Understanding the biases to sepsis surveillance and quality assurance caused by inaccurate coding in administrative health data.

PURPOSE: Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care. METHODS: We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015-2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information. RESULTS: ICD-coding of sepsis in IAHD showed high positive predictive value (76.9-85.7% depending on sepsis definition), but low sensitivity (26.8-38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29-71.7%, of ICD-diagnosis: 10.7-58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09). CONCLUSION: Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care.

Cardiac index-guided therapy to maintain optimised postinduction cardiac index in high-risk patients having major open abdominal surgery: the multicentre randomised iPEGASUS trial.

BACKGROUND: It is unclear whether optimising intraoperative cardiac index can reduce postoperative complications. We tested the hypothesis that maintaining optimised postinduction cardiac index during and for the first 8 h after surgery reduces the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. METHODS: In three German and two Spanish centres, high-risk patients having elective major open abdominal surgery were randomised to cardiac index-guided therapy to maintain optimised postinduction cardiac index (cardiac index at which pulse pressure variation was <12%) during and for the first 8 h after surgery using intravenous fluids and dobutamine or to routine care. The primary outcome was the incidence of a composite outcome of moderate or severe complications within 28 days after surgery. RESULTS: We analysed 318 of 380 enrolled subjects. The composite primary outcome occurred in 84 of 152 subjects (55%) assigned to cardiac index-guided therapy and in 77 of 166 subjects (46%) assigned to routine care (odds ratio: 1.87, 95% confidence interval: 1.03-3.39, P=0.038). Per-protocol analyses confirmed the results of the primary outcome analysis. CONCLUSIONS: Maintaining optimised postinduction cardiac index during and for the first 8 h after surgery did not reduce, and possibly increased, the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. Clinicians should not strive to maintain optimised postinduction cardiac index during and after surgery in expectation of reducing complications. CLINICAL TRIAL REGISTRATION: NCT03021525.

Preoperative routine measurement of NT-proBNP predicts postoperative morbidity after non-cardiac surgery with intermediate or high surgical risk: an observational study.

BACKGROUND: Chronic heart failure (HF) is a common clinical condition associated with adverse outcomes in elderly patients undergoing non-cardiac surgery. This study aimed to estimate a clinically applicable NT-proBNP cut-off that predicts postoperative 30-day morbidity in a non-cardiac surgical cohort. METHODS: One hundred ninety-nine consecutive patients older than 65 years undergoing elective non-cardiac surgery with intermediate or high surgical risk were analysed. Preoperative NT-proBNP was measured, and clinical events were assessed up to postoperative day 30. The primary endpoint was the composite morbidity endpoint (CME) consisting of rehospitalisation, acute decompensated heart failure (ADHF), acute kidney injury (AKI), and infection at postoperative day 30. Secondary endpoints included perioperative fluid balance and incidence, duration, and severity of perioperative hypotension. RESULTS: NT-proBNP of 443 pg/ml had the highest accuracy in predicting the composite endpoint; a clinical cut-off of 450 pg/ml was implemented to compare clinical endpoints. Although 35.2% of patients had NT-proBNP above the threshold, only 10.6% had a known history of HF. The primary endpoint was the composite morbidity endpoint (CME) consisting of rehospitalisation, acute decompensated heart failure (ADHF), acute kidney injury (AKI), and infection. Event rates were significantly increased in patients with NT-proBNP > 450 pg/ml (70.7% vs. 32.4%, p < 0.001), which was due to the incidence of cardiac rehospitalisation (4.4% vs. 0%, p = 0.018), ADHF (20.1% vs. 4.0%, p < 0.001), AKI (39.8% vs. 8.3%, p < 0.001), and infection (46.3% vs. 24.4%, p < 0.01). Perioperative fluid balance and perioperative hypotension were comparable between groups. Preoperative NT-proBNP > 450 pg/ml was an independent predictor of the CME in a multivariable Cox regression model (hazard ratio 2.92 [1.72-4.94]). CONCLUSIONS: Patients with NT-proBNP > 450 pg/ml exhibited profoundly increased postoperative morbidity. Further studies should focus on interdisciplinary approaches to improve outcomes through integrated interventions in the perioperative period. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00027871, 17/01/2022.

