Background - Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015. Objectives - To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment. Search methods - We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009. Selection criteria - We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis. Data collection and analysis - All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials. Main results - We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting. Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value \textless 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD -2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value \textless 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value \textless 0.0001, fixed-effect model). Authors' conclusions - Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders

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Corticosteroids for treating sepsis

To assess the effect of low dose corticosteroids on outcomes in adults with septic shock. We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay. There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89–1.08, p = 0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91–1.02, p = 0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90–1.02, p = 0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03–2.70, p = 0.04, I2 = 78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) −1.52 days; 95% CI −1.71 to −1.32, p < 0.0001], duration of mechanical ventilation (MD −1.38 days; 95% CI −1.96 to −0.80, p < 0.0001), and ICU stay (MD −0.75 days; 95% CI −1.34 to −0.17, p = 0.01) were shorter with corticosteroids versus placebo. In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037.

Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis

Glucocorticosteroids (steroids) are widely used for sepsis patients. However, the potential benefits and harms of both high and low dose steroids remain unclear. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis (TSA) might shed light on this clinically important question. A systematic review was conducted according to a published protocol and The Cochrane Handbook methodology including meta-analyses, TSA of randomised clinical trials, and external validity estimation (GRADE). Randomised clinical trials evaluating steroids were included for sepsis patients (systemic inflammatory response syndrome, sepsis, severe sepsis or septic shock) aged >18 years. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/Medline, Embase, Web of Science and Cinahl were searched until 18 February 2015. No language restrictions were applied. Primary outcomes were mortality at longest follow-up and serