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Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.

In Germany, more than 2.1 million patients are admitted to the intensive care unit (ICU) annually (Federal Statistical Office 2016). To enhance quality of care in the ICU, the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) has issued ten evidence-based quality indicators (QIs) for acute critical care., Mission – Innovation: Telematics, eHealth and High-Definition Medicine in Patient-Centered Acute Medicine, p. 225

Additional file 3: Figure S2. Core body temperature time series of the septic shock patients. Core body temperature was measured every hour during a 24-h period during the blood draw. The raw time series in (A) was linearly detrended (trend is shown in blue) to obtain (B).

Additional file 2: Figure S1. Gene expression patterns for all clock genes quantified in septic shock patients. The lines are colored according to the classification of rhythmicity in Fig. 2. The empty boxes represent clock genes that did not pass the inclusion criteria for the analysis.

Introduction Sepsis is a major cause of preventable deaths in hospitals. This study aims to investigate if sepsis incidence and quality of care can be assessed using inpatient administrative health data (IAHD). Methods and analysis Design: Retrospective observational validation study using routine data to assess the diagnostic accuracy of sepsis coding in IAHD regarding sepsis diagnosis based on medical record review. Procedure: A stratified sample of 10 000 patients with an age ≥15 years treated in between 2015 and 2017 in 10 German hospitals is investigated. All available information of medical records is screened by trained physicians to identify true sepsis cases (‘gold standard’) both according to current (‘sepsis-1’) definitions and new (‘sepsis-3’) definitions. Data from medical records are linked to IAHD on patient level using a pseudonym. Analyses: Proportions of cases with sepsis according to sepsis-1 and sepsis-3 definitions are calculated and compared with estimates from coding of sepsis in IAHD. Predictive accuracy (sensitivity, specificity) of different coding abstraction strategies regarding the gold standard is estimated. Predictive accuracy of mortality risk factors obtained from IAHD regarding the respective risk factors obtained from medical records is calculated. An IAHD-based risk model for hospital mortality is compared with a record-based risk model regarding model-fit and predicted risk of death. Analyses adjust for sampling weights. The obtained estimates of sensitivity and specificity for sepsis coding in IAHD are used to estimate adjusted incidence proportions of sepsis based on German national IAHD. Ethics and dissemination The study has been approved by the ethics commission of the Jena University Hospital (No. 2018-1065-Daten). The results of the study will be discussed in an expert panel to write a memorandum on improving the utility of IAHD for epidemiological surveillance and quality management of sepsis care. Trial registration number DRKS00017775; Pre-results.