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Venovenous Extracorporeal Membrane Oxygenation in the Rat.

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, liver, and critically damaged lungs is unknown. Therefore, the aim of this study was to measure the hepatic and intestinal microcirculation and pulmonary inflammatory response in a model of V-V ECMO and septic shock in the rat. Twenty male Lewis rats were randomly assigned to receive V-V ECMO therapy or a sham procedure. Hemodynamic data were measured by a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by the intravenous infusion of lipopolysaccharide (1 mg/kg). During V-V ECMO therapy, rats received lung-protective ventilation. The hepatic and intestinal microcirculation was assessed by micro-lightguide spectrophotometry after median laparotomy for 2 h. Systemic and pulmonary inflammation was measured by enzyme-linked immunosorbent assays of plasma and bronchoalveolar lavage (BAL), respectively, which included tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-10, C-X-C motif ligand 2 (CXCL2), and CXCL5. Reduced oxygen saturation and relative hemoglobin concentration were measured in the hepatic and intestinal microcirculation during treatment with V-V ECMO. These animals also showed increased systolic, mean, and diastolic blood pressures. While no differences in left ventricular ejection fraction were observed, animals in the V-V ECMO group presented an increased heart rate, stroke volume, and cardiac output. Blood gas analysis showed dilutional anemia during V-V ECMO, whereas plasma analysis revealed a decreased concentration of IL-10 during V-V ECMO therapy, and BAL measurements showed increased concentrations of TNF-α, CXCL2, and CXCL5. Rats treated with V-V ECMO showed impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Despite lung-protective ventilation, increased pulmonary inflammation was recognized during V-V ECMO therapy in septic shock.

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation in the Rat.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

The Role of the Kinin System and the Effect of Des-Arginine9-Bradykinin on Coagulation and Platelet Function in Critically Ill COVID-19 Patients: A Secondary Analysis of a Prospective Observational Study.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the coagulation system is not fully understood. SARS-CoV-2 penetrates cells through angiotensin-converting enzyme 2 (ACE2) receptors, leading to its downregulation. Des-arginine9-bradykinin (DA9B) is degraded by ACE2 and causes vasodilation and increased vascular permeability. Furthermore, DA9B is associated with impaired platelet function. Therefore, the aim of this study was to evaluate the effects of DA9B on platelet function and coagulopathy in critically ill coronavirus disease 2019 (COVID-19) patients. In total, 29 polymerase-positive SARS-CoV-2 patients admitted to the intensive care unit of the University Hospital of Giessen and 29 healthy controls were included. Blood samples were taken, and platelet impedance aggregometry and rotational thromboelastometry were performed. Enzyme-linked immunosorbent assays measured the concentrations of DA9B, bradykinin, and angiotensin 2. Significantly increased concentrations of DA9B and angiotensin 2 were found in the COVID-19 patients. A negative effect of DA9B on platelet function and intrinsic coagulation was also found. A sub-analysis of moderate and severe acute respiratory distress syndrome patients revealed a negative association between DA9B and platelet counts and fibrinogen levels. DA9B provokes inhibitory effects on the intrinsic coagulation system in COVID-19 patients. This negative feedback seems reasonable as bradykinin, which is transformed to DA9B, is released after contact activation. Nevertheless, further studies are needed to confirm our findings.

Impact of the fluid challenge infusion rate on cardiac stroke volume during major spinal neurosurgery: a prospective single center randomized interventional trial.

BACKGROUND: Fluid therapy, including the choice of a crystalloid or colloid infusion, the execution time of a volume bolus, and the expected volume need of a patient during surgery, varies greatly in clinical practice. Different goal directed fluid protocols have been developed, where fluid boluses guided by dynamic preload parameters are administered within a specific period. OBJECTIVE: To study the efficacy of two fluid bolus infusion rates measured by the response of hemodynamic parameters. DESIGN: Monocentric randomized controlled interventional trial. SETTING: University hospital. PATIENTS: Forty patients undergoing elective major spinal neurosurgery in prone position were enrolled, thirty-one were finally analyzed. INTERVENTIONS: Patients were randomly assigned to receive 250 ml crystalloid and colloid boluses within 5 min (group 1) or 20 min (group 2) when pulse pressure variation (PPV) exceeded 14%. MAIN OUTCOME MEASURES: Changes in stroke volume (SV), mean arterial pressure (MAP), and catecholamine administration. RESULTS: Group 1 showed a greater increase in SV (P = 0.031), and MAP (P = 0.014), while group 2 still had higher PPV (P = 0.005), and more often required higher dosages of noradrenalin after fluid administration (P = 0.033). In group 1, fluid boluses improved CI (P < 0.01), SV (P < 0.01), and MAP (P < 0.01), irrespective of whether crystalloids or colloids were used. In group 2, CI and SV did not change, while MAP was slightly increased (P = 0.011) only after colloid infusion. CONCLUSIONS: A fluid bolus within 5 min is more effective than those administered within 20 min and should therefore be the primary treatment option. Furthermore, bolus infusions administered within 20 min may result in volume overload without achieving relevant hemodynamic improvements. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00022917.

Severe COVID-19 acute respiratory distress syndrome in an adult with single-ventricle physiology: a case report.

BACKGROUND: COVID-19 can induce acute respiratory distress syndrome (ARDS). In patients with congenital heart disease, established treatment strategies are often limited due to their unique cardiovascular anatomy and passive pulmonary perfusion. CASE PRESENTATION: We report the first case of an adult with single-ventricle physiology and bidirectional cavopulmonary shunt who suffered from severe COVID-19 ARDS. Treatment strategies were successfully adopted, and pulmonary vascular resistance was reduced, both medically and through prone positioning, leading to a favorable outcome. CONCLUSION: ARDS treatment strategies including ventilatory settings, prone positioning therapy and cannulation techniques for extracorporeal oxygenation must be adopted carefully considering the passive venous return in patients with single-ventricle physiology.

Dopamine, norepinephrine, and vasopressin accelerate particle transport velocity in murine tracheal epithelium via substance-specific receptor pathways: dependency on intra- and extracellular Ca2+ sources.

Background: The unique ability of the respiratory tract to protect the integrity of the airways by removing potentially harmful substances is defined as mucociliary clearance. This complex physiological mechanism protects the lower airways by ridding them of pollutants and pathogens. This study aimed to evaluate the potential influence of clinically relevant vasopressors on mucociliary clearance. Material and methods: The particle transport velocity (PTV) of isolated murine tracheae was measured as a surrogate for mucociliary clearance under the influence of dopamine, norepinephrine, and vasopressin. Inhibitory substances were applied to elucidate relevant signal transduction cascades and the value and origin of calcium ions. Reverse-transcription polymerase chain reactions (RT-PCR) were performed to identify the expression of vasopressin receptor subtypes. Results: Dopamine, norepinephrine, and vasopressin significantly increased the PTV in a dose-dependent manner with half maximal effective concentrations of 0.58 µM, 1.21 µM, and 0.10 µM, respectively. Each substance increased the PTV via separate receptor pathways. While dopamine acted on D1-like receptors to increase the PTV, norepinephrine acted on ß-adrenergic receptors, and vasopressin acted on V1a receptors. RT-PCR revealed the expression of V1a in the murine whole trachea and tracheal epithelium. PTV increased when protein kinase A was inhibited and norepinephrine or vasopressin were applied, but not when dopamine was applied. Phospholipase C inhibition decreased the PTV when vasopressin was applied. In general, maximum PTV was significantly reduced when extracellular calcium entry was inhibited. When intracellular calcium stores were depleted, no increase in PTV was observed after administering all three substances. Inositol trisphosphate receptor activation was found to be pivotal in the increase in murine PTV after applying dopamine and vasopressin. Discussion: Dopamine, norepinephrine, and vasopressin accelerate the murine PTV via substance-specific receptor pathways. Further investigations should assess the value and interaction of these substances on mucociliary clearance in clinical practice.

Comparison of preoperative NT-proBNP and simple cardiac risk scores for predicting postoperative morbidity after non-cardiac surgery with intermediate or high surgical risk.

