Severe Septic Patients Research Articles

Proprotein Convertase Subtilisin Kexin 9 Inhibitor in Severe Sepsis and Septic Shock Patients in a Phase II Prospective Cohort Study—Preliminary Results

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection that has a high mortality rate. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease secreted by the liver. Its binding to the low-density lipoprotein (LDL) receptor enhances its degradation, causing an increase in LDL levels in the blood. Objectives: Administering a PCSK9 inhibitor leading to an increase in lipid uptake by the liver may positively affect septic patients due to the increased removal of endotoxins. Methods: This preliminary study aimed to examine the safety of PCSK9 inhibitor use in septic and septic shock patients. We treated five septic patients in the intensive care unit with 300 mg of alirocumab following serious adverse events for 28 days. Results: Four of our patients did not experience any adverse events, and all of them survived. One patient died after discharge from the intensive care unit, and this death was presumably not related to the study drug. The patients rapidly recovered from the inflammatory stage of sepsis. Conclusions: Alirocumab appears safe in severe sepsis and septic shock patients. The outcome data are promising. Only a basic safety profile can be assessed based on this pilot study. Further study with a PCSK-9 inhibitor in septic or septic shock patients is required to further determine its benefit in ICU patients.

The beneficial effects of neutrophil elastase inhibitor on gastrointestinal dysfunction in sepsis.

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.

Antimicrobial therapy in severe septic ICU major burn patients to combat bacterial resistance by pharmacokinetic-pharmacodymamics of vancomycin, meropenem, and piperacillin, cultures, and inflammatory biomarkers

Antimicrobial therapy in severe septic ICU major burn patients to combat bacterial resistance by pharmacokinetic-pharmacodymamics of vancomycin, meropenem, and piperacillin, cultures, and inflammatory biomarkers

Effects of High-Dose Selenium on Mortality of Sepsis and Septic Shock Patients with Severe Selenium Deficiency in Taiwan

The relationship between serum selenium levels and mortality was investigated in septic patients with severe selenium deficiency (baseline selenium ≤ 80 ng/mL). Eligible patients of sepsis or septic shock were randomized to receive Placebo or High-Dose Selenium (1,000 μg/day) via intravenous injection. Safety, serum selenium, mortality, SOFA, and Glasgow Coma Scale (GCS) scores were monitored. Among all 330 subjects, 27.9% subjects (n=92) had severe selenium deficiency (mean serum selenium = 66.5 ng/mL). Mortality of severe selenium deficiency patients was 27.2%, significantly higher than 17.9% of all subjects. In severe selenium deficiency Placebo group (n=45), 62% subjects showed gradual increase of selenium levels to ~110 ng/mL (mortality ~21.4%), while 38% subjects remained at low selenium ≤ 110 ng/mL throughout study (mortality ~41.2%). Mortality for Placebo subjects with normal baseline selenium ≥ 110 ng/mL was 13.6%. With High-Dose Selenium treatment, 91% of severe selenium deficiency subjects showed quick selenium increase to ~110 ng/mL (mortality 25.5%). Mortality was reduced to 8.6% for High-Dose Selenium subjects with baseline selenium ≥ 110 ng/mL. The odds ratio showed significantly greater survival of High-Dose Selenium subjects with baseline selenium ≥ 110 ng/mL (91.4%) than severe selenium deficiency Placebo subjects (74.1%). Mean baseline SOFA scores for severe selenium deficiency patients were 9.1–9.4, decrease of SOFA scores in High-Dose Selenium subjects was significantly greater than Placebo subjects, along with significant improvement of GCS scores. Repeated infusion of High-Dose Selenium in severe selenium deficiency patients for 14 days was safe and well-tolerated. Mortality for patients with sepsis was clearly affected by serum selenium concentrations. High mortality (41–50%) was observed in the sepsis patients constantly with low selenium £ 80 ng/mL; mortality was reduced to 21–23% if their serum selenium could be increased to ≥ 110 ng/mL. High-Dose Selenium resulted in rapid restoration of serum selenium and improved the survival of severe selenium deficiency septic patients. Low mortality (9–14%) was observed in the sepsis patients starting with baseline selenium ≥ 110 ng/mL. Overall this study demonstrates the significant impact of insufficient selenium levels on the mortality of septic patients. Treatment with high-dose selenium reduced the mortality of severe selenium deficiency septic subjects.

