Septic Adults Research Articles

Association between base excess and mortality in septic older adults.

Septic older adults represent a vulnerable population with high mortality rates. Base excess (BE), an indicator of acid-base status, may serve as a prognostic marker in sepsis. This study aimed to investigate the association between BE and mortality in septic older adults. A retrospective analysis included septic older adults (age ≥ 65 years) from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was 30-day mortality. Multivariate Cox regression models and Kaplan-Meier analysis were used to assess the association between BE and 30-day mortality. A two-segment linear regression model with smooth curve fitting was employed to examine threshold effects of BE on clinical outcomes. The study comprised 7379 participants, with a 21.8% 30-day mortality rate and an 18.6% in-hospital mortality rate. A nonlinear, U-shaped relationship (P < 0.001) was observed between BE and 30-day mortality in septic older adults, indicating increased risk with higher or lower BE levels. Various BE groups showed different hazard ratios for mortality: 2.7 (2.26-3.22), 1.86 (1.65-2.09), 1.41 (1.19-1.67), and 1.9 (1.4-2.58), respectively, compared with the reference group (-3 mEq/L ≤ BE < 3 mEq/L). The inflection point was calculated as 0.5 mEq/L. Our findings suggest a U-shaped relationship between BE and mortality in septic older adults, emphasizing the importance of monitoring acid-base status in sepsis management for this population. Geriatr Gerontol Int 2025; ••: ••-••.

Development and validation of an interpretable machine learning for mortality prediction in patients with sepsis.

Sepsis is a leading cause of death. However, there is a lack of useful model to predict outcome in sepsis. Herein, the aim of this study was to develop an explainable machine learning (ML) model for predicting 28-day mortality in patients with sepsis based on Sepsis 3.0 criteria. We obtained the data from the Medical Information Mart for Intensive Care (MIMIC)-III database (version 1.4). The overall data was randomly assigned to the training and testing sets at a ratio of 3:1. Following the application of LASSO regression analysis to identify the modeling variables, we proceeded to develop models using Extreme Gradient Boost (XGBoost), Logistic Regression (LR), Support Vector Machine (SVM), and Random Forest (RF) techniques with 5-fold cross-validation. The optimal model was selected based on its area under the curve (AUC). Finally, the Shapley additive explanations (SHAP) method was used to interpret the optimal model. A total of 5,834 septic adults were enrolled, the median age was 66 years (IQR, 54-78 years) and 2,342 (40.1%) were women. After feature selection, 14 variables were included for developing model in the training set. The XGBoost model (AUC: 0.806) showed superior performance with AUC, compared with RF (AUC: 0.794), LR (AUC: 0.782) and SVM model (AUC: 0.687). SHAP summary analysis for XGBoost model showed that urine output on day 1, age, blood urea nitrogen and body mass index were the top four contributors. SHAP dependence analysis demonstrated insightful nonlinear interactive associations between factors and outcome. SHAP force analysis provided three samples for model prediction. In conclusion, our study successfully demonstrated the efficacy of ML models in predicting 28-day mortality in sepsis patients, while highlighting the potential of the SHAP method to enhance model transparency and aid in clinical decision-making.

The association between body mass index and mortality in septic older adults

BackgroundThere is limited evidence on the association between body mass index (BMI) and outcomes in older adults with sepsis. ObjectivesThe purpose of this study was to explore the relationship between BMI and the clinical outcome in the older adults with sepsis. MethodsAll older adults (age 65 or older) with sepsis were analyzed retrospectively in the Intensive Care Medical Information Mart (MIMIC)- IV database. The primary outcome was 30-day mortality. The relationship between BMI and 30-day mortality was estimated by multivariate logistic regression model. The interaction and stratified analysis were performed by sex, race, renal disease, congestive heart failure (CHF), diabetes, and chronic pulmonary disease. ResultsThe total number of participants was 6604. After adjustment for potential covariates, there was a significant correlation between BMI and 30-day mortality. A 1 kg/m2 increase in BMI was associated with a 3 % decrease in 30-day mortality (adjusted HR = 0.97, 95 % CI: 0.96–0.98, P < 0.001). The correlation between BMI and 30-day mortality showed a statistically significant nonlinear association with an l-shaped curve (p = 0.001). Significant interactions were observed only for sex in the stratified analyses (P = 0.001). ConclusionsIn this study, it was observed that a higher BMI is linked with better survival rates among older adults suffering from sepsis, while being underweight raises the risk of mortality. Notably, male patients with a higher BMI had a lower mortality risk compared to female patients.

