Mortality Prediction by Kinetic Parameters of Lactate and S-Adenosylhomocysteine in a Cohort of Critically Ill Patients.

Tissue hypoxia is associated with the development of organ dysfunction and death in critically ill patients commonly captured using blood lactate. The kinetic parameters of serial lactate evaluations are superior at predicting mortality compared with single values. S-adenosylhomocysteine (SAH), which is also associated with hypoxia, was recently established as a useful predictor of septic organ dysfunction and death. We evaluated the performance of kinetic SAH parameters for mortality prediction compared with lactate parameters in a cohort of critically ill patients. For lactate and SAH, maxima and means as well as the normalized area scores were calculated for two periods: the first 24 h and the total study period of up to five days following ICU admission. Their performance in predicting in-hospital mortality were compared in 99 patients. All evaluated parameters of lactate and SAH were significantly higher in non-survivors compared with survivors. In univariate analysis, the predictive power for mortality of SAH was higher compared with lactate in all forms of application. Multivariable models containing SAH parameters demonstrated higher predictive values for mortality than models based on lactate parameters. The optimal models for mortality prediction incorporated both lactate and SAH parameters. Compared with lactate, SAH displayed stronger predictive power for mortality in static and dynamic application in critically ill patients.

S-Adenosylhomocysteine Is a Useful Metabolic Factor in the Early Prediction of Septic Disease Progression and Death in Critically Ill Patients: A Prospective Cohort Study.

A common final pathway of pathogenetic mechanisms in septic organ dysfunction and death is a lack or non-utilization of oxygen. Plasma concentrations of lactate serve as surrogates for the oxygen-deficiency-induced imbalance between energy supply and demand. As S-adenosylhomocysteine (SAH) was shown to reflect tissue hypoxia, we compared the ability of SAH versus lactate to predict the progression of inflammatory and septic disease to septic organ dysfunction and death. Using univariate and multiple logistic regression, we found that SAH but not lactate, taken upon patients' inclusion in the study close to ICU admission, significantly and independently contributed to the prediction of disease progression and death. Due to the stronger increase in SAH in relation to S-adenosylmethionine (SAM), the ratio of SAM to SAH, representing methylation potential, was significantly decreased in patients with septic organ dysfunction and non-survivors compared with SIRS/sepsis patients (2.8 (IQR 2.3-3.9) vs. 8.8 (4.9-13.8); p = 0.003) or survivors (4.9 (2.8-9.5) vs. 8.9 (5.1-14.3); p = 0.026), respectively. Thus, SAH appears to be a better contributor to the prediction of septic organ dysfunction and death than lactate in critically ill patients. As SAH is a potent inhibitor of SAM-dependent methyltransferases involved in numerous vital biochemical processes, the impairment of the SAM-to-SAH ratio in severely critically ill septic patients and non-survivors warrants further studies on the pathogenetic role of SAH in septic multiple organ failure.

Ground truth labels challenge the validity of sepsis consensus definitions in critical illness.

BACKGROUND: Sepsis is the leading cause of death in the intensive care unit (ICU). Expediting its diagnosis, largely determined by clinical assessment, improves survival. Predictive and explanatory modelling of sepsis in the critically ill commonly bases both outcome definition and predictions on clinical criteria for consensus definitions of sepsis, leading to circularity. As a remedy, we collected ground truth labels for sepsis. METHODS: In the Ground Truth for Sepsis Questionnaire (GTSQ), senior attending physicians in the ICU documented daily their opinion on each patient's condition regarding sepsis as a five-category working diagnosis and nine related items. Working diagnosis groups were described and compared and their SOFA-scores analyzed with a generalized linear mixed model. Agreement and discriminatory performance measures for clinical criteria of sepsis and GTSQ labels as reference class were derived. RESULTS: We analyzed 7291 questionnaires and 761 complete encounters from the first survey year. Editing rates for all items were > 90%, and responses were consistent with current understanding of critical illness pathophysiology, including sepsis pathogenesis. Interrater agreement for presence and absence of sepsis was almost perfect but only slight for suspected infection. ICU mortality was 19.5% in encounters with SIRS as the "worst" working diagnosis compared to 5.9% with sepsis and 5.9% with severe sepsis without differences in admission and maximum SOFA. Compared to sepsis, proportions of GTSQs with SIRS plus acute organ dysfunction were equal and macrocirculatory abnormalities higher (p < 0.0001). SIRS proportionally ranked above sepsis in daily assessment of illness severity (p < 0.0001). Separate analyses of neurosurgical referrals revealed similar differences. Discriminatory performance of Sepsis-1/2 and Sepsis-3 compared to GTSQ labels was similar with sensitivities around 70% and specificities 92%. Essentially no difference between the prevalence of SIRS and SOFA ≥ 2 yielded sensitivities and specificities for detecting sepsis onset close to 55% and 83%, respectively. CONCLUSIONS: GTSQ labels are a valid measure of sepsis in the ICU. They reveal suspicion of infection as an unclear clinical concept and refute an illness severity hierarchy in the SIRS-sepsis-severe sepsis spectrum. Ground truth challenges the accuracy of Sepsis-1/2 and Sepsis-3 in detecting sepsis onset. It is an indispensable intermediate step towards advancing diagnosis and therapy in the ICU and, potentially, other health care settings.