Thrombopoietin levels in sepsis and septic shock-a systematic review and meta-analysis.

Sepsis is a life-threatening condition implicating an inadequate activation of the immune system. Platelets act as modulators and contributors to immune processes. Indeed, altered platelet turnover, thrombotic events, and changes in thrombopoietin levels in systemic inflammation have been reported, but thrombopoietin-levels in sepsis and septic-shock have not yet been systematically evaluated. We therefore performed a meta-analysis of thrombopoietin (TPO)-levels in patients with sepsis. Two independent reviewers screened records and full-text articles for inclusion. Scientific databases were searched for studies examining thrombopoietin levels in adult sepsis and septic-shock patients until August 1st 2022. Of 95 items screened, six studies met the inclusion criteria, including 598 subjects. Both sepsis and severe sepsis were associated with increased levels of thrombopoietin (sepsis vs. control: standardized mean difference 3.06, 95 % CI 1.35-4.77; Z=3.50, p=0.0005) (sepsis vs. severe sepsis: standardized mean difference-1.67, 95 % CI-2.46 to-0.88; Z=4.14, p<0.0001). TPO-levels did not show significant differences between severe sepsis and septic shock patients butdiffered between sepsis and inflammation-associated non-septic controls. Overall, high heterogeneity and low sample size could be noted. Concluding, increased levels of thrombopoietin appear to be present both in sepsis and severe sepsis with high heterogeneity but thrombopoietin does not allow to differentiate between severe sepsis and septic-shock. TPO may potentially serve to differentiate sepsis from non-septic trauma and/or tissue damage related (systemic) inflammation. Usage of different assays and high heterogeneity demand standardization of methods and further large multicenter trials.

Effect of a quality improvement program on compliance to the sepsis bundle in non-ICU patients: a multicenter prospective before and after cohort study.

Sepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a "simplified 1-h bundle" (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU). Emergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort). The effect of QIP on bundle compliance and hospital mortality was evaluated in a before-after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the "simplified rapid (1 h) intervention bundle" (the Sepsis 6 bundle - S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p < 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients' cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate <4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality. A multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality.

α 2 -ADRENORECEPTOR ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION.

Pulmonary fibrosis is an important factor affecting the prognosis of severe septic patients with acute lung injury. The objective of this study was to explore the effect of norepinephrine (NE) and α 2 -adrenoreceptor (AR) on sepsis-associated pulmonary fibrosis and the mechanism underlying these effects. We found pulmonary fibrotic changes, and increased NE production and α 2A -AR expression in the pulmonary tissue of mice subjected to cecal ligation and puncture surgery. Reserpine and yohimbine alleviated pulmonary fibrosis in mice with sepsis by exhausting NE derived from the lung's adrenergic nerve and blocking α 2 -AR, respectively. There was no significant difference in the expression of the three α 1 -AR subtypes. The effect of NE on promoting pulmonary fibroblast differentiation in vitro was suppressed by yohimbine. Both the protein and mRNA expression levels of α 2A -AR were increased in pulmonary fibroblasts treated with LPS. Clonidine, a selective α 2 -AR agonist, enhanced LPS-induced differentiation in pulmonary fibroblasts, as indicated by the increase in α-smooth muscle actin and collagen I/III, which was mitigated by inhibiting PKC and p38. Further in vivo results indicated that yohimbine alleviated pulmonary fibrosis and inhibited the phosphorylation of PKC, p38, and Smad2/3 in lung tissue of mice exposed to LPS for 4 weeks. Clonidine showed the opposite effect to yohimbine, which aggravated LPS-induced pulmonary fibrosis. These findings demonstrated that the sepsis-induced increase in NE promoted fibroblast differentiation via activating α 2 -AR. Blockage of α 2 -AR effectively ameliorated sepsis-associated pulmonary fibrosis by abolishing NE-induced lung fibroblast differentiation and inhibiting the PKC-p38-Smad2/3 pathway.