BACKGROUND: Chronic heart failure (HF) is frequent in elderly patients undergoing non-cardiac surgery. Preoperative risk stratification is vital and can be achieved using simple clinical risk scores or preoperative N-terminal prohormone of brain natriuretic peptide (NT-proBNP) measurement. This study aimed to compare the predictivity of the revised cardiac risk index (RCRI), the American University of Beirut cardiovascular risk index (AUB-HAS2), and a score proposed by Andersson et al. for postoperative 30-day morbidity to preoperative NT-proBNP. METHODS: Preoperative NT-proBNP was measured in 199 consecutive patients aged ≥ 65 years undergoing elective non-cardiac surgery with intermediate or high surgical risk. The areas under the receiver operating characteristic curve (AUCROC) for the composite morbidity endpoint (CME) comprising the incidence of any rehospitalisation, acute decompensated HF, acute kidney injury, and any infection at postoperative day 30 were assessed. Multivariable logistic regression analysis derived new scores from the simple risk scores and the NT-proBNP cut-off of 450 pg/mL. RESULTS: AUB-HAS2, but not RCRI or Andersson score, significantly predicted the CME (AUB-HAS2: AUCROC 0.646, p < 0.001; RCRI: AUCROC 0.560, p = 0.126; Andersson: AUCROC 0.487, p = 0.760). The AUCROC was comparable between preoperative NT-proBNP (0.679, p < 0.001) and AUB-HAS2 (p = 0.334). Multivariable analyses revealed a preoperative NT-proBNP ≥ 450 pg/mL to be the strongest predictor of CME among the individual score components (p < 0.001). Adding preoperative NT-proBNP improved the predictive value of AUB-HAS2 and RCRI (modified AUB-HAS2: AUCROC 0.703, p < 0.001; modified RCRI: AUCROC 0.679, p < 0.001; both p < 0.001 vs original scores). The predictive value of the modified RCRI and AUB-HAS2 was comparable to preoperative NT-proBNP alone (p = 0.988 vs modified RCRI, p = 0.367 vs modified AUB-HAS2). CONCLUSIONS: The predictive value of postoperative morbidity varies significantly between the available simple perioperative risk scores and can be enhanced by preoperative NT-proBNP. New scores, including preoperative NT-proBNP, should be evaluated in large multicentre cohorts. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00027871.

A Novel Model of Venovenous Extracorporeal Membrane Oxygenation in Rats with Femoral Cannulation and Insights into Hemodynamic Changes.

The application of venovenous (VV) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance for the treatment of acute severe respiratory failure. Since no rat model of VV ECMO therapy with femoral drainage has yet been described, although this cannulation strategy is commonly used in humans, this study aimed to establish such a model. Twenty male Lewis rats were randomly assigned to receive a sham procedure or VV ECMO therapy. After the inhalative induction of anesthesia, animals were intubated and the vascular accesses were placed surgically. While venous drainage was achieved through a modified multi-orifice 18 G cannula that was placed in the inferior vena cava through the femoral vein over a guide wire with an ultra-flexible tip, the venous return was realized via a shortened 20 G cannula into the jugular vein. Hemodynamic data were obtained from a tail artery and left ventricular pressure-volume catheter. Repetitive blood gas analyses were carried out, and systemic inflammation was measured using an enzyme-linked immunosorbent assay. While animals in the ECMO group showed adequate oxygenation and decarboxylation, there was no evidence of recirculation. VV ECMO therapy increased stroke volume (SV), cardiac output (CO), and left ventricular end-diastolic volume (LVEDV). ECMO-induced inflammation was reflected in increased levels of tumor necrosis factor alpha. However, no differences in interleukins 6 and 10 were seen. This study describes a frequently used cannulation strategy in humans for a rat model of VV ECMO. Despite successful oxygenation and decarboxylation, the oxygenated blood may reduce pulmonary vascular resistance and lead to an increased LVEDV, which is associated with increased SV and CO. This model allows us to answer research questions about topics such as intestinal microcirculation in further studies.

Nucleated red blood cells are a late biomarker in predicting intensive care unit mortality in patients with COVID-19 acute respiratory distress syndrome: an observational cohort study.

