Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission.

BACKGROUND: Timely diagnosis is crucial for sepsis treatment. Current machine learning (ML) models suffer from high complexity and limited applicability. We therefore created an ML model using only complete blood count (CBC) diagnostics. METHODS: We collected non-intensive care unit (non-ICU) data from a German tertiary care centre (January 2014 to December 2021). Using patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells), we trained a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature. RESULTS: After exclusion, 1 381 358 laboratory requests (2016 from sepsis cases) were available. The CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857-0.887). External validations show AUROCs of 0.805 (95% CI, 0.787-0.824) for University Medicine Greifswald and 0.845 (95% CI, 0.837-0.852) for MIMIC-IV. The model including PCT revealed a significantly higher AUROC (0.857; 95% CI, 0.836-0.877) than PCT alone (0.790; 95% CI, 0.759-0.821; P < 0.001). CONCLUSIONS: Our results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.

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.

Continuation of chronic antiplatelet therapy is not associated with increased need for transfusions: a cohort study in critically ill septic patients.

BACKGROUND: The decision to maintain or halt antiplatelet medication in septic patients admitted to intensive care units presents a clinical dilemma. This is due to the necessity to balance the benefits of preventing thromboembolic incidents and leveraging anti-inflammatory properties against the increased risk of bleeding. METHODS: This study involves a secondary analysis of data from a prospective cohort study focusing on patients diagnosed with severe sepsis or septic shock. We evaluated the outcomes of 203 patients, examining mortality rates and the requirement for transfusion. The cohort was divided into two groups: those whose antiplatelet therapy was sustained (n = 114) and those in whom it was discontinued (n = 89). To account for potential biases such as indication for antiplatelet therapy, propensity score matching was employed. RESULTS: Therapy continuation did not significantly alter transfusion requirements (discontinued vs. continued in matched samples: red blood cell concentrates 51.7% vs. 68.3%, p = 0.09; platelet concentrates 21.7% vs. 18.3%, p = 0.82; fresh frozen plasma concentrates 38.3% vs. 33.3%, p = 0.7). 90-day survival was higher within the continued group (30.0% vs. 70.0%; p < 0.001) and the Log-rank test (7-day survivors; p = 0.001) as well as Cox regression (both matched samples) suggested an association between continuation of antiplatelet therapy < 7 days and survival (HR: 0.24, 95%-CI 0.10 to 0.63, p = 0.004). Sepsis severity expressed by the SOFA score did not differ significantly in matched and unmatched patients (both p > 0.05). CONCLUSIONS: The findings suggest that continuing antiplatelet therapy in septic patients admitted to intensive care units could be associated with a significant survival benefit without substantially increasing the need for transfusion. These results highlight the importance of a nuanced approach to managing antiplatelet medication in the context of severe sepsis and septic shock.

Ethical aspects of time in intensive care decision making.

The decision-making environment in intensive care units (ICUs) is influenced by the transformation of intensive care medicine, the staffing situation and the increasing importance of patient autonomy. Normative implications of time in intensive care, which affect all three areas, have so far barely been considered. The study explores patterns of decision making concerning the continuation, withdrawal and withholding of therapies in intensive care. A triangulation of qualitative data collection methods was chosen. Data were collected through non-participant observation on a surgical ICU at an academic medical centre followed by semi-structured interviews with nurses and physicians. The transcribed interviews and observation notes were coded and analysed using qualitative content analysis according to Mayring. Three themes related to time emerged regarding the escalation or de-escalation of therapies: influence of time on prognosis, time as a scarce resource and timing in regards to decision making. The study also reveals the ambivalence of time as a norm for decision making. The challenge of dealing with time-related efforts in ICU care results from the tension between the need to wait to optimise patient care, which must be balanced against the significant time pressure which is characteristic of the ICU setting.

Quality Improvement Initiative for Severe Sepsis and Septic Shock Reduces 90-Day Mortality: A 7.5-Year Observational Study.