Systematic Review: Impact of Vitamin C, Hydrocortisone, and Thiamine Therapy on Sepsis and Septic Shock Patients

Systematic Inflammatory Response Syndrome and Sepsis are inflammatory responses to many health manifestations. Sepsis mortality is high despite global treatment standards, with metabolic resuscitation being a novel approach for managing Sepsis. The purpose of this systematic review is to assess the effectiveness of the critical care combination comprising hydrocortisone, Vitamin C, and thiamine in potentially mitigating Sepsis, reducing mortality associated with septic shock, and alleviating organ failure. In order to execute this scoping review, recent research based on the effect of vitamin C, hydrocortisone, and thiamine therapy in Sepsis and Septic Shock was identified. Data was gathered from Google Scholar, PubMed, NCBI, Hindawi, Scirp, Journal of Immunology, and Critical Care Medicine. Studies selected from different years ranging between 2017 to 2023 using keywords ‘Severe Sepsis,’ ‘Septic Shock,’ ‘Effect of Vitamin C on Sepsis, ‘Effect of Thiamine on Sepsis Treatment,’ ‘Hydrocortisone Therapy in Sepsis,’ ‘SIRS,’ ‘Septic Shock Criteria.’ Access was made to the whole texts of the articles that were found. This review could provide fundamental strategic plans dealing with specific risk factors and managing accordingly. The systemic review has been completed according to the guidelines regulated by Preferred Reporting Items for Systemic Research and Meta-Analysis. The initial search for publications on vitamin C, hydrocortisone, and thiamine in Sepsis and septic shock retrieved 1710 papers, from which 265 were selected. The reviews’ articles were further evaluated to assess vitamin C, hydrocortisone, and thiamine’s effects on Sepsis. Over 80 references were considered for their potential use in medical diagnosis and therapy. This review has included ten recent articles for the last seven years. Intravenous vitamin C, corticosteroids, hydrocortisone, and thiamine prevent organ failure, reduce vasopressor use, and decrease mortality in severe Sepsis and septic shock patients.

Combating bacterial resistance to antimicrobials in severe septic ICU patients: importance of meropenem, piperacillin serum monitoring as a dose adjustment and duration of infusion strategies

Combating bacterial resistance to antimicrobials in severe septic ICU patients: importance of meropenem, piperacillin serum monitoring as a dose adjustment and duration of infusion strategies

Combination of transcriptional biomarkers and clinical parameters for early prediction of sepsis indued acute respiratory distress syndrome.

As a common yet intractable complication of severe sepsis, acute respiratory distress syndrome (ARDS) is closely associated with poor clinical outcomes and elevated medical expenses. The aim of the current study is to generate a model combining transcriptional biomarkers and clinical parameters to alarm the development of ARDS in septic patients. Gene expression profile (GSE66890) was downloaded from the Gene Expression Omnibus database and clinical data were extracted. Differentially expressed genes (DEGs) from whole blood leukocytes were identified between patients with sepsis alone and septic patients who develop ARDS. ARDS prediction model was constructed using backward stepwise regression and Akaike Information Criterion (AIC). Meanwhile, a nomogram based on this model was established, with subsequent internal validation. A total of 57 severe septic patients were enrolled in this study, and 28 (49.1%) developed ARDS. Based on the differential expression analysis, six DEGs (BPI, OLFM4, LCN2, CD24, MMP8 and MME) were screened. According to the outcome prediction model, six valuable risk factors (direct lung injury, shock, tumor, BPI, MME and MMP8) were incorporated into a nomogram, which was used to predict the onset of ARDS in septic patients. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. The area under the receiver operating characteristic (AUROC) for the prediction of ARDS occurrence in septic patients by the nomogram was 0.86 (95% CI = 0.767-0.952). A sensitivity analysis showed that the AUROC for the prediction of ARDS development in septic patients without direct lung injury was 0.967 (95% CI = 0.896-1.0). The nomogram based on transcriptional biomarkers and clinical parameters showed a good performance for the prediction of ARDS occurrence in septic patients.

Elevated endothelial dysfunction-related biomarker levels indicate the severity and predict sepsis incidence

This study was conducted to investigate the relationship between serum endothelial dysfunction-related biomarker levels and organ dysfunction severity in septic patients and the predictive value of these levels during sepsis. In total, 105 patients admitted to the Department of Critical Care Medicine were enrolled between September 2020 and November 2021. Serum syndecan-1 and soluble thrombomodulin(sTM) levels were measured by enzyme-linked immunosorbent assay, and clinical and laboratory data were recorded. Enroll patients were divided into the infection (n = 28), septic nonshock (n = 31), and septic shock (n = 46) groups . Serum syndecan-1 (102.84 ± 16.53 vs. 55.38 ± 12.34 ng/ml), and sTM(6.60 ± 1.44 ng/ml vs. 5.23 ± 1.23 ng/ml, P < 0.01) levels were increased in the septic group compared with those in the infection group. Serum syndecan-1 levels were closely positively correlated with serum sTM (rs = 0.712, r2 = 0.507, P < 0.001). Additionally, serum syndecan-1(rs = 0.687, r2 = 0.472, P < 0.001) and sTM levels (rs = 0.6, r2 = 0.36, P < 0.01) levels were significantly positively correlated with the sequential organ failure assessment scores respectively. Syndecan-1 (AUC 0.95 ± 0.02, P < 0.0001) was more valuable for prediction sepsis than was sTM (AUC 0.87 ± 0.04, P < 0.0001). Compared with sTM (AUC 0.88 ± 0.03, P < 0.001), syndecan-1 (AUC 0.95 ± 0.02, P < 0.001) and SOFA score (AUC 0.95 ± 0.02, P < 0.001) were better predictors of septic shock. Serum syndecan-1 and sTM levels were associated with organ dysfunction severity in septic patients, and both were good predictors for early identification of sepsis, particularly in patients undergoing septic shock.

Diagnostic value of early bedside ultrasound measurement of quadriceps femoris on in-hospital mortality of septic patients

To investigate the changes of quadriceps femoris thickness with the length of stay in intensive care unit (ICU) in patients with sepsis, and to evaluate the diagnostic value of muscle changes in mortality. A prospective study was conducted, and 92 patients with sepsis who were admitted to the ICU of the Affiliated Hospital of Jining Medical College from January 2020 to December 2021 were enrolled. The thickness of quadriceps femoris [including the quadriceps femoris muscle thickness at the midpoint of the anterior superior iliac spine and the upper edge of the patella (M-QMLT), and at the middle and lower 1/3 of the patella (T-QMLT)] measured by ultrasound 1 day (D1), 3 days (D3), and 7 days (D7) after admission to the ICU were collected. The atrophy rate of quadriceps femoris was calculated 3 and 7 days after admission to the ICU compared with 1 day [(D3-D1)/D1 and (D7-D1)/D1, (TD3-TD1)/TD1 and (TD7-TD1)/TD1, respectively]. The demographic information, underlying diseases, vital signs when admission to the ICU and in-hospital mortality of all patients were recorded, and the differences of the above indicators between the two groupswere compared. Multivariate Logistic regression was used to analyze the influence of quadriceps femoris muscle thickness and atrophy rate on in-hospital mortality of septic patients. The receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of quadriceps femoris muscle thickness and atrophy rate on in-hospital mortality of septic patients. A total of 92 patients with severe sepsis were included, of which 41 patients died in hospital, 51 patients discharged. The in-hospital mortality was 44.6%. The muscle thickness of quadriceps femoris in severe septic patients decreased with the prolongation of ICU stay, and there was no significant difference between the two groups at the first and third day of ICU admission. The muscle thickness of quadriceps femoris at different measuring positions in the survival group was significantly greater than those in the death group 7 days after admission to the ICU [M-QMLT D7 (cm): 0.50±0.26 vs. 0.39±0.19, T-QMLT D7 (cm): 0.58±0.29 vs. 0.45±0.21, both P < 0.05]. The atrophy rate of quadriceps femoris muscle thickness at different measuring positions 3 and 7 days after admission to ICU in the survival group was significantly lower than those in the death group [(D3-D1)/D1: (8.33±3.44)% vs. (9.74±3.91)%, (D7-D1)/D1: (12.21±4.76)% vs. (19.80±6.15)%, (TD3-TD1)/TD1: (7.83±4.26)% vs. (10.51±4.75)%, (TD7-TD1)/TD1: (11.10±5.46)% vs. (20.22±6.05)%, all P < 0.05]. Multivariate Logistic regression analysis showed that M-QMLT D7, T-QMLT D7, (D3-D1)/D1, (D7-D1)/D1, (TD3-TD1)/TD1, (TD7-TD1)/TD1 were independent risk factors for in-hospital mortality (all P < 0.05). The results were stable after adjusting for confounding factors. ROC curve analysis showed that (TD7-TD1)/TD1 [area under the ROC curve (AUC) was 0.853, 95% confidence interval (95%CI) was 0.773-0.934] was superior to (D7-D1)/D1, T-QMLT D7, M-QMLT D7, (TD3-TD1)/TD1 and (D3-D1)/D1 [AUC was 0.821 (0.725-0.917), 0.692 (0.582-0.802), 0.683 (0.573-0.794), 0.680 (0.569-0.791), 0.622 (0.502-0.742)]. For septic patients in ICU, bedside ultrasound monitoring of quadriceps femoris muscle thickness and atrophy rate has a certain predictive value for in-hospital mortality, and a certain guiding significance in clinical treatment and predicting the prognosis of sepsis.