Das Delir gehört zu den häufigsten psychiatrischen Diagnosen auf der Intensivstation (ITS). Patienten mit Delir haben einen längeren ITS-Aufenthalt und eine höhere ITS-Sterblichkeit. Nach durchlebter Delir-Episode besteht die Möglichkeit, dass die Patienten langfristige Schäden in Form einer postoperativen kognitiven Dysfunktion (POCD) erleiden. Insgesamt beeinflusst das Delir die 12-Monats-Sterblichkeit sowie die Lebensqualität der Patienten. In der Literatur werden unterschiedliche Modelle zur Entstehung des Delirs diskutiert. Hierbei stehen Neurotransmitterdysbalancen, Entzündungen sowie septischer und psychischer Stress im Vordergrund. Pneumonie und Sepsis treten dabei häufiger bei Patienten mit Delir als bei Patienten ohne Delir auf. Die Untersuchung der zeitlichen Abfolge von Delir und Infektion ist die primäre Fragestellung. Als sekundäre Fragenstellungen wurden nach Unterschieden bezüglich der Basischarakteristika, der Vorerkrankungen, der durchgeführten Operationen, der Infektionsart, der antibiotischen Standardtherapie, der intensivmedizinischen Scores, der Behandlungsdauer und ITS-Sterblichkeit gesucht. Einschlusskriterien dieser prospektiven Kohortenstudie mit einem retrospektiven Expertenaudit waren ein Alter ≥ 60 Jahre, ITS-Behandlung > 36h und eine mit der ITS-Behandlungsepisode im Zusammenhang stehende Operation. Ausschlusskriterien waren vorbestehende kognitive Einschränkungen, Demenz, nicht ausreichende Deutschkenntnisse, bekannter Alkohol-, Nikotin- und Drogenabusus sowie ein intrakranieller Eingriff. Das Delir wurde anhand der DSM-IV Kriterien diagnostiziert. Erfasst wurden Alter, Geschlecht, Vorerkrankungen, intensivmedizinische Scores (SAPS II, APACHE II, TISS-28, SOFA), durchgeführte Operationen, diagnostizierte und behandelte Infektionen, Einhaltung der antibiotischen Standardtherapien sowie die Gesamtverweildauer auf der ITS. Insgesamt wurden 632 Patienten gescreent. 101 Patienten konnten aufgrund der Einschlusskriterien in die statistische Analyse eingeschlossen werden. Von den 101 Patienten wurden nur die Patienten statistisch untersucht, die während der intensivmedizinischen Behandlung sowohl eine Infektion als auch ein Delir entwickelt hatten. Die Patienten wurden in zwei Gruppen eingeteilt. In der DDI (Delir dann Infektion) -Gruppe entwickelten die Patienten das Delir vor der Infektion und in der IDD (Infektion dann Delir) -Gruppe trat das Delir nach der Infektion auf. Es konnte gezeigt werden, dass eine Infektion häufiger vor einem Delir auftritt. Bezüglich der Basischarkteristika, der intensivmedizinischen Scores bei ITS-Aufnahme, der durchgeführten Operationen und der Standardantibiotikatherapie unterschieden sich die beiden Gruppen nicht signifikant. Außer bezüglich des TISS-28 Scores, welcher in der IDD-Gruppe signifikante höhere Score-Werte zeigte, was als ein Indiz eines größeren therapeutischen Aufwandes gewertet werden könnte. Bei den Vorerkrankungen konnten psychische/neurologische Vorerkrankungen häufiger in der DDI-Gruppe gesehen werden. Außerdem traten Katheter-assoziierte Infektionen häufiger in dieser Gruppe auf. Bei der zeitlichen Betrachtung der intensivmedizinischen Scores ab ITS-Aufnahme konnten keine Unterschiede gesehen werden. Eine Differenzierung der zwei Gruppen scheint mithilfe der intensivmedizinischen Scores nicht möglich zu sein. Zusammenfassend zeigt die vorliegende wissenschaftliche Untersuchung, dass in der untersuchten Patientenpopulation eine Infektion häufiger vor einem Delir auftritt., The delir belongs to most frequent psychiatric diagnosis on the Intensive- Care-Unit (ICU). Patients with delir have a prolonged ICU-stay and a higher ICU-mortality. After experienced episode of delir there is the possibility of suffering from long-range damage like the postoperative cognitive dysfunction (POCD). All in all the delir influences the 12-month mortality as well as the patients’ quality of life. In the literature different models concerning the development of delir are discussed. In those models neurotransmitter- imbalances, infections as well as septic and psychical stress are playing the leading role. Pneumonia and sepsis are more often seen in patients with delir than in patients without delir. The primary aim was the time course of infection and delirium. Secondary aims were an investigation for differences concerning basic characteristics, pre-existing diseases, performed operations, distribution of infections, adherence to antibiotic Standard Operating Procedures (SOPs), ICU-scores, ICU length of stay and ICU mortality. Inclusion criteria of this prospective cohort study with a retrospective audit of experts were an age ≥ 60, ICU-treatment > 36h and an operation connected with the ICU-stay. Exclusion criteria were known cognitive disabilities, dementia, non-sufficient knowledge of the German language, a known abuse of alcohol, nicotine and drugs as well as an intracranial operation. The delir was diagnosed by the DSM-IV criteria. Age, sex, former illnesses, ICU-scores (SAPS II, APACHE II, TISS-28, SOFA), performed operations, diagnosed and treated infections, obeying of the Standard Operating Procedures (SOPs) for the antibiotic treatments as well as the length of the ICU-stay were recorded. All in all 632 patients were examined. 101 patients had an evaluation of the DMS- IV criteria and were therefore included in the statistic analysis. Out of these 101 patients only patients with a development of infection and delir were statistically analyzed. These patients were separated into two groups. In the DDI (delir then infection)-group patients developed the delir before the infection and in the IDD (infection then delir)-group the delir appeared after the infection. It could be shown, that infections appear more frequently before a delir. With regards to the basis-characteristics, the ICU-scores at ICU-admission, performed operations and standard therapy of antibiotics the groups did not differ significantly, except the TISS-28 score. This score was higher in the ITD-group which could be caused by a greater amount of therapeutic interventions. Concerning the former illnesses the psychiatric/neurological illnesses were seen more often in the DDI-group. Furthermore catheter-associated infections appeared more frequent in this group. In terms of the time analysis of the ICU-scores no difference could be seen. A differentiation of the two groups does not seem to be possible with the aid of the ICU-scores. In summary this scientific study shows, that in this analyzed cohort an infection appears more often before the delir.