OBJECTIVE: To investigate the impact of a quality improvement initiative for severe sepsis and septic shock focused on the resuscitation bundle on 90-day mortality. Furthermore, effects on compliance rates for antiinfective therapy within the recommended 1-hour interval are evaluated. DESIGN: Prospective observational before-after cohort study. SETTING: Tertiary university hospital in Germany. PATIENTS: All adult medical and surgical ICU patients with severe sepsis and septic shock. INTERVENTION: Implementation of a quality improvement program over 7.5 years. MEASUREMENTS: The primary endpoint was 90-day mortality. Secondary endpoints included ICU and hospital mortality rates and length of stay, time to broad-spectrum antiinfective therapy, and compliance with resuscitation bundle elements. MAIN RESULTS: A total of 14,115 patients were screened. The incidence of severe sepsis and septic shock was 9.7%. Ninety-day mortality decreased from 64.2% to 45.0% (p < 0.001). Hospital length of stay decreased from 44 to 36 days (p < 0.05). Compliance with resuscitation bundle elements was significantly improved. Antibiotic therapy within the first hour after sepsis onset increased from 48.5% to 74.3% (p < 0.001). Multivariate analysis revealed blood cultures before antibiotic therapy (hazard ratio, 0.60-0.84; p < 0.001), adequate calculated antibiotic therapy (hazard ratio, 0.53-0.75; p < 0.001), 1-2 L crystalloids within the first 6 hours (hazard ratio 0.67-0.97; p = 0.025), and greater than or equal to 6 L during the first 24 hours (hazard ratio, 0.64-0.95; p = 0.012) as predictors for improved survival. CONCLUSIONS: The continuous quality improvement initiative focused on the resuscitation bundle was associated with increased compliance and a persistent reduction in 90-day mortality over a 7.5-year period. Based on the observational study design, a causal relationship cannot be proven, and respective limitations need to be considered.

Evaluation of a non-invasive multisensor accelerometer for calculating energy expenditure in ventilated intensive care patients compared to indirect calorimetry and predictive equations.

Continuous measurement of resting energy expenditure (REE) in critically ill patients remains challenging but is required to prevent malnutrition. SenseWear Pro 3 Armband (SWA) is a research grade accelerometer for assessment of REE with the advantage of easy handling. In a prospective study we compared SWA with indirect calorimetry (IC) and predictive equations in critically ill, ventilated patients. REE was measured by SWA, IC and calculated by predictive formulas. Potential confounding factors that influence REE were also recorded. Results of SenseWear Armband and indirect calorimetry were compared using the Bland-Altman method. 34 ICU patients were investigated. SWA underestimated resting energy expenditure compared to IC with a mean bias of ΔREE = -253.6 ± 333.2 kcal, equivalent to -11.7 % (p = 0.025). This underestimation was seen in both, medical (-14.9 %) and surgical (-12.9 %) patients and the bias was greater in patients with fever (-19.0 %), tachycardia (-18.7 %) or tachypnea (-26.2 %). Differences were also noted when SWA was compared to predictive formulas. At present, SWA cannot be regarded as an alternative to indirect calorimetry. Individual measurements are often inaccurate and should be used with caution until improved algorithms, based on the results of this study, have been implemented.

Discrepant post filter ionized calcium concentrations by common blood gas analyzers in CRRT using regional citrate anticoagulation.

INTRODUCTION: Ionized calcium (iCa) concentration is often used in critical care and measured using blood gas analyzers at the point of care. Controlling and adjusting regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) involves measuring the iCa concentration in two samples: systemic with physiological iCa concentrations and post filter samples with very low iCa concentrations. However, modern blood gas analyzers are optimized for physiological iCa concentrations which might make them less suitable for measuring low iCa in blood with a high concentration of citrate. We present results of iCa measurements from six different blood gas analyzers and the impact on clinical decisions based on the recommendations of the dialysis' device manufacturer. METHOD: The iCa concentrations of systemic and post filter samples were measured using six distinct, frequently used blood gas analyzers. We obtained iCa results of 74 systemic and 84 post filter samples from patients undergoing RCA for CRRT at the University Medicine of Greifswald. RESULTS: The systemic samples showed concordant results on all analyzers with median iCa concentrations ranging from 1.07 to 1.16 mmol/L. The medians of iCa concentrations for post filter samples ranged from 0.21 to 0.50 mmol/L. Results of >70% of the post filter samples would lead to major differences in decisions regarding citrate flow depending on the instrument used. CONCLUSION: Measurements of iCa in post filter samples may give misleading information in monitoring the RCA. Recommendations of the dialysis manufacturer need to be revised. Meanwhile, little weight should be given to post filter iCa. Reference methods for low iCa in whole blood containing citrate should be established.

Prevalence and clinical implications of anti-PF4/heparin antibodies in intensive care patients: a prospective observational study.