Estimated Cerebral Perfusion Pressure and Intracranial Pressure in Septic Patients.

Sepsis-associated brain dysfunction (SABD) is frequent and is associated with poor outcome. Changes in brain hemodynamics remain poorly described in this setting. The aim of this study was to investigate the alterations of cerebral perfusion pressure and intracranial pressure in a cohort of septic patients. We conducted a retrospective analysis of prospectively collected data in septic adults admitted to our intensive care unit (ICU). We included patients in whom transcranial Doppler recording performed within 48h from diagnosis of sepsis was available. Exclusion criteria were intracranial disease, known vascular stenosis, cardiac arrhythmias, pacemaker, mechanical cardiac support, severe hypotension, and severe hypocapnia or hypercapnia. SABD was clinically diagnosed by the attending physician, anytime during the ICU stay. Estimated cerebral perfusion pressure (eCPP) and estimated intracranial pressure (eICP) were calculated from the blood flow velocity of the middle cerebral artery and invasive arterial pressure using a previously validated formula. Normal eCPP was defined as eCPP ≥ 60mmHg, low eCPP was defined as eCPP < 60mmHg; normal eICP was defined as eICP ≤ 20mmHg, and high eICP was defined as eICP > 20mmHg. A total of 132 patients were included in the final analysis (71% male, median [interquartile range (IQR)] age was 64 [52-71] years, median [IQR] Acute Physiology and Chronic Health Evaluation II score on admission was 21 [15-28]). Sixty-nine (49%) patients developed SABD during the ICU stay, and 38 (29%) were dead at hospital discharge. Transcranial Doppler recording lasted 9 (IQR 7-12) min. Median (IQR) eCPP was 63 (58-71) mmHg in the cohort; 44 of 132 (33%) patients had low eCPP. Median (IQR) eICP was 8 (4-13) mmHg; five (4%) patients had high eICP. SABD occurrence and in-hospital mortality did not differ between patients with normal eCPP and patients with low eCPP or between patients with normal eICP and patients with high eICP. Eighty-six (65%) patients had normal eCPP and normal eICP, 41 (31%) patients had low eCPP and normal eICP, three (2%) patients had low eCPP and high eICP, and two (2%) patients had normal eCPP and high eICP; however, SABD occurrence and in-hospital mortality were not significantly different among these subgroups. Brain hemodynamics, in particular CPP, were altered in one third of critically ill septic patients at a steady state of monitoring performed early during the course of sepsis. However, these alterations were equally common in patients who developed or did not develop SABD during the ICU stay and in patients with favorable or unfavorable outcome.

Correlation between Mean Platelet Volume and Procalcitonin in Sepsis Patients

Sepsis is a clinical condition of potentially life-threatening organ dysfunction caused by the host's response to infection. Delayed diagnosis and treatment of sepsis lead to worsening of the disease, which can lead to circulatory collapse, multiple organ failure, and death, therefore accurate and timely diagnosis can prevent death. Procalcitonin (PCT) is the most widely used, studied, and promising marker for the diagnosis of sepsis. Recent studies have shown that procalcitonin plays an important role in the clinical diagnosis of sepsis because it can differentiate sepsis from SIRS. Most studies found an increase in the Mean Platelet Volume (MPV) in septic patients, both neonates, and adults. The MPV value can be used as a parameter to assess the prognosis of septic patients. This cross-sectional analytical study was conducted on 21 septic patients at Dr. M. Djamil Hospital, Padang from January 2020 to April 2021. Mean platelet volume values were determined using an automatic hematology analyzer based on the formula made by the device. Procalcitonin levels were measured using the enzym-linked immunofluorescent assay method. Data were analyzed by Pearson correlation test and p &lt; 0.05 was significant. The mean age of the research subjects was 54 years and the range was 22-77 years. The number of male and female research subjects in this study was almost the same, consisting of 10 male (48%) and 11 female (52%) patients. The average MPV was 10.59(0.56) fL and the median procalcitonin was 9.35(2.08-200) ng/mL. Pearson correlation test showed that MPV was positively correlated with procalcitonin with moderate correlation (r=0.435, p=0.049). There was a moderate positive correlation between MPV and procalcitonin in septic patients.

The predictive value of left ventricular global longitudinal strain in normotensive critically ill septic patients.

Evaluation of left ventricular systolic function using speckle tracking echocardiography is more sensitive than conventional echocardiographic measurement in detecting subtle left ventricular dysfunction in septic patients. Our purpose was to investigate the predictive significance of left ventricular global longitudinal strain in normotensive septic intensive care patients. This observational, prospective cohort study included septic normotensive adults admitted to the intensive care unit between June 1, 2021, and August 31, 2021. Left ventricular systolic function was measured using speckle-tracking echocardiography within 24 hours of admission. One hundred fifty-two patients were enrolled. The intensive care unit mortality rate was 27%. Left ventricular global longitudinal strain was less negative, which indicated worse left ventricular function in non-survivors than survivors (median [interquartile range], -15.2 [-17.2 - -12.5] versus -17.3 [-18.8 - -15.5]; p < 0.001). The optimal cutoff value for left ventricular global longitudinal strain was -17% in predicting intensive care unit mortality (area under the curve, 0.728). Patients with left ventricular global longitudinal strain > -17% (less negative than -17%, which indicated worse left ventricular function) showed a significantly higher mortality rate (39.2% versus 13.7%; p < 0.001). According to multivariate analysis, left ventricular global longitudinal strain was an independent predictor of intensive care unit mortality [OR (95%CI), 1.326 (1.038 - 1.693); p = 0.024], along with invasive mechanical ventilation and Glasgow coma scale, APACHE II, and SOFA risk scores. Impaired left ventricular global longitudinal strain is associated with mortality and provided predictive data in normotensive septic intensive care patients.

Antimicrobial stewardship, procalcitonin testing, and rapid blood-culture identification to optimize sepsis care in critically ill adult patients: A quality improvement initiative.

We examined the effect of an antimicrobial stewardship program (ASP), procalcitonin testing and rapid blood-culture identification on hospital mortality in a prospective quality improvement project in critically ill septic adults. Secondarily, we have reported antimicrobial guideline concordance, acceptance of ASP interventions, and antimicrobial and health-resource utilization.

Anticardiolipin Autoantibodies as Useful Biomarkers for the Prediction of Mortality in Septic Patients.

Background The detection of antiphospholipid antibodies (aPL) is of interest because of their importance in the pathogenesis of arterial or venous thrombosis. They could be a “second hit” of an inflammatory event such as infection. The aim of our study was to assess the performance of antiphospholipid antibody biomarker to predict in-hospital mortality in intensive care unit (ICU) septic patients. Methods We conducted a prospective single-center observational study including consecutive critically ill septic adults admitted to the intensive care unit. Clinical and laboratory data including enzyme-linked immunosorbent assay for antiphospholipid antibodies (anticardiolipin (aCL), antiphosphatidylserine (aPS)) were obtained. Blood samples were collected on days 1, 3, 5, 8, and 10 of hospitalization. The primary study endpoint was ICU mortality defined as death before ICU discharge. Secondary end points included correlation between SOFA score and biological parameters. Results A total of 53 patients were enrolled. 18.8% of patients were aPL positive. In-hospital mortality rate was 60%. Multivariate analysis showed that age and aCL at days 3 and 5 along with SOFA at day 3 were independent outcome predictors. A significant positive correlation existed between SOFA at days 3, 5, and 8 and antiphospholipid antibody concentrations. Conclusions Our data showed that antiphospholipid was useful biomarkers for the prediction of mortality in critically ill septic patients. We found a positive correlation between SOFA score and antiphospholipid antibodies.

