Proinflammatory Cytokine Levels in Sepsis and in Health and TNFα Association with Sepsis Mortality and patient characteristics: a Systematic Review and Meta-analysis

Background: Sepsis is a global health problem associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to a "cytokine storm." However, anti-cytokine therapies have failed to lower sepsis mortality. We aim to characterize levels of key cytokines in sepsis patients and healthy controls and relate TNFα levels to patient characteristics and outcomes. Methods: We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1985 to May 2020 for studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy persons. Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800). Findings: We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8-85.8 pg/ml) and 5.5 pg/ml (95% CI 3.8-8.0 pg/ml) in healthy controls. Pooled estimate means for IL-1β and IFNγ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNFα concentrations associated with increased 28-day sepsis mortality (p=0.001). In subgroup analyses, TNFα levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. Interpretation: TNFα concentration in sepsis is increased approximately 10-fold compared to healthy persons, and TNFα associated with sepsis mortality but not with sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data.

Correlation of Platelet-Lymphocyte Ratio (PLR) as 28-Days Sepsis Mortality Predictor in Intensive Care Unit of RSMH Palembang

Introduction. Inflammatory and anti-inflammatory response are important in pathophysiology and mortality of sepsis. Platelet as first line inflammatory marker was found increasing during early phase of infection. Decrease in lymphocyte was caused by disrupted balance between inflammatory and anti-inflammatory response. Platelet-to- lymphocyte ratio (PLR) is a cheap and accessible biomarker of sepsis mortality. This study aims to find the sensitivity and specificity of PLR as mortality predictor of sepsis in 28 days. Methods. This observational analytic study with retrospective cohort design was conducted to 91 sepsis patients in intensive care unit of Dr. Mohammad Hoesin Palembang Central Hospital between January and December 2019. Samples were secondarily collected from medical record during June-July 2020. Data was analyzed using chi-square test, cog regression test, and ROC curve analysis. Results. The result found 50 patients (54,9%) died in 28 days. Morbidity score (Charlson) was the only statistically significant mortality parameter (p=0,009). The study reported PLR cut-off point of >272,22. The sensitivity and specificity of PLR as 28-days sepsis mortality predictor are 84% and 80,49% respectively. Conclusion. PLR is alternatively reliable mortality predictor in sepsis patient, accounted to its relatively high sensitivity and specificity.

1003. Cytokine Levels in Sepsis and TNFα Association with Mortality but not Sepsis Severity or Infection Source: a Systematic Review and Meta-analysis

Background Sepsis is a global health problem associated with significant morbidity and mortality and is attributed to a “cytokine storm.”. However, anti-cytokine therapies have failed to lower sepsis mortality in clinical trials. Linking cytokine excess to sepsis pathogenesis requires quantification of cytokine levels in sepsis. This systematic review and meta-analysis characterizes levels of key cytokines in the circulation of sepsis patients and relates TNFα levels to mortality and patient characteristics. Methods Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1946 to May 2020 for studies in English disclosing cytokine levels in sepsis. Keywords included sepsis, septic shock, purpura fulminans, and tumor necrosis factor (TNF)α. We related cytokine amounts to 28-day mortality. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). This systematic review is registered in PROSPERO under number CRD42020179800. Results A total of 3656 records were identified. After exclusions, 103 studies were included. Among these studies, 72 disclosed TNFα levels, 25 showed interleukin (IL)-1β levels, and 6 presented interferon (IFN)γ levels. The pooled estimate mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% CI, 39.8-85.8 pg.ml; I2 = 99.4%). Pooled estimate means for IL-1α and IFNγ in sepsis patients were 21.8 pg/ml (95% CI, 12.6-37.8 pg.ml; I2 =99.8%) and 63.3 pg/ml (95% CI, 19.4-206.6 pg/ml; I2 = 99.7%), respectively. Elevated TNFα concentrations were associated with increased 28-day mortality (P=0.001). In a subgroup analysis, TNFα levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score (figure 1). In a metaregression, TNFα associated with age, percentage of females and mortality at 28 days. Figure 1: A: TNFa levels according to sepsis source. B: TNFa levels according to measurement technique. C: TNFa levels according to presence or absence of cardiovascular disease. D: TNFa levels according to presence or absence of malignancy. E: TNFa levels according to sepsis severity. F: TNFa levels in fungal compared to other causes of sepsis (Yes=fungal sepsis; No= Other types of sepsis). G: TNFa levels according to SOFA score. H: TNFa levels and mortality at 28 days. Conclusion We presented levels of TNFα, IL-1β, and IFNγ in human sepsis and showed that TNFα elevations are associated with sepsis mortality. TNFα concentrations did not correlate with sepsis severity. We believe the concept that elevated cytokines cause sepsis should be revisited in the context of these data. Disclosures All Authors: No reported disclosures

Heart rate n-variability (HRnV) measures for prediction of mortality in sepsis patients presenting at the emergency department