Sepsis and delayed cerebral ischemia are associated and have a cumulative effect on poor functional outcome in aneurysmal subarachnoid hemorrhage.

Objective: Although sepsis and delayed cerebral ischemia (DCI) are severe complications in patients with aneurysmal subarachnoid hemorrhage (aSAH) and share pathophysiological features, their interrelation and additive effect on functional outcome is uncertain. We investigated the association between sepsis and DCI and their cumulative effect on functional outcome in patients with aSAH using current sepsis-3 definition. Methods: Patients admitted to our hospital between 11/2014 and 11/2018 for aSAH were retrospectively analyzed. The main explanatory variable was sepsis, diagnosed using sepsis-3 criteria. Endpoints were DCI and functional outcome at hospital discharge (modified Rankin Scale (mRS) 0-3 vs. 4-6). Propensity score matching (PSM) and multivariable logistic regressions were performed. Results: Of 238 patients with aSAH, 55 (23.1%) developed sepsis and 74 (31.1%) DCI. After PSM, aSAH patients with sepsis displayed significantly worse functional outcome (p < 0.01) and longer ICU stay (p = 0.046). Sepsis was independently associated with DCI (OR = 2.46, 95%CI: 1.28-4.72, p < 0.01). However, after exclusion of patients who developed sepsis before (OR = 1.59, 95%CI: 0.78-3.24, p = 0.21) or after DCI (OR = 0.85, 95%CI: 0.37-1.95, p = 0.70) this statistical association did not remain. Good functional outcome gradually decreased from 56.3% (76/135) in patients with neither sepsis nor DCI, to 43.8% (21/48) in those with no sepsis but DCI, to 34.5% (10/29) with sepsis but no DCI and to 7.7% (2/26) in patients with both sepsis and DCI. Conclusion: Our study demonstrates a strong association between sepsis, DCI and functional outcome in patients with aSAH and suggests a complex interplay resulting in a cumulative effect towards poor functional outcome, which warrants further studies.

Dissecting contributions of individual systemic inflammatory response syndrome criteria from a prospective algorithm to the prediction and diagnosis of sepsis in a polytrauma cohort.

Background: Sepsis is the leading cause of death in intensive care units (ICUs), and its timely detection and treatment improve clinical outcome and survival. Systemic inflammatory response syndrome (SIRS) refers to the concurrent fulfillment of at least two out of the following four clinical criteria: tachycardia, tachypnea, abnormal body temperature, and abnormal leukocyte count. While SIRS was controversially abandoned from the current sepsis definition, a dynamic SIRS representation still has potential for sepsis prediction and diagnosis. Objective: We retrospectively elucidate the individual contributions of the SIRS criteria in a polytrauma cohort from the post-surgical ICU of University Medical Center Mannheim (Germany). Methods: We used a dynamic and prospective SIRS algorithm tailored to the ICU setting by accounting for catecholamine therapy and mechanical ventilation. Two clinically relevant tasks are considered: (i) sepsis prediction using the first 24 h after admission to our ICU, and (ii) sepsis diagnosis using the last 24 h before sepsis onset and a time point of comparable ICU treatment duration for controls, respectively. We determine the importance of individual SIRS criteria by systematically varying criteria weights when summarizing the SIRS algorithm output with SIRS descriptors and assessing the classification performance of the resulting logistic regression models using a specifically developed ranking score. Results: Our models perform better for the diagnosis than the prediction task (maximum AUROC 0.816 vs. 0.693). Risk models containing only the SIRS level average mostly show reasonable performance across criteria weights, with prediction and diagnosis AUROCs ranging from 0.455 (weight on leukocyte criterion only) to 0.693 and 0.619 to 0.800, respectively. For sepsis prediction, temperature and tachypnea are the most important SIRS criteria, whereas the leukocytes criterion is least important and potentially even counterproductive. For sepsis diagnosis, all SIRS criteria are relevant, with the temperature criterion being most influential. Conclusion: SIRS is relevant for sepsis prediction and diagnosis in polytrauma, and no criterion should a priori be omitted. Hence, the original expert-defined SIRS criteria are valid, capturing important sepsis risk determinants. Our prospective SIRS algorithm provides dynamic determination of SIRS criteria and descriptors, allowing their integration in sepsis risk models also in other settings.