Background: Nucleated red blood cells (nRBC) are precursor cells of the erythropoiesis that are absent from the peripheral blood under physiological conditions. Their presence is associated with adverse outcomes in critically ill patients. This study aimed to evaluate the predictive value of nRBC on mortality in intensive care unit (ICU) patients with COVID-19 acute respiratory distress syndrome (ARDS). Material and methods: This retrospective, observational cohort study analyzed data on 206 ICU patients diagnosed with COVID-19 ARDS between March 2020 and March 2022. The primary endpoint was ICU mortality, and secondary endpoints included ICU and hospital stay lengths, ventilation hours, and the time courses of disease severity scores and clinical and laboratory parameters. Results: Among the included patients, 68.9% tested positive for nRBC at least once during their ICU stay. A maximum nRBC of 105 µl-1 had the highest accuracy in predicting ICU mortality (area under the curve of the receiver operating characteristic [AUCROC] 0.780, p < 0.001, sensitivity 69.0%, specificity 75.5%). Mortality was significantly higher among patients with nRBC >105 µl-1 than ≤105 µl-1 (86.5% vs. 51.3%, p = 0.008). Compared to patients negative for nRBC in their peripheral blood, those positive for nRBC required longer mechanical ventilation (127 [44 - 289] h vs. 517 [255 - 950] h, p < 0.001), ICU stays (12 [8 - 19] vs. 27 [13 - 51] d, p < 0.001), and hospital stays (19 [12 - 29] d vs. 31 [16 - 58] d, p < 0.001). Peak Sepsis-related Organ Failure Assessment (SOFA), Simplified Acute Physiology Score, PaO2/FiO2, interleukin-6, and procalcitonin values were reached before the peak nRBC level. However, the predictive performance of the SOFA (AUCROC 0.842, p < 0.001) was considerably improved when a maximum SOFA score >8 and nRBC >105 µl-1 were combined. Discussion: nRBC predict ICU mortality and indicate disease severity among patients with COVID-19 ARDS, and they should be considered a clinical alarm signal for a worse outcome. nRBC are a late predictor of ICU mortality compared to other established clinical scoring systems and laboratory parameters but improve the prediction accuracy when combined with the SOFA score.

Micro-lightguide spectrophotometry assessment of hepatic and intestinal microcirculation in endotoxemic rats during intravenous treatment with angiotensin II.

INTRODUCTION: During septic shock, impairment of microcirculation leads to enhanced permeability of intestinal mucosa triggered by generalized vasodilation and capillary leak. Intravenous angiotensin II (AT-II) has been approved for the treatment of septic shock; however, no in-vivo data exist on the influence of AT-II on hepatic and intestinal microcirculation. MATERIAL AND METHODS: Sixty male Lewis rats were randomly assigned to six study groups (each n = 10): sham, lipopolysaccharide-induced septic shock, therapy with low- or high-dose AT-II (50 or 100 ng/kg/min, respectively), and septic shock treated with low- or high-dose AT-II. After median laparotomy, hepatic and intestinal microcirculation measures derived from micro-lightguide spectrophotometry were assessed for 3 h and included oxygen saturation (SO2), relative blood flow (relBF) and relative hemoglobin level (relHb). Hemodynamic measurements were performed using a left ventricular conductance catheter, and blood samples were taken hourly to analyze blood gasses and systemic cytokines. RESULTS: AT-II increased mean arterial pressure in a dose-dependent manner in both septic and non-septic animals (p < 0.001). Lower hepatic and intestinal SO2 (both p < 0.001) were measured in animals without endotoxemia who received high-dose AT-II treatment, however, significantly impaired cardiac output was also reported in this group (p < 0.001). In endotoxemic rats, hepatic relBF and relHb were comparable among the treatment groups; however, hepatic SO2 was reduced during low- and high-dose AT-II treatment (p < 0.001). In contrast, intestinal SO2 remained unchanged despite treatment with AT-II. Intestinal relBF (p = 0.028) and interleukin (IL)-10 plasma levels (p < 0.001) were significantly elevated during treatment with high-dose AT-II compared with low-dose AT-II. CONCLUSIONS: A dose-dependent decrease of hepatic and intestinal microcirculation during therapy with AT-II in non-septic rats was observed, which might have been influenced by a corresponding reduction in cardiac output due to elevated afterload. While hepatic microcirculation was reduced during endotoxemia, no evidence for a reduction in intestinal microcirculation facilitated by AT-II was found. In contrast, both intestinal relBF and anti-inflammatory IL-10 levels were increased during high-dose AT-II treatment.