195 Older adults show biomarker evidence of PICS after sepsis

OBJECTIVES/GOALS: Many older sepsis survivors develop chronic critical illness (CCI) with poor outcomes. Sepsis is caused by a dysregulated immune response and biomarkers reflecting PICS. The purpose was to compare serial PICS biomarkers in a) older (versus young) adults and b) older CCI (versus older RAP) patients to gain insight into underlying pathobiology of CCI. METHODS/STUDY POPULATION: Prospective longitudinal study with young (≤ 45 years) and older (≥ 65 years) septic adults who were characterized by a) baseline predisposition, b) hospital outcomes, c) serial SOFA organ dysfunction scores over 14 days, d) Zubrod Performance status at three, six and 12-month follow-up and e) mortality over 12 months. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. RESULTS/ANTICIPATED RESULTS: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status and mortality over 12 months. Additionally, older (versus young) and older CCI (versus older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism and anti-angiogenesis over 14 days after sepsis. DISCUSSION/SIGNIFICANCE: Older (versus young) and older CCI (versus older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS. The population of older sepsis survivors is need of interventions to lower systemic inflammation and stimulate anabolism to prevent skeletal muscle wasting and disability.

Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. Single-center, prospective, open-label, randomized controlled trial. One thousand two hundred-bed academic medical center. Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

Older adults show biomarker evidence of PICS after sepsis

Background: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in a) older (versus young) adults and b) older CCI (versus older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. Methods: Prospective longitudinal study with young (≤ 45 years) and older (≥ 65 years) septic adults who were characterized by a) baseline predisposition, b) hospital outcomes, c) serial SOFA organ dysfunction scores over 14 days, d) Zubrod Performance status at three, six and 12-month follow-up and e) mortality over 12 months. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status and mortality over 12 months. Additionally, older (versus young) and older CCI (versus older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism and anti-angiogenesis over 14 days after sepsis. Conclusion: Older (versus young) and older CCI (versus older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

Mortality benefit of crystalloids administered in 1–6 hours in septic adults in the ED: systematic review with narrative synthesis

BackgroundBased on the 2018 update of the Surviving Sepsis Campaign, the Committee for Quality Improvement of the NHSs of England recommended the instigation of the elements of the ‘Sepsis-6 bundle’...

Older Adults Demonstrate Biomarker Evidence of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) After Sepsis.

Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis. Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

Left Ventricular Diastolic Dysfunction in Pediatric Sepsis: Outcomes in a Single-Center Retrospective Cohort Study.

Left ventricular diastolic dysfunction is associated with difficulty in ventilator weaning and increased mortality in septic adults. We evaluated the association of left ventricular diastolic dysfunction with outcomes in a cohort of children with severe sepsis and septic shock. Retrospective cohort study. Single-center noncardiac PICU. Age greater than 1 month to less than 18 years old with severe sepsis or septic shock from January 2011 to June 2017 with echocardiogram within 48 hours of sepsis onset. None. Echocardiograms were retrospectively assessed for mitral inflow E (early) and A (atrial) velocity and e' (early mitral annular motion) septal and lateral velocity. Left ventricular diastolic dysfunction was defined as E/e' greater than 10, E/A less than 0.8, or E/A greater than 1.5. Left ventricular diastolic dysfunction was present in 109 of 204 patients (53%). The data did not demonstrate an association between the presence of left ventricular diastolic dysfunction and the proportion of children requiring invasive mechanical ventilation at the time of echocardiogram (difference in proportion, +5% [72% vs 67%; 95% CI, -8% to 17%]; p = 0.52). The duration of mechanical ventilation was median 192.9 hours (interquartile range, 65.0-378.4 hr) in the left ventricular diastolic dysfunction group versus 151.0 hours (interquartile range, 45.7-244.3 hr) in the group without left ventricular diastolic dysfunction. The presence of left ventricular diastolic dysfunction was not significantly associated with ICU length of stay or mortality. Exploratory analyses revealed that an alternative definition of left ventricular diastolic dysfunction, solely defined by E/e' greater than 10, was found to have an association with mechanical ventilation requirement at the time of echocardiogram (difference in proportion, +15%; 95% CI, 3-28%; p = 0.02) and duration of mechanical ventilation (median, 207.3 vs 146.9 hr). The data failed to show an association between the presence of left ventricular diastolic dysfunction defined by both E/e' and E/A and the primary and secondary outcomes. When an alternative definition of left ventricular diastolic dysfunction with E/e' alone was used, there was a significant association with respiratory outcomes.