Pneumonia in the first week after polytrauma is associated with reduced blood levels of soluble herpes virus entry mediator.

Background: Pneumonia develops frequently after major surgery and polytrauma and thus in the presence of systemic inflammatory response syndrome (SIRS) and organ dysfunction. Immune checkpoints balance self-tolerance and immune activation. Altered checkpoint blood levels were reported for sepsis. We analyzed associations of pneumonia incidence in the presence of SIRS during the first week of critical illness and trends in checkpoint blood levels. Materials and methods: Patients were studied from day two to six after admission to a surgical intensive care unit (ICU). Blood was sampled and physician experts retrospectively adjudicated upon the presence of SIRS and Sepsis-1/2 every eight hours. We measured the daily levels of immune checkpoints and inflammatory markers by bead arrays for polytrauma patients developing pneumonia. Immune checkpoint time series were additionally determined for clinically highly similar polytrauma controls remaining infection-free during follow-up. We performed cluster analyses. Immune checkpoint time trends in cases and controls were compared with hierarchical linear models. For patients with surgical trauma and with and without sepsis, selected immune checkpoints were determined in study baseline samples. Results: In polytrauma patients with post-injury pneumonia, eleven immune checkpoints dominated subcluster 3 that separated subclusters 1 and 2 of myeloid markers from subcluster 4 of endothelial activation, tissue inflammation, and adaptive immunity markers. Immune checkpoint blood levels were more stable in polytrauma cases than controls, where they trended towards an increase in subcluster A and a decrease in subcluster B. Herpes virus entry mediator (HVEM) levels (subcluster A) were lower in cases throughout. In unselected surgical patients, sepsis was not associated with altered HVEM levels at the study baseline. Conclusion: Pneumonia development after polytrauma until ICU-day six was associated with decreased blood levels of HVEM. HVEM signaling may reduce pneumonia risk by strengthening myeloid antimicrobial defense and dampening lymphoid-mediated tissue damage. Future investigations into the role of HVEM in pneumonia and sepsis development and as a predictive biomarker should consider the etiology of critical illness and the site of infection.

Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission.

Infection can induce granulopoiesis. This process potentially contributes to blood gene classifiers of sepsis in systemic inflammatory response syndrome (SIRS) patients. This study aimed to identify signature genes of blood granulocytes from patients with sepsis and SIRS on intensive care unit (ICU) admission. CD15+ cells encompassing all stages of terminal granulocytic differentiation were analyzed. CD15 transcriptomes from patients with sepsis and SIRS on ICU admission and presurgical controls (discovery cohort) were subjected to differential gene expression and pathway enrichment analyses. Differential gene expression was validated by bead array in independent sepsis and SIRS patients (validation cohort). Blood counts of granulocyte precursors were determined by flow cytometry in an extension of the validation cohort. Despite similar transcriptional CD15 responses in sepsis and SIRS, enrichment of canonical pathways known to decline at the metamyelocyte stage (mitochondrial, lysosome, cell cycle, and proteasome) was associated with sepsis but not SIRS. Twelve of 30 validated genes, from 100 selected for changes in response to sepsis rather than SIRS, were endo-lysosomal. Revisiting the discovery transcriptomes revealed an elevated expression of promyelocyte-restricted azurophilic granule genes in sepsis and myelocyte-restricted specific granule genes in sepsis followed by SIRS. Blood counts of promyelocytes and myelocytes were higher in sepsis than in SIRS. Sepsis-induced granulopoiesis and signature genes of early terminal granulocytic differentiation thus provide a rationale for classifiers of sepsis in patients with SIRS on ICU admission. Yet, the distinction of this process from noninfectious tissue injury-induced granulopoiesis remains to be investigated.

Comparative Analyses of the Impact of Different Criteria for Sepsis Diagnosis on Outcome in Patients with Spontaneous Subarachnoid Hemorrhage.