A fixed 20:1 combination of cafedrine/theodrenaline increases cytosolic Ca2+ concentration in human tracheal epithelial cells via ryanodine receptor-mediated Ca2+ release.

Mucociliary clearance is a pivotal physiological mechanism that protects the lung by cleaning the airways from pollution and colonization, thereby preventing infection. Ciliary function is influenced by various signal transduction cascades, and Ca2+ represents a key second messenger. A fixed 20:1 combination of cafedrine and theodrenaline has been widely used to treat perioperative hypotension and emergency hypotensive states since the 1960s; however, its effect on the intracellular Ca2+ concentration ([Ca2+]i) of respiratory epithelium remains unknown. Therefore, human tracheal epithelial cells were exposed to the clinically applied 20:1 mixture of cafedrine/theodrenaline and the individual substances separately. [Ca2+]i was assessed by FURA-2 340/380 fluorescence ratio. Pharmacological inhibitors were applied to elucidate relevant signal transduction cascades, and reverse transcription polymerase chain reaction (RT-PCR) was performed on murine tracheal epithelium to analyze ryanodine receptor (RyR) subtype expression. All three pharmacological preparations instantaneously induced a steep increase in [Ca2+]i that quickly returned to its baseline value despite the persistence of each substance. Peak [Ca2+]i following the administration of 20:1 cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone increased in a dose-dependent manner, with median effective concentrations of 0.35 mM (7.32 mM cafedrine and 0.35 mM theodrenaline), 3.14 mM, and 3.45 mM, respectively. When extracellular Ca2+ influx was inhibited using a Ca2+-free buffer solution, the peak [Ca2+]i following the administration of cafedrine alone and theodrenaline alone were reduced but not abolished. No alteration in [Ca2+]i compared with baseline [Ca2+]i was observed during ß-adrenergic receptor inhibition. Depletion of caffeine-sensitive stores and inhibition of RyR, but not IP3 receptors, completely abolished any increase in [Ca2+]i. However, [Ca2+]i still increased following the depletion of mitochondrial Ca2+ stores using 2,4-dinitrophenol. RT-PCR revealed RyR-2 and RyR-3 expression on murine tracheal epithelium. Although our experiments showed that cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone release Ca2+ from intracellular stores through mechanisms that are exclusively triggered by ß-adrenergic receptor stimulation, which most probably lead to RyR activation, clinical plasma concentrations are considerably lower than those used in our experiments to elicit an increase in [Ca2+]i; therefore, further studies are needed to evaluate the ability of cafedrine/theodrenaline to alter mucociliary clearance in clinical practice.

A 20:1 synergetic mixture of cafedrine/theodrenaline accelerates particle transport velocity in murine tracheal epithelium via IP3 receptor-associated calcium release.

Background: Mucociliary clearance is a pivotal physiological mechanism that protects the lung by ridding the lower airways of pollution and colonization by pathogens, thereby preventing infections. The fixed 20:1 combination of cafedrine and theodrenaline has been used to treat perioperative hypotension or hypotensive states due to emergency situations since the 1960s. Because mucociliary clearance is impaired during mechanical ventilation and critical illness, the present study aimed to evaluate the influence of cafedrine/theodrenaline on mucociliary clearance. Material and Methods: The particle transport velocity (PTV) of murine trachea preparations was measured as a surrogate for mucociliary clearance under the influence of cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone. Inhibitory substances were applied to elucidate relevant signal transduction cascades. Results: All three applications of the combination of cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone induced a sharp increase in PTV in a concentration-dependent manner with median effective concentrations of 0.46 µM (consisting of 9.6 µM cafedrine and 0.46 µM theodrenaline), 408 and 4 µM, respectively. The signal transduction cascades were similar for the effects of both cafedrine and theodrenaline at the murine respiratory epithelium. While PTV remained at its baseline value after non-selective inhibition of ß-adrenergic receptors and selective inhibition of ß1 receptors, cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone increased PTV despite the inhibition of the protein kinase A. However, IP3 receptor activation was found to be the pivotal mechanism leading to the increase in murine PTV, which was abolished when IP3 receptors were inhibited. Depleting intracellular calcium stores with caffeine confirmed calcium as another crucial messenger altering the PTV after the application of cafedrine/theodrenaline. Discussion: Cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone exert their effects via IP3 receptor-associated calcium release that is ultimately triggered by ß1-adrenergic receptor stimulation. Synergistic effects at the ß1-adrenergic receptor are highly relevant to alter the PTV of the respiratory epithelium at clinically relevant concentrations. Further investigations are needed to assess the value of cafedrine/theodrenaline-mediated alterations in mucociliary function in clinical practice.

