Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Purpose: Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models. Methods: 31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013). Results: Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2 and 3). Conclusions: We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental

Unchanged plasma levels of the soluble urokinase plasminogen activator receptor in elective coronary artery bypass graft surgery patients and cardiopulmonary bypass use.

The soluble urokinase plasminogen activator receptor (suPAR) has been recently recognized as a potential biological marker of various disease states, but the impact of a major surgical intervention on the suPAR level has not yet been established. The aim of our study was to investigate if the induction of a systemic inflammatory reaction in response to cardiopulmonary bypass would be accompanied by an increase in the plasma suPAR level.Patients undergoing coronary artery bypass grafting under cardiopulmonary bypass (CPB) were added. Based on the baseline suPAR level, patients were divided into group 1 (suPAR within normal range) or group 2 (suPAR above range). Blood was collected before the induction of anesthesia and 6 and 24 hours after surgery. Plasma suPAR, IL-6, IL-8, TNF-α, troponin I, NT-proBNP, and NGAL were quantified to assess the impact of surgical trauma on these markers.The baseline suPAR level was within the normal range in 31 patients (3.3 ng/mL), and elevated in 29 (5.1 ng/mL) (p<0.001). Baseline mediators of systemic inflammatory reaction concentrations (IL-6, TNF-α, and IL-8) and organ injury indices (troponin I, NT-proBNP, and NGAL) were low and increased after surgery in all patients (p<0.05). The surgery did not cause significant changes in the suPAR level either at 6 or 24 hours after, however the difference between groups observed at baseline remained substantial during the postoperative period.There was no change in the suPAR level observed in patients subjected to elective cardiac coronary artery bypass surgery and CPB, despite activation of a systemic inflammatory reaction

Platelet Receptor Activity for Predicting Survival in Patients with Intracranial Bleeding

Blood coagulation disorders in patients with intracranial bleeding as a result of head injuries or ruptured aneurysms are a diagnostic and therapeutic problem and appropriate assessments are needed to limit CNS damage and to implement preventive measures. The aim of the study was to monitor changes in platelet aggregation and to assess the importance of platelet dysfunction for predicting survival. Platelet receptor function analysis was performed using the agonists arachidonic acid (ASPI), adenosine diphosphate (ADP), collagen (COL), thrombin receptor activating protein (TRAP), ristocetin (RISTO) upon admission to the ICU and on days 2, 3, and 5. On admission, the ASPI, ADP, COL, TRAP, and RISTO tests indicated there was reduced platelet aggregation, despite there being a normal platelet count. In ‘Non-survivors’, the platelet response to all agonists was suppressed throughout the study period, while in ‘Survivors’ it improved. Measuring platelet function in ICU patients with intracranial bleeding is a strong predictor related to outcome: patients with impaired platelet aggregation had a lower 28-day survival rate compared to patients with normal platelet aggregation (log-rank test p = 0.014). The results indicated that measuring platelet aggregation can be helpful in the early detection, diagnosis, and treatment of bleeding disorders

Baseline characteristics of patients.

<p>*ACE inhibitors, angiotensin-converting-enzyme inhibitor; CPB, cardiopulmonary bypass. Data presented as medians with 25th and 75th percentiles.</p

Indices of organ damage measured in group 1(n = 32) and group 2(n = 29) measured at three time intervals.

<p>NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NGAL, neutrophil gelatinase associated lipocalin; AST, <i>aspartate</i>.</p><p>Data presented as medians with 25th and 75th percentiles;</p><p>*p<0.05 compared to the baseline;</p>#<p>p<0.0001 compared to the baseline.</p

Indices of systemic inflammatory reaction in group 1(n = 31) and group 2(n = 29), measured at three time intervals.

<p>CRP, c-reactive protein; WBC, white blood cell count; IL-6, interleukin 6; IL-8, interleukin 8; TNF alpha, tumor necrosis factor-alpha. Data presented as medians with 25th and 75th percentiles;</p><p>*p<0.05 compared to the baseline;</p>#<p>p<0.0001 compared to the baseline.</p

Brain-Specific Biomarkers as Mortality Predictors after Aneurysmal Subarachnoid Haemorrhage

Aneurysmal subarachnoid haemorrhage (aSAH) is a serious condition with a high mortality and high permanent disability rate for those who survive the initial haemorrhage. The purpose of this study was to investigate markers specific to the central nervous system as potential in-hospital mortality predictors after aSAH. In patients with an external ventricular drain, enolase, S100B, and GFAP levels were measured in the blood and cerebrospinal fluid (CSF) on days 1, 2, and 3 after aSAH. Compared to survivors, non-survivors showed a significantly higher peak of S100B and enolase levels in the blood (S100B: 5.7 vs. 1.5 ng/mL, p = 0.031; enolase: 6.1 vs. 1.4 ng/mL, p = 0.011) and the CSF (S100B: 18.3 vs. 0.9 ng/mL, p = 0.042; enolase: 109.2 vs. 6.1 ng/mL, p = 0.015). Enolase showed the highest level of predictability at 1.8 ng/mL in the blood (AUC of 0.873) and 80.0 ng/mL in the CSF (AUC of 0.889). The predictive ability of S100B was also very good with a threshold of 5.7 ng/mL in the blood (AUC 0.825) and 4.5 ng/mL in the CSF (AUC 0.810). In conclusion, enolase and S100B, but not GFAP, might be suitable as biomarkers for the early prediction of in-hospital mortality after aSAH