80 Identifying Positive Deviant Nurses in the Speed of Administering Antibiotics for Sepsis and Discovering Their Tactics

Positive deviance (PD) is an application of complexity leadership theory that fosters organizational learning of difficult tasks. PD may also be able to avoid the increased burnout associated with the top-down management tactics of traditional quality improvement (QI). We assessed whether PD may be an appropriate strategy to improve sepsis care by testing for the presence of heterogeneity in nursing antibiotic administration time (AAT) for severe sepsis or septic shock patients and identifying the positive deviant nurses.

Prognostic significance of non-thyroidal illness syndrome in sepsis and septic shock cases: a systematic review and meta-analysis

Background: This study aimed to assess non-thyroidal illness syndrome (NTIS) as a prognostic determinant in patients with sepsis, severe sepsis, and septic shock by evaluating thyroid hormone (TH) levels.&#x0D; Methodology: A systematic search was performed through electronic databases including PubMed, Embase, Scopus, and Medline. Following medical subject headings (MeSH) and free-text terms: "euthyroid sick syndrome" or "Euthyroid Sick Syndromes" or "non–thyroidal illness syndrome" or "non–thyroidal illness syndrome" or "sick euthyroid syndrome" or "low T3 syndrome" or "low tri-iodothyronine syndrome" AND "sepsis" or "septic shock" or "systemic inflammatory response syndrome" or "septicemia" or "bacteremia". Boolean operators’ combinations were applied to broaden and narrow the search results. Investigators independently reviewed the search results. For the purpose of the meta-analysis each thyroid hormone level was converted into the same unit: nmol/L for T3, T4 and rT3; μIU/mL for TSH; and pmol/L for fT3 and fT4. Statistical analysis was performed using Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC.&#x0D; Results: A total of 843 patients from 9 studies were included in this analysis. In septic patients, the lowest effect size of thyroid function parameter was TSH (g = 2.05; 95% CI = 1.56-2.54), while T3, fT3, and fT4 had the lowest effect size in severe septic patients (g [95%CI]: 0.83 [0.22-1.44]; 1.92 [0.57-3.27]; 1.00 [0.87-1.13]). Patients with septic shock had the highest effect size of TSH (g = 2.08; 95% CI = 1.54-2.61) and fT4 (g = 9.26; 95% CI = 0.98-17.53). Meanwhile, the lowest was T4 (g = 65.60; 95% CI = 64.63-66.57) and rT3 (g = 0.29; 95% CI = 0.24-0.34). A lower effect size of T3 (g = 0.83; 95% CI = 0.76-0.91), T4 (g = 59.48; 95% CI = 57.92-61.04), fT3 (g = 2.25; 95% CI = 1.83-2.66), and fT4 (g = 9.19; 95% CI = 1.56-16.81) were found in non-survivor groups.&#x0D; Conclusion: Thyroid hormone levels differ according to the severity of sepsis in septic patients. Non-thyroidal illness syndrome is a prognostic factor in septic patients and is associated with the risk of the mortality.&#x0D; Abbreviations: ESS - Euthyroid Sick Syndrome; NTIS - Non-Thyroidal Illness Syndrome; Tg - Thyroglobulin&#x0D; Key words: Non-thyroidal illness syndrome; Euthyroid sick syndrome; Sepsis; Septic shock; Prognosis&#x0D; Citation: Wironegoro R, Kloping NA, Witarto AP, Nugraha D, Yogiswara N, Luke K, KlopingYP, Maulydia M, Adi S. Prognostic significance of non-thyroidal illness syndrome in sepsis and septic shock cases: a systematic review and meta-analysis. Anaesth. pain intensive care 2021;26(1):54-62.&#x0D; DOI: 10.35975/apic.v26i1.1768&#x0D; Received: July 16, 2021, Reviewed: December 15, 2021, Accepted: December 28, 2021