Using best subset regression to identify clinical characteristics and biomarkers associated with sepsis-associated acute kidney injury.

Sepsis-associated acute kidney injury (AKI) is a complex clinical disorder associated with inflammation, endothelial dysfunction, and dysregulated coagulation. With standard regression methods, collinearity among biomarkers may lead to the exclusion of important biological pathways in a single final model. Best subset regression is an analytic technique that identifies statistically equivalent models, allowing for more robust evaluation of correlated variables. Our objective was to identify common clinical characteristics and biomarkers associated with sepsis-associated AKI. We enrolled 453 septic adults within 24 h of intensive care unit admission. Using best subset regression, we evaluated for associations using a range of models consisting of 1-38 predictors (composed of clinical risk factors and plasma and urine biomarkers) with AKI as the outcome [defined as a serum creatinine (SCr) increase of ≥0.3 mg/dL within 48 h or ≥1.5× baseline SCr within 7 days]. Two hundred ninety-seven patients had AKI. Five-variable models were found to be of optimal complexity, as the best subset of five- and six-variable models were statistically equivalent. Within the subset of five-variable models, 46 permutations of predictors were noted to be statistically equivalent. The most common predictors in this subset included diabetes, baseline SCr, angiopoetin-2, IL-8, soluble tumor necrosis factor receptor-1, and urine neutrophil gelatinase-associated lipocalin. The models had a c-statistic of ∼0.70 (95% confidence interval: 0.65-0.75). In conclusion, using best subset regression, we identified common clinical characteristics and biomarkers associated with sepsis-associated AKI. These variables may be especially relevant in the pathogenesis of sepsis-associated AKI.

2043. The “Resistance Calculator”: Refining Empiric Practices of Antimicrobials Prescription in the Era of Widespread Resistance

BackgroundIn the era of widespread resistance, there are two events in the course of a hospitalized septic patient where the majority of empiric prescription errors occur: (1) infections upon admission (UA) due to multi-drug-resistant organisms (MDRO) and (2) nosocomial infections due to extensively drug-resistant organisms (XDRO). These errors seriously impact patient outcomes and the ecological burden of resistance. Our objective was to develop a tool, to calculate the probability of MDRO UA, and nosocomial XDRO infections, in order to reduce delays in initiating appropriate therapy to the “right population,” i.e., with “resistant pathogens,” while avoiding overuse of broader (frequently more toxicת less efficacious) therapeutics to the “wrong population,” i.e., with “susceptible pathogens.”MethodsRetrospective case–control analyses were conducted for septic adults at Shamir Medical Center, Israel (2016). Logistic regression was used to develop models of risk factors. All parameters incorporated into the models were readily accessible at the point of care. The performances of the development cohorts, and on 8 other validation cohorts, were assessed by the area under the receiver operating characteristic curve (ROC AUC). A web calculator (mobile modifiable) was generated.ResultsA total of 4,199 patients were enrolled: 2,472 with sepsis UA, and 1,727 with nosocomial sepsis. The “MDR UA score” included 10 parameters and with a cutoff of ≥22 points, had a ROC AUC of 0.85 (sensitivity 86%, NPV 98%). The “Nosocomial XDR score” included 7 parameters and with a cutoff of ≥36 points, had a ROC AUC of 0.88 (sensitivity 90%, NPV 96%). The median ROC AUC was 0.75 among the validation cohorts of the “MDR UA score,” and 0.66 among the “Nosocomial XDR score.” A free web tool was generated: https://assafharofe.azurewebsites.net/.ConclusionA simple electronic calculator was generated to aid in bedside empiric prescription practices. The tool is composed of two scores to assist in common scenarios where the majority of errors occur. Prospective interventional investigations, should trial the performances of this tool in improving patient outcomes and the ecological burden in the facility.Disclosures All authors: No reported disclosures.