Data on sepsis in patients with a subarachnoid hemorrhage (SAH) are scarce. We assessed the impact of different sepsis criteria on the outcome in an SAH cohort. Adult patients admitted to our ICU with a spontaneous SAH between 11/2014 and 11/2018 were retrospectively included. In patients developing an infection, different criteria for sepsis diagnosis (Sepsis-1, Sepsis-3_original, Sepsis-3_modified accounting for SAH-specific therapy, alternative sepsis criteria compiled of consensus conferences) were applied and their impact on functional outcome using the modified Rankin Scale (mRS) on hospital discharge and in-hospital mortality was evaluated. Of 270 SAH patients, 129 (48%) developed an infection. Depending on the underlying criteria, the incidence of sepsis and septic shock ranged between 21-46% and 9-39%. In multivariate logistic regression, the Sepsis-1 criteria were not associated with the outcome. The Sepsis-3 criteria were not associated with the functional outcome, but in shock with mortality. Alternative sepsis criteria were associated with mortality for sepsis and in shock with mortality and the functional outcome. While Sepsis-1 criteria were irrelevant for the outcome in SAH patients, septic shock, according to the Sepsis-3 criteria, adversely impacted survival. This impact was higher for the modified Sepsis-3 criteria, accounting for SAH-specific treatment. Modified Sepsis-3 and alternative sepsis criteria diagnosed septic conditions of a higher relevance for outcomes in patients with an SAH.

Differential Network Testing Reveals Diverging Dynamics of Organ System Interactions for Survivors and Non-survivors in Intensive Care Medicine.

Statistical network analyses have become popular in many scientific disciplines, where an important task is to test for differences between two networks. We describe an overall framework for differential network testing procedures that vary regarding (1) the network estimation method, typically based on specific concepts of association, and (2) the network characteristic employed to measure the difference. Using permutation-based tests, our approach is general and applicable to various overall, node-specific or edge-specific network difference characteristics. The methods are implemented in our freely available R software package DNT, along with an R Shiny application. In a study in intensive care medicine, we compare networks based on parameters representing main organ systems to evaluate the prognosis of critically ill patients in the intensive care unit (ICU), using data from the surgical ICU of the University Medical Centre Mannheim, Germany. We specifically consider both cross-sectional comparisons between a non-survivor and a survivor group and longitudinal comparisons at two clinically relevant time points during the ICU stay: first, at admission, and second, at an event stage prior to death in non-survivors or a matching time point in survivors. The non-survivor and the survivor networks do not significantly differ at the admission stage. However, the organ system interactions of the survivors then stabilize at the event stage, revealing significantly more network edges, whereas those of the non-survivors do not. In particular, the liver appears to play a central role for the observed increased connectivity in the survivor network at the event stage.

Maintaining oxygen delivery is crucial to prevent intestinal ischemia in critical ill patients.

BACKGROUND: Intestinal ischemia is a common complication with obscure pathophysiology in critically ill patients. Since insufficient delivery of oxygen is discussed, we investigated the influence of oxygen delivery, hemoglobin, arterial oxygen saturation, cardiac index and the systemic vascular resistance index on the development of intestinal ischemia. Furthermore, we evaluated the predictive power of elevated lactate levels for the diagnosis of intestinal ischemia. METHODS: In a retrospective case-control study data (mean oxygen delivery, minimum oxygen delivery, systemic vascular resistance index) of critical ill patients from 02/2009-07/2017 were analyzed using a proportional hazard model. General model fit and linearity were tested by likelihood ratio tests. The components of oxygen delivery (hemoglobin, arterial oxygen saturation and cardiac index) were individually tested in models. RESULTS: 59 out of 874 patients developed intestinal ischemia. A mean oxygen delivery less than 250ml/min/m2 (LRT vs. null model: p = 0.018; LRT for non-linearity: p = 0.012) as well as a minimum oxygen delivery less than 400ml/min/m2 (LRT vs null model: p = 0.016; LRT for linearity: p = 0.019) were associated with increased risk of the development of intestinal ischemia. We found no significant influence of hemoglobin, arterial oxygen saturation, cardiac index or systemic vascular resistance index. Receiver operating characteristics analysis for elevated lactate levels, pH, CO2 and central venous saturation was poor with an area under the receiver operating characteristic of 0.5324, 0.52, 0.6017 and 0.6786. CONCLUSION: There was a significant correlation for mean and minimum oxygen delivery with the incidence of intestinal ischemia for values below 250ml/min/m2 respectively 400ml/min/m2. Neither hemoglobin, arterial oxygen saturation, cardiac index, systemic vascular resistance index nor elevated lactate levels could be identified as individual risk factors.