Clinical outcomes of severe sepsis and septic shock patients with left ventricular dysfunction undergoing continuous renal replacement therapy

Baseline left ventricular (LV) dysfunction is associated with subsequent risks of acute kidney injury (AKI) and mortality in patients with sepsis. This study investigated the therapeutic effects of continuous renal replacement therapy (CRRT) in hemodynamically unstable patients with severe sepsis and septic shock combined with LV dysfunction. In this multicenter retrospective study, severe sepsis and septic shock patients with LV dysfunction were classified into one of two groups according to the timing of CRRT: the early group (before AKI was detected) or the control group (patients with AKI). Patients from the control group received an accelerated strategy or a standard strategy of CRRT. The primary outcome was all-cause intensive care unit (ICU) mortality. Patients were weighted by stabilized inverse probability of treatment weights (sIPTW) to overcome differences in baseline characteristics. After sIPTW analysis, the ICU mortality was significantly lower in the early group than the control group (27.7% vs. 63.5%, p < 0.001). Weighted multivariable analysis showed that early CRRT initiation was a protective factor for the risk of ICU mortality (OR 0.149; 95% CI 0.051–0.434; p < 0.001). The ICU mortality was not different between the accelerated- and standard-strategy group (52.5% vs. 52.9%, p = 0.970). Early CRRT in the absence of AKI is suggested for hemodynamically unstable patients with severe sepsis and septic shock combined with LV dysfunction since it benefits survival outcomes.

Correlation of the Changing Trends of ScvO2, Serum Lactate, Standard Base Excess and Anion Gap in Patients with Severe Sepsis and Septic Shock Managed by Early Goal Directed Therapy (EGDT): A Prospective Observational Study.

To observe the correlation of central venous oxygen saturation (ScvO2), serum lactate, standard base excess (SBE), and anion gap (AG) in septic and septic shock patients resuscitated with early goal-directed therapy (EGDT). A review was made of 130 severe septic shock patients (15-65 years) according to the consensus conference criteria admitted in intensive care unit. Blood samples were obtained from arterial and central venous line for ScvO2, serum lactate, SBE, and AG on admission and after achieving all aims of EGDT i.e.; mean arterial pressure >65 mmHg, central venous pressure = 8-12 mmHg, ScvO2 >70%, and urine output >0.5 mL.kg-1.h-1, and on 12 and 24 h. The statistical analysis was done using SPSS for windows version 16 software. For comparison, Pearson test was used. A P < 0.05 was considered as statistically significant. There were a positive correlation between ScvO2 and SBE, a negative correlation between ScvO2 and AG, a negative correlation between ScvO2 and lactate, a negative correlation between SBE and AG, a negative correlation between AG and lactate, and a negative correlation between SBE and lactate. The ScvO2 was initially low but was in an improving trend after a resuscitative period, SBE was initially low and correction of SBE was linear. AG was high in the beginning and goes on decreasing after resuscitation. Lactate level was also high initially and in decreasing trend after a resuscitative period. ScvO2 and SBE are correlated and can be used as a surrogate marker. ScvO2 and AG are related but not absolutely codependent. ScvO2 and lactate are correlated but they are not absolutely codependent. SBE and AG are correlated and can be used as a surrogate marker. AG and lactate are not related to each other. Hence, AG cannot be considered as a surrogate for lactate testing. SBE and lactate are related and can be used as a surrogate marker.

Resistin production does not affect outcomes in a mouse model of acute surgical sepsis.

Because of the strong correlation between the blood concentration of circulating resistin and the illness severity of septic patients, resistin has been proposed as a mediator of sepsis pathophysiology. In vitro data indicate that human resistin directly impairs neutrophil migration and intracellular bacterial killing, although the significance of these findings in vivo remain unclear. The objectives of the present study were: (1) to validate the expression of human resistin in a clinically relevant, murine model of surgical sepsis, (2) to assess how sepsis-induced changes in resistin correlate with markers of infection and organ dysfunction, and (3) to investigate whether the expression of human resistin alters immune function or disease outcomes in vivo. 107 male, C57BL/6 mice transgenic for the human resistin gene and its promoter elements (Retn+/-/-, or Retn+) were generated on a Retn-/- (mouse resistin knockout, or Rko) background. Outcomes were compared between age-matched transgenic and knockout mice. Acute sepsis was defined as the initial 24 h following cecal ligation and puncture (CLP). Physiologic and laboratory parameters correlating to the human Sequential Organ Failure Assessment (SOFA) Score were measured in mice, and innate immune cell number/function in the blood and peritoneal cavity were assessed. CLP significantly increased circulating levels of human resistin. The severity of sepsis-induced leukopenia was comparable between Retn+ and Rko mice. Resistin was associated with increased production of neutrophil reactive oxygen species, a decrease in circulating neutrophils at 6 h and an increase in peritoneal Ly6Chi monocytes at 6 h and 24 h post-sepsis. However, intraperitoneal bacterial growth, organ dysfunction and mouse survival did not differ with resistin production in septic mice. Ex vivo resistin-induced impairment of neutrophil function do not appear to translate to increased sepsis severity or poorer outcomes in vivo following CLP.