Antibiotic- and Fluid-Focused Bundles Potentially Improve Sepsis Management, but High-Quality Evidence Is Lacking for the Specificity Required in the Centers for Medicare and Medicaid Service's Sepsis Bundle (SEP-1).

To address three controversial components in the Centers for Medicare and Medicaid Service's sepsis bundle for performance measure (SEP-1): antibiotics within 3 hours, a 30 mL/kg fluid infusion for all hypotensive patients, and repeat lactate measurements within 6 hours if initially elevated. We hypothesized that antibiotic- and fluid-focused bundles like SEP-1 would probably show benefit, but evidence supporting specific antibiotic timing, fluid dosing, or serial lactate requirements would not be concordant. Therefore, we performed a meta-analysis of studies of sepsis bundles like SEP-1. PubMed, Embase, ClinicalTrials.gov through March 15, 2018. Studies comparing survival in septic adults receiving versus not receiving antibiotic- and fluid-focused bundles. Two investigators (D.J.P., P.Q.E.). Seventeen observational studies (11,303 controls and 4,977 bundle subjects) met inclusion criteria. Bundles were associated with increased odds ratios of survival (odds ratio [95% CI]) in 15 studies with substantial heterogeneity (I = 61%; p < 0.01). Survival benefits were consistent in the five largest (1,697-12,486 patients per study) (1.20 [1.11-1.30]; I = 0%) and six medium-sized studies (167-1,029) (2.03 [1.52-2.71]; I = 8%) but not the six smallest (64-137) (1.25 [0.42-3.66]; I = 57%). Bundles were associated with similarly increased survival benefits whether requiring antibiotics within 1 hour (n = 7 studies) versus 3 hours (n = 8) versus no specified time (n = 2); or 30 mL/kg fluid (n = 7) versus another volume (≥ 2 L, n = 1; ≥ 20 mL/kg, n = 2; 1.5-2 L or 500 mL, n = 1 each; none specified, n = 4) (p = 0.19 for each comparison). In the only study employing serial lactate measurements, survival was not increased versus others. No study had a low risk of bias or assessed potential adverse bundle effects. Available studies support the notion that antibiotic- and fluid-focused sepsis bundles like SEP-1 improve survival but do not demonstrate the superiority of any specific antibiotic time or fluid volume or of serial lactate measurements. Until strong reproducible evidence demonstrates the safety and benefit of any fixed requirement for these interventions, the present findings support the revision of SEP-1 to allow flexibility in treatment according to physician judgment.

Matched Retrospective Cohort Study of Thiamine to Treat Persistent Hyperlactatemia in Pediatric Septic Shock.