Sepsis is a potentially life-threatening condition that requires prompt recognition and treatment. Recently, heart rate variability (HRV), a measure of the cardiac autonomic regulation derived from short electrocardiogram tracings, has been found to correlate with sepsis mortality. This paper presents using novel heart rate n-variability (HRnV) measures for sepsis mortality risk prediction and comparing against current mortality prediction scores. This study was a retrospective cohort study on patients presenting to the emergency department of a tertiary hospital in Singapore between September 2014 to April 2017. Patients were included if they were above 21 years old and were suspected of having sepsis by their attending physician. The primary outcome was 30-day in-hospital mortality. Stepwise multivariable logistic regression model was built to predict the outcome, and the results based on 10-fold cross-validation were presented using receiver operating curve analysis. The final predictive model comprised 21 variables, including four vital signs, two HRV parameters, and 15 HRnV parameters. The area under the curve of the model was 0.77 (95% confidence interval 0.70–0.84), outperforming several established clinical scores. The HRnV measures may have the potential to allow for a rapid, objective, and accurate means of patient risk stratification for sepsis severity and mortality. Our exploration of the use of wealthy inherent information obtained from novel HRnV measures could also create a new perspective for data scientists to develop innovative approaches for ECG analysis and risk monitoring.

Effective continuing interprofessional healthcare education to improve sepsis care in a tertiary children and women’s hospital in the State of Qatar “Culture of think sepsis”

Background: Sepsis is a medical emergency and a global economic and health burden. It is one of the leading causes of death worldwide with 1 death every 2.8 seconds and represents 20% of all deaths worldwide. Sidra Medicine, the only pediatric tertiary care centre in the State of Qatar, in collaboration with Qatar’s Ministry of Public Health, Hamad Medical Corporation (HMC), and Hamad Healthcare Improvement Institute (HHQI) share the national goal of reducing mortality due to sepsis and septic shock through an increase in healthcare provider compliance to the sepsis six bundle of care from 0% to 95% by the end of 2022. Methods: A multifaceted, interdisciplinary, comprehensive education and training program was designed and provided to healthcare practitioners across Sidra and comprised: • Pre-implementation education • Multidisciplinary education sessions and workshops • Train-the-trainer nurse educator workshop • Bedside interdisciplinary simulation-based education • Sepsis case discussions during morning reports, academic activities, grand rounds, and morbidity and mortality meetings • Annual Qatar National Sepsis Symposium • September Sepsis-Awareness Month • Pediatric and women sepsis e-learning module • National Patient Safety Collaborative (NPSC) training sessions and storyboards in collaboration with the Institute for Healthcare Improvement (IHI) and HHQI In addition, sepsis pathway posters, think-sepsis booklets and pocket cards, antibiotic preparation and administration cards, and family education materials in Arabic and English were produced and utilized. Results: Improved sepsis awareness and education was observed. 95% of providers successfully completed the e-learning module. Compliance to the sepsis six bundle of care subsequently reached 81%. Sepsis mortality rate was 1.8% in the first two quarters of 2020 which is well below international mortality rates. Conclusion: Since 2018, Sidra Medicine embraced sepsis education and care through a national evidence-based sepsis guideline for early recognition and treatment which is positively reflected in low sepsis mortality rates for 2020.

Type 2 Diabetic Sepsis Patients Have a Lower Mortality Rate in Pioglitazone Use: A Nationwide 15-Year Propensity Score Matching Observational Study in Taiwan

Background. Pioglitazone use via the PPARγ agonist in sepsis patients is inconclusive. It was based on a great number of animal studies. However, except for information from animal studies, there are merely any data of human studies for reference. Methods. This study was conducted by a unique database including 1.6 million diabetic patients. From 1999 to 2013, a total of 145,327 type 2 diabetic patients, first admitted for sepsis, were enrolled. Propensity score matching was conducted in a 1 : 5 ratio between pioglitazone users and nonusers. Multivariate logistic regression was conducted to evaluate the adjusted odds ratios (aORs) of hospital mortality in pioglitazone users. Further stratification analysis was done and Kaplan–Meier plot was used. Results. A total of 9,310 sepsis pioglitazone users (defined as “ever” use of pioglitazone in any dose within 3 months prior to the first admission for sepsis) and 46,550 matched nonusers were retrieved, respectively. In the multivariate logistic regression model, the cohort of pioglitazone users (9,310) had a decreased aOR of 0.95 (95% CI, 0.89–1.02) of sepsis mortality. Further stratification analysis demonstrated that “chronic pioglitazone users” (defined as “at least” 4-week drug use within 3 months) (3,399) were more associated with significant aOR of 0.80 (95% CI, 0.72–0.89) in reducing sepsis mortality. Conclusions. This first human cohort study demonstrated the potential protective effect of chronic pioglitazone use in type 2 diabetic sepsis patients.