Data on the frequency of anti-platelet factor 4/heparin (PF4/H) antibodies and their association with outcomes in intensive care unit (ICU) patients are sparse. In this prospective, observational study we screened 320 consecutive surgical/medical ICU patients for anti-PF4/H antibodies by enzyme-immunoassay (EIA) for immunoglobulin (Ig)G/A/M separately and heparin-induced platelet activation assay (HIPA) at ICU admission (=baseline), day 6, and day 10. HIPA-positive patients were additionally tested by serotonin-release assay (SRA). Patients tested positive by day 10: for anti-PF4/H-IgG = 17.2 % and for anti-PF4/H-IgM = 42.1 %. Within the first 10 ICU days, platelet counts decreased to <100 Gpt/L in 27.8 % patients. However, only seven patients (2.2 %) experienced a drop in the platelet count ≥50 % beginning after the fourth ICU day. These included the only two patients (0.6 %; 95 % confidence interval 0.08-2.2 %) with heparin-induced thrombocytopenia (HIT). Only strong reactions in the HIPA were reproducible by SRA. This study confirms that testing for anti-PF4/H IgG antibodies should be restricted to ICU-patients who develop a platelet count decrease of >50 % that begins after day four of heparin treatment (which may have started before ICU admission). Among patients testing positive by IgG-specific EIA a functional platelet activation assay should be performed (regarding only strong reactions as positive).

Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.

INTRODUCTION: Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host-pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose-response trial is necessary to assess the potential harm of this drug in this new indication. METHODS AND ANALYSIS: Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05033808.

[Preclinical early detection and diagnosis of sepsis - step by step]. / Präklinische Früherkennung und Diagnostik der Sepsis ­ Schritt für Schritt.

Because of very unspecific sepsis symptoms, early recognition of the emergency sepsis is difficult. If the disease is recognized in time it is possible to initiate diagnosis and treatment quickly. Rapid treatment of sepsis leads to lower mortality and less severe long-term consequences. Early detection is therefore of central importance in the diagnostic and therapeutic process, also in the outpatient setting.

Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.

CONTEXT: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00534287.

[Percutaneous tracheostomy in intensive care medicine - Update 2012]. / Punktionstracheotomie in der Intensivmedizin - Update 2012.

Percutaneous tracheostomy has become an established procedure in airway management of critically ill patients. It offers advantages over prolonged tracheal intubation. To date, there is no evidence of the optimal timing of the procedure. The Ciaglia Blue Rhino technique is the most common technique and, as any other techniques of percutaneous tracheostomy, is performed under general anaesthesia and with continuous bronchoscopic control. The recently introduced Ciaglia Blue Dolphin technique is based on radial dilatation with a fluid-filled high pressure balloon. Provided that specific contraindications are observed (e.g. difficult tracheal intubation, inability to identify anatomic landmarks, severe coagulopathy etc.), all techniques have low complication rates. The use of ultrasound may further enhance perioperative safety. Finally it must be noted that percutaneous tracheostomy is an elective procedure that requires informed consent from the patient or an attorney of law.

The German Quality Network Sepsis: Evaluation of a Quality Collaborative on Decreasing Sepsis-Related Mortality in a Controlled Interrupted Time Series Analysis.

Background: Sepsis is one of the leading causes of preventable deaths in hospitals. This study presents the evaluation of a quality collaborative, which aimed to decrease sepsis-related hospital mortality. Methods: The German Quality Network Sepsis (GQNS) offers quality reporting based on claims data, peer reviews, and support for establishing continuous quality management and staff education. This study evaluates the effects of participating in the GQNS during the intervention period (April 2016-June 2018) in comparison to a retrospective baseline (January 2014-March 2016). The primary outcome was all-cause risk-adjusted hospital mortality among cases with sepsis. Sepsis was identified by International Classification of Diseases (ICD) codes in claims data. A controlled time series analysis was conducted to analyze changes from the baseline to the intervention period comparing GQNS hospitals with the population of all German hospitals assessed via the national diagnosis-related groups (DRGs)-statistics. Tests were conducted using piecewise hierarchical models. Implementation processes and barriers were assessed by surveys of local leaders of quality improvement teams. Results: Seventy-four hospitals participated, of which 17 were university hospitals and 18 were tertiary care facilities. Observed mortality was 43.5% during baseline period and 42.7% during intervention period. Interrupted time-series analyses did not show effects on course or level of risk-adjusted mortality of cases with sepsis compared to the national DRG-statistics after the beginning of the intervention period (p = 0.632 and p = 0.512, respectively). There was no significant mortality decrease in the subgroups of patients with septic shock or ventilation >24 h or predefined subgroups of hospitals. A standardized survey among 49 local quality improvement leaders in autumn of 2018 revealed that most hospitals did not succeed in implementing a continuous quality management program or relevant measures to improve early recognition and treatment of sepsis. Barriers perceived most commonly were lack of time (77.6%), staff shortage (59.2%), and lack of participation of relevant departments (38.8%). Conclusion: As long as hospital-wide sepsis quality improvement efforts will not become a high priority for the hospital leadership by assuring adequate resources and involvement of all pertinent stakeholders, voluntary initiatives to improve the quality of sepsis care will remain prone to failure.