The use of artificial intelligence and machine learning monitoring to safely administer a fluid-restrictive goal-directed treatment protocol to minimize the risk of transfusion during major spine surgery of a Jehovah's Witness: a case report.

BACKGROUND: The Hypotension Prediction Index (HPI) displays an innovative monitoring tool which predicts intraoperative hypotension before its onset. CASE PRESENTATION: We report the case of an 84-year-old Caucasian woman undergoing major spinal surgery with no possibility for the transfer of blood products given her status as a Jehovah's Witness. The hemodynamic treatment algorithm we employed was based on HPI and resulted in a high degree of hemodynamic stability during the surgical procedure. Further, the patient was not at risk for either hypo- or hypervolemia, conditions which might have caused dilution anemia. By using HPI as a tool for patient blood management, it was possible to reduce the incidence of intraoperative hypotension to a minimum. CONCLUSIONS: In sum, this HPI-based treatment algorithm represents a useful application for the treatment of complex anesthesia and perioperative patient blood management. It is a simple but powerful extension of standard monitoring for the prevention of intraoperative hypotension.

Minimized Extracorporeal Circulation Is Associated with Reduced Plasma Levels of Free-Circulating Mitochondrial DNA Compared to Conventional Cardiopulmonary Bypass: A Secondary Analysis of an Exploratory, Prospective, Interventional Study.

The use of minimized extracorporeal circulation (MiECC) during cardiac surgery is associated with a reduced inflammatory reaction compared to conventional cardiopulmonary bypass (cCPB). Since it is unknown if MiECC also reduces the amount of free-circulating mitochondrial DNA (mtDNA), this study aims to compare MiECC-induced mtDNA release to that of cCPB as well as to identify potential relations between the plasma levels of mtDNA and an adverse outcome. Overall, 45 patients undergoing cardiac surgery with either cCPB or MiECC were included in the study. MtDNA encoding for NADH dehydrogenase 1 was quantified with quantitative polymerase chain reaction. The plasma amount of mtDNA was significantly lower in patients undergoing cardiac surgery with MiECC compared to cCPB (MiECC: 161.8 (65.5−501.9); cCPB 190.8 (82−705.7); p < 0.001). Plasma levels of mtDNA showed comparable kinetics independently of the study group and peaked during CPB (MiECC preoperative: 68.2 (26.5−104.9); MiECC 60 min after start of CPB: 536.5 (215.7−919.6); cCPB preoperative: 152.5 (80.9−207.6); cCPB 60 min after start of CPB: 1818.0 (844.2−3932.2); all p < 0.001). Patients offering an mtDNA blood concentration of >650 copies/µL after the commencement of CPB had a 5-fold higher risk for postoperative atrial fibrillation independently of the type of cardiopulmonary bypass. An amount of mtDNA being higher than 650 copies/µL showed moderate predictive power (AUROC 0.71 (0.53−071)) for the identification of postoperative atrial fibrillation. In conclusion, plasma levels of mtDNA were lower in patients undergoing cardiac surgery with MiECC compared to cCPB. The amount of mtDNA at the beginning of the CPB was associated with postoperative atrial fibrillation independent of the type of cardiopulmonary bypass.

Cerebral Tissue Oxygen Saturation Is Enhanced in Patients following Transcatheter Aortic Valve Implantation: A Retrospective Study.

Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement. The aim of this study was to evaluate whether a relevant alteration in cerebral tissue oxygen saturation (rSO2) could be detected following TAVI. Retrospective data analysis included 275 patients undergoing TAVI between October 2016 and December 2020. Overall, rSO2 significantly increased following TAVI (64.6 ± 10% vs. 68.1 ± 10%, p < 0.01). However, a significant rise was only observed in patients with a preoperative rSO2 < 60%. Of the hemodynamic confounders studied, hemoglobin, mean arterial pressure and blood pH were lowered, while central venous pressure and arterial partial pressure of carbon dioxide (PaCO2) were slightly elevated (PaCO2: 39 (36−43) mmHg vs. 42 (37−47) mmHg, p = 0.03; pH: 7.41 (7.3−7.4) vs. 7.36 (7.3−7.4), p < 0.01). Multivariate linear regression modeling identified only hemoglobin as a predictor of altered rSO2. Patients with a EuroScore II above 4% and an extended ICU stay were found to have lower rSO2, while no difference was observed in patients with postoperative delirium or between the implanted valve types. Further prospective studies that eliminate differences in potential confounding variables are necessary to confirm the rise in rSO2. Future research should provide more information on the value of cerebral oximetry for identifying high-risk patients who will require further clinical interventions in the setting of the TAVI procedure.

Ultrasound-accelerated thrombolysis in high-risk perioperative pulmonary embolism: two case reports and review of literature.

INTRODUCTION: Treatment of high-risk pulmonary embolism (PE) in perioperative patients remains challenging. Systemic thrombolysis is associated with a high risk of major bleedings and intracranial haemorrhage. High mortality rates are reported for open pulmonary embolectomy. Therefore, postoperative surgical patients may benefit substantially from catheter-directed ultrasound-accelerated thrombolysis (USAT). CASE PRESENTATION: We report two cases of high-risk perioperative PE. Both patients developed severe haemodynamic instability leading to cardiac arrest. After the implantation of a veno-arterial extracorporeal membrane oxygenation (ECMO), they were both successfully treated with USAT. Adequate improvement of right ventricular function was achieved; thus, ECMO could be successfully weaned after 3 and 4 days, respectively. Both patients showed favourable outcomes and could be discharged to rehabilitation. CONCLUSION: Current guidelines on treatment of PE offer no specific therapies for perioperative patients with high-risk PE. However, systemic thrombolysis is often excluded due to the perioperative setting and the risk of major bleeding. Catheter-directed thrombolysis was shown to utilise less thrombolytic agent while obtaining comparable thrombolytic effects. The risk for major bleeding (including intracranial haemorrhage) is also significantly lowered. Until further trials determining the value of adopted treatment strategies of high-risk PE in perioperative patients are available, USAT should be considered in similar cases.

Clinical, Angiographic, and Procedural Correlates of Very Late Absorb Scaffold Thrombosis: Multistudy Registry Results.

OBJECTIVES: The aim of this study was to identify independent correlates of very late scaffold thrombosis (VLST) from an analysis of consecutively treated patients from 15 multicenter studies. BACKGROUND: Recent analyses suggest an increased risk for VLST with the Absorb Bioresorbable Vascular Scaffold compared with drug-eluting stents, but insights as to correlates of risk are limited. METHODS: A total of 55 patients were identified with scaffold thrombosis. They were matched 2:1 with control subjects selected randomly from patients without thrombosis from the same study. Quantitative coronary angiography was available for 96.4% of patients. Multiple logistic and Cox regression analysis were used to identify significant independent outcome correlates from 6 pre-specified characteristics. RESULTS: Patients had scaffold thrombosis at a median of 20 months (interquartile range: 17 to 27 months). Control subjects were followed for 36 months (interquartile range: 24 to 38 months). For the combined groups, reference vessel diameter (RVD) was 2.84 ± 0.50 mm, scaffold length was 26 ± 16 mm, and post-dilatation was performed in 56%. Univariate correlates of thrombosis were smaller nominal scaffold/RVD ratio (linear p = 0.001; ratio <1.18:1; odds ratio: 7.5; p = 0.002) and larger RVD (linear p = 0.001; >2.72 mm; odds ratio: 3.4; p = 0.001). Post-dilatation at ≥16 atm, post-dilatation balloon/scaffold ratio, final percentage stenosis, and dual antiplatelet therapy were not correlated with VLST. Only scaffold/RVD ratio remained a significant independent correlate of VLST (p = 0.001), as smaller ratio was correlated with RVD (p < 0.001). Post hoc analysis of 8 other potential covariates revealed no other correlates of outcome. CONCLUSIONS: In the present analysis, the largest to date of its type, relative scaffold undersizing was the strongest determinant of VLST. Given current understanding of "scaffold dismantling," this finding likely has ramifications for all bioresorbable scaffolds.