Thiamine deficiency may propagate lactate production by limiting pyruvate dehydrogenase activity, and studies suggest benefit for thiamine administration in septic adults. We studied the effect of thiamine on physiologic and clinical outcomes for children with septic shock and hyperlactatemia. Retrospective matched cohort study. Single academic PICU. Six thiamine-treated cases and nine matched controls. None. The primary outcome was change in blood lactate from prethiamine (T0, cases) or maximum (T0, controls) lactate through 24 hours later (T24). Secondary outcomes were change in lactate over 48 hours (T48) and 72 hours (T72), time to lactate normalization, changes in vasoactive-inotrope score, organ dysfunction severity (daily Pediatric Logistic Organ Dysfunction 2 score), and creatinine, PICU length of stay, and hospital mortality. Lactate was greater than 5 mmol/L for a median of 39 hours (range, 16.1-64.3 hr) prior to thiamine administration for cases compared with 3.4 hours (range, 0-22.9 hr) prior to maximum lactate for controls (p = 0.002). There was no difference in median (interquartile range) change in lactate from T0 to T24 between thiamine-treated cases and controls (-9.0, -17.0 to -5.0 vs -7.2, -9.0 to -5.3 mmol/L, p = 0.78), with both groups exhibiting a rapid decrease in lactate. There were also no differences in secondary outcomes between groups. Treatment of pediatric septic shock with thiamine was followed by rapid improvement in physiologic and clinical outcomes after prolonged hyperlactatemia. Although we are not able to infer that thiamine provided benefit over usual care, the rapid decline in lactate after thiamine despite a prolonged period of hyperlactatemia raises the possibility that thiamine helped to reverse lactate production.

Reporting of Organ Support Outcomes in Septic Shock Randomized Controlled Trials: A Methodologic Review-The Sepsis Organ Support Study.

Many recent randomized controlled trials in the field of septic shock failed to demonstrate a benefit on mortality. Randomized controlled trials increasingly report organ support duration and organ support-free days as primary or secondary outcomes. We conducted a methodologic systematic review to assess how organ support outcomes were defined and reported in septic shock randomized controlled trials. MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. We included randomized controlled trials published between January 2004 and March 2018 that involved septic shock adults and assessed organ support duration and/or organ support-free days for hemodynamic support, respiratory support, or renal replacement therapy. For each randomized controlled trial, we extracted the definitions of organ support duration and organ support-free days. We particularly evaluated how nonsurvivors were accounted for. Study authors were contacted to provide any missing information regarding these definitions. We included 28 randomized controlled trials. Organ support duration and organ support-free days outcomes were reported in 17 and 15 randomized controlled trials, respectively, for hemodynamic support, 15 and 15 for respiratory support, and five and nine for renal replacement therapy. Nonsurvivors were included in the organ support duration calculation in 13 of 14 randomized controlled trials (93%) for hemodynamic support and nine of 10 (90%) for respiratory support. The organ support-free days definition for hemodynamic support, respiratory support, and renal replacement therapy was reported in six of 15 randomized controlled trials (40%), eight of 15 randomized controlled trials (53%), and six of nine randomized controlled trials (67%) reporting an organ support-free days outcome, respectively. Of these, one half assigned "0" to nonsurvivors, and the other half attributed one point per day alive free of organ support up to a predefined time point. This study highlights the heterogeneity and infrequency of organ support duration/organ support-free days outcome reporting in septic shock trials. When reported, the definitions of these outcome measures and methods of calculation are also infrequently reported, in particular how nonsurvivors were accounted for, which may have an important impact on interpretation.

Immune Modulation in Pediatric Sepsis.

The initial host immune response to sepsis in children is characterized by a proinflammatory surge that can be associated with fever, capillary leak, and organ dysfunction. There is, however, a concurrent anti-inflammatory response that results in hyporesponsiveness of innate and adaptive immune cells. When severe, this response is termed immunoparalysis and is known to be associated with prolonged organ dysfunction, increased risk for nosocomial infection, and death in septic adults and children. Sepsis-induced immune suppression can be defined in the laboratory by reduced whole blood ex vivo - stimulated cytokine production capacities, reduced expression of human leukocyte antigen (HLA)-DR on circulating monocytes, and reduced absolute cell counts. While anti-inflammatory therapies have largely been unsuccessful at improving outcomes from adult and pediatric sepsis, the use of immunostimulatory therapies such as granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with sepsis-induced immunoparalysis shows promise. A greater understanding of the risk factors for immunoparalysis along with the development and execution of immunophenotype-specific clinical trials of strategies to optimize innate and adaptive immune function are needed to further improve outcomes in septic children.