Influence of hypomagnesemia on the prognosis of severe septic patients

To investigate the influence of hypomagnesemia on the prognosis of patients with severe sepsis. A retrospective study was conducted. The clinical data of 207 septic patients admitted to the department of critical care medicine of the First Affiliated Hospital of University of Science and Technology of China from January 1, 2016 to December 21, 2020 were analyzed, including gender, age and laboratory indicators within 24 hours after sepsis diagnosis [procalcitonin (PCT), C-reactive protein (CRP), blood lactic acid (Lac), pH value and blood magnesium, calcium, chlorine and phosphorus levels]. The acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score and 28-day prognosis were collected. The patients were divided into survival group and non-survival group according to the prognosis, and the clinical data and laboratory indexes were compared between the two groups. Pearson correlation test was used to analyze the correlation between clinical indicators. Multivariate Logistic regression analysis was used to screen the risk factors affecting the prognosis. The receiver operator characteristic curve (ROC curve) was drawn, and the area under ROC curve (AUC) was calculated to evaluate the potential prognostic indicators. Among the 207 septic patients, 102 survived and 105 died on the 28th day, and the 28-day mortality was 50.72%. There were no significant differences in gender, age, CRP, pH value, blood chlorine or blood phosphorus levels between the two groups. The blood magnesium and blood calcium levels in the non-survival group were significantly lower than those in the survival group [blood magnesium (mmol/L): 0.68±0.14 vs. 0.80±0.12, blood calcium (mmol/L): 1.93±0.21 vs. 2.01±0.20, both P > 0.01], and PCT, Lac, APACHE II score and SOFA score were significantly higher than those in the survival group [PCT (mg/L): 8.32 (1.64, 55.01) vs. 3.55 (0.97, 12.31), Lac (mmol/L): 2.90 (1.70, 4.30) vs. 2.10 (1.03, 3.89), APACHE II score: 21.24±6.40 vs. 17.42±7.02, SOFA score: 9.14±3.55 vs. 6.91±3.31, all P > 0.01]. Among the 207 patients, 96 patients had normal blood magnesium level (0.75-1.25 mmol/L) and 111 patients had hypomagnesemia (> 0.75 mmol/L). The 28-day mortality of septic patients in the hypomagnesemia group was significantly higher than that in the normal magnesium group [61.26% (68/111) vs. 38.54% (37/96), P < 0.01]. Pearson correlation analysis showed that the blood magnesium level of sepsis patients was negatively correlated with PCT (r = -0.173, P < 0.05), and it was positively correlated with APACHE II score (r = 0.159, P < 0.05), but it had no correlation with CRP or SOFA score (r values were -0.029 and 0.091, both P > 0.05). Logistic regression analysis showed that serum magnesium, APACHE II score and SOFA score were independent risk factors for 28-day death in patients with sepsis [serum magnesium: odds ratio (OR) < 0.001, 95% confidence interval (95%CI) was 0.000-0.002, P < 0.001; APACHE II score: OR = 1.092, 95%CI was 1.022-1.168, P = 0.010; SOFA score: OR = 1.168, 95%CI was 1.026-1.330, P = 0.019]. ROC curve analysis showed that blood magnesium and APACHE II score had a certain predictive value for 28-day mortality in patients with severe sepsis [AUC (95%CI) was 0.723 (0.655-0.791) and 0.680 (0.607-0.754), respectively]. When the blood magnesium threshold was 0.64 mmol/L, the sensitivity was 41.0% and the specificity was 93.1%. When APACHE II score threshold was 16.50, the sensitivity was 78.1% and the specificity was 55.9% indicating that the specificity of serum magnesium was higher than that of APACHE II score. Severe septic patients complicated with hypomagnesemia have a poor prognosis. Serum magnesium level can be used as a prognostic indicator for severe septic patients.