A multifaceted educational intervention improved anti-infectious measures but had no effect on mortality in patients with severe sepsis.

Sepsis is a major reason for preventable hospital deaths. A cluster-randomized controlled trial on an educational intervention did not show improvements of sepsis management or outcome. We now aimed to test an improved implementation strategy in a second intervention phase in which new intervention hospitals (former controls) received a multifaceted educational intervention, while controls (former intervention hospitals) only received feedback of quality indicators. Changes in outcomes from the first to the second intervention phase were compared between groups using hierarchical generalized linear models controlling for possible confounders. During the two phases, 19 control hospitals included 4050 patients with sepsis and 21 intervention hospitals included 2526 patients. 28-day mortality did not show significant changes between study phases in both groups. The proportion of patients receiving antimicrobial therapy within one hour increased in intervention hospitals, but not in control hospitals. Taking at least two sets of blood cultures increased significantly in both groups. During phase 2, intervention hospitals showed higher proportion of adequate initial antimicrobial therapy and de-escalation within 5 days. A survey among involved clinicians indicated lacking resources for quality improvement. Therefore, quality improvement programs should include all elements of sepsis guidelines and provide hospitals with sufficient resources for quality improvement.Trial registration: ClinicalTrials.gov, NCT01187134. Registered 23 August 2010, https://www.clinicaltrials.gov/ct2/show/study/NCT01187134 .

(1 → 3)-ß-D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial.

PURPOSE: To investigate whether (1 → 3)-ß-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI). METHODS: Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality. RESULTS: 339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80-1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0-2.2] days in the BDG group and 4.4 (IQR 2.0-9.1, p < 0.01) days in the control group. CONCLUSIONS: Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

Efficacy and Safety of Vilobelimab (IFX-1), a Novel Monoclonal Anti-C5a Antibody, in Patients With Early Severe Sepsis or Septic Shock-A Randomized, Placebo-Controlled, Double-Blind, Multicenter, Phase IIa Trial (SCIENS Study).

Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES: This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN: Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS: Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES: Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS: Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE: Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis.

Propranolol selectively blocks the enhanced parietal old/new effect during long-term recollection of unpleasant pictures: a high density ERP study.

Evidence from both animal and human research suggests that the formation of emotional memories is triggered by the beta-adrenergic system. To confirm whether modulation of central beta-adrenergic transmission is specifically involved in the neural signature of memory performance, the pre-encoding effect of propranolol (80 mg) on event-related potentials (ERPs) was measured in a placebo-controlled, double-blind, parallel-group study in 46 male healthy subjects using high density EEG and source imaging analysis during encoding and retrieval (after 1 week) of IAPS pictures of unpleasant, neutral and pleasant contents; for recognition 90 old pictures were randomly mixed with 90 new pictures. During retrieval correctly remembered old pictures elicited a significantly larger positive voltage change over the centro-parietal cortex than new pictures. Propranolol significantly reduced this old/new difference of the mean ERP amplitudes (500-800 ms) for unpleasant but not for neutral and pleasant memories. This effect correlated with salivary alpha-amylase activity, a surrogate for central adrenergic stimulation. In conclusion, propranolol selectively blocked the neural signature of unpleasant memories by mechanisms in which the parietal cortex seems to be specifically involved.

Comparison of arterial pressure cardiac output monitoring with transpulmonary thermodilution in septic patients.

BACKGROUND: The measurement of cardiac output in critically ill patients is complicated by rapid pathophysiological changes. The aim of this study was to compare the recently developed Arterial Pressure Cardiac Output algorithm (APCO) with transpulmonary thermodilution (TDCO). Clinical and hemodynamic parameters were tested for their impact on the measurements. MATERIAL/METHODS: Twenty septic patients were examined. Cardiac output measurements were performed simultaneously on 3 consecutive days. The data were evaluated using regression analysis and the Bland Altman approach. RESULTS: Bland Altman analysis presented a bias of 0.72 L/min and limits of agreement of 2.16 to 3.61 L/min for TDCO vs. APCO. Statistically significant covariables in the regression analysis were systemic vascular resistance (p<0.001), mean arterial pressure (p<0.001), cardiac function index (p=0.01), global end-diastolic index (p=0.02) and stroke volume index (p=0.005). Multiple linear regression analysis showed the residual percentage error decreased from 49.1% to 21.5%. CONCLUSIONS: The APCO algorithm provides a broad range of hemodynamic measurements with a minimally invasive approach and simple access to the patient's hemodynamic state. However, an underestimation at high cardiac output and an overestimation at low cardiac output relative to transpulmonary thermodilution were observed in septic patients. Therefore, the APCO algorithm in its current state cannot be substituted for transpulmonary thermodilution.