major complications such as stroke or heart attacks. It is known that extracellular vesicles (EVs) are important in intercellular communication in atherosclerotic disorders and carry many components of their cells of origin, including microRNAs (miRNAs). In this study, we test the assumption that miRNAs present in material acquired from plaques in patients undergoing surgery for atherosclerotic carotid artery stenosis are also expressed in circulating EVs obtained from the identical patients. This would allow the adoption of a liquid biopsy approach for the detection of plaques. Methods: We studied 22 surgical patients with atherosclerotic carotid arterial stenosis and 28 healthy controls. EVs were isolated from serum by precipitation. miRNA expression profiles of serum-derived EVs were obtained by small RNA sequencing and in plaque material simultaneously acquired from patients. A comparative analysis was performed to identify circulating atherosclerosis-associated miRNAs that are also detectable in plaques. Results: Seven miRNAs were found to be differentially regulated in patient serum compared with the serum of healthy controls. Of these, miR-193b-5p, miR-193a-5p, and miR-125a-3p were significantly upregulated in patients compared with that in healthy controls and present in both, circulating EVs and plaque material. An overrepresentation analysis of experimentally validated mRNA targets revealed an increased regulation of inflammation and vascular growth factors, key players in atherosclerosis and plaque formation. Conclusion: Our findings suggest that circulating EVs reflect plaque development in patients with symptomatic carotid artery stenosis, which can serve as biomarker candidates for detecting the presence of atherosclerotic plaques.

Anesthetic­specific lncRNA and mRNA profile changes in blood during colorectal cancer resection: A prospective, matched­case pilot study.

Prometastatic and antitumor effects of different anesthetics have been previously analyzed in several studies with conflicting results. Thus, the underlying perioperative molecular mechanisms mediated by anesthetics potentially affecting tumor phenotype and metastasis remain unclear. It was hypothesized that anesthetic­specific long non­coding RNA (lncRNA) expression changes are induced in the blood circulation and play a crucial role in tumor outcome. In the present study, high­throughput sequencing and quantitative PCR were performed in order to identify lncRNA and mRNA expression changes affected by two therapeutic regimes, total intravenous anesthesia (TIVA) and volatile anesthetic gas (VAG) in patients undergoing colorectal cancer (CRC) resection. Total blood RNA was isolated prior to and following resection and characterized using RNA sequencing. mRNA­lncRNA interactions and their roles in cancer­related signaling of differentially expressed lncRNAs were identified using bioinformatics analyses. The comparison of these two time points revealed 35 differentially expressed lncRNAs in the TIVA­group, and 25 in the VAG­group, whereas eight were shared by both groups. Two lncRNAs in the TIVA­group, and 23 in the VAG­group of in silico identified target­mRNAs were confirmed as differentially regulated in the NGS dataset of the present study. Pathway analysis was performed and cancer relevant canonical pathways for TIVA were identified. Target­mRNA analysis of VAG revealed a markedly worsened immunological response against cancer. In this proof­of­concept study, anesthesic­specific expression changes in lncRNA and mRNA profiles in blood were successfully identified. Moreover, the data of the present study provide the first evidence that anesthesia­induced lncRNA pattern changes may contribute further in the observed differences in CRC outcome following tumor resection.

Extensive blood transcriptome analysis reveals cellular signaling networks activated by circulating glycocalyx components reflecting vascular injury in COVID-19.

Background: Degradation of the endothelial protective glycocalyx layer during COVID-19 infection leads to shedding of major glycocalyx components. These circulating proteins and their degradation products may feedback on immune and endothelial cells and activate molecular signaling cascades in COVID-19 associated microvascular injury. To test this hypothesis, we measured plasma glycocalyx components in patients with SARS-CoV-2 infection of variable disease severity and identified molecular signaling networks activated by glycocalyx components in immune and endothelial cells. Methods: We studied patients with RT-PCR confirmed COVID-19 pneumonia, patients with COVID-19 Acute Respiratory Distress Syndrome (ARDS) and healthy controls (wildtype, n=20 in each group) and measured syndecan-1, heparan sulfate and hyaluronic acid. The in-silico construction of signaling networks was based on RNA sequencing (RNAseq) of mRNA transcripts derived from blood cells and of miRNAs isolated from extracellular vesicles from the identical cohort. Differentially regulated RNAs between groups were identified by gene expression analysis. Both RNAseq data sets were used for network construction of circulating glycosaminoglycans focusing on immune and endothelial cells. Results: Plasma concentrations of glycocalyx components were highest in COVID-19 ARDS. Hyaluronic acid plasma levels in patients admitted with COVID-19 pneumonia who later developed ARDS during hospital treatment (n=8) were significantly higher at hospital admission than in patients with an early recovery. RNAseq identified hyaluronic acid as an upregulator of TLR4 in pneumonia and ARDS. In COVID-19 ARDS, syndecan-1 increased IL-6, which was significantly higher than in pneumonia. In ARDS, hyaluronic acid activated NRP1, a co-receptor of activated VEGFA, which is associated with pulmonary vascular hyperpermeability and interacted with VCAN (upregulated), a proteoglycan important for chemokine communication. Conclusions: Circulating glycocalyx components in COVID-19 have distinct biologic feedback effects on immune and endothelial cells and result in upregulation of key regulatory transcripts leading to further immune activation and more severe systemic inflammation. These consequences are most pronounced during the early hospital phase of COVID-19 before pulmonary failure develops. Elevated levels of circulating glycocalyx components may early identify patients at risk for microvascular injury and ARDS. The timely inhibition of glycocalyx degradation could provide a novel therapeutic approach to prevent the development of ARDS in COVID-19.