Accuracy of pulse pressure variations for fluid responsiveness prediction in mechanically ventilated patients with biphasic positive airway pressure mode.

The accuracy of pulse pressure variation (PPV) to predict fluid responsiveness using pressure-controlled (PC) instead of volume-controlled modes is under debate. To specifically address this issue, we designed a study to evaluate the accuracy of PPV to predict fluid responsiveness in severe septic patients who were mechanically ventilated with biphasic positive airway pressure (BIPAP) PC-ventilation mode. 45 patients with sepsis or septic shock and who were mechanically ventilated with BIPAP mode and a target tidal volume of 7-8ml/kg were included. PPV was automatically assessed at baseline and after a standard fluid challenge (Ringer's lactate 500ml). A 15% increase in stroke volume (SV) defined fluid responsiveness. The predictive value of PPV was evaluated through a receiver operating characteristic (ROC) curve analysis and "gray zone" statistical approach. 20 (44%) patients were considered fluid responders. We identified a significant relationship between PPV decrease after volume expansion and SV increase (spearman ρ = -0.5, p < 0.001). The area under ROC curve for PPV was 0.71 (95%CI 0.56-0.87, p = 0.007). The best cut-off (based on Youden's index) was 8%, with a sensitivity of 80% and specificity of 60%. Using a gray zone approach, we identified that PPV values comprised between 5 and 15% do not allow a reliable fluid responsiveness prediction. In critically ill septic patients ventilated under BIPAP mode, PPV appears to be an accurate method for fluid responsiveness prediction. However, PPV values comprised between 5 and 15% constitute a gray zone that does not allow a reliable fluid responsiveness prediction.

9 Are There Positive Deviant Providers in the Speed of Ordering Antibiotics for Sepsis?

Positive deviance (PD) is an application of complexity leadership theory that fosters organizational learning of difficult tasks. PD may also be able to avoid the increased burnout associated the top-down management tactics of traditional quality improvement (QI). We assessed whether PD may be an appropriate strategy to improve sepsis care by testing for the presence of heterogeneity in provider antibiotic ordering time (AOT) for severe sepsis or septic shock patients and identifying the positive deviant providers. We included all patients with severe sepsis or septic shock who presented to the University of Kansas Emergency Department over a 7-month period (September 2020 to March 2021), were cared for by categorical emergency medicine residents, and each member of the care team (resident physician, attending physician, and nurse) cared for at least three patients during the study period. First, we measured the percent heterogeneity (I2) of AOTs with separate random effects analyses for each personnel type (resident physician, attending physician, and nurse) on the patients’ health care teams. Then, the positive deviant personnel were identified as the individuals whose mean AOT and confidence interval were faster than the mean AOT for their personnel type. The results of the first analysis were displayed in forest plots. Second, to assess the contributions of each personnel type to the AOT, we performed regression analyses to measure the percent of variance (R2) of the AOTs attributable to each personnel type. The regression analyses were weighted by the inverse of the variance of the AOTs for each member of the patients’ care teams. The incremental contribution of each personnel type was measured by regression of their AOTs with the residual times of the regression of the dominant personnel. 371 patients were included. Random effects analyses showed statistically significant heterogeneity with “moderate” I2 values of 42%, 58%, and 32% for the residents, nurses, and attendings, respectively. There were 3, 6, and 2 positive deviants, respectively. Regression found that the residents, nurses, and attendings all made statistically significant contributions to the variation in AOT with percent R2s of 0.9%, 0.3%, and 0.3%, respectively. Regression of residuals showed significant, independent effects of the residents and nurses. The contributions to the variations are much higher when all ordering providers are studied (60.2% for ordering provider and 42.5% for nurse) We noted heterogeneity in mean AOT across both resident and attending physicians. In addition, the AOT for a given patient was associated with AOTs of other cases managed by the same care team. Within each personnel type, some providers on average demonstrated quicker AOTs compared to peers. Considering the practice environment is constant, the heterogeneity in mean AOT suggests differences in practice patterns. These results support the role of a positive deviance approach to QI with focus on the residents and nurses in identifying and disseminating best tactics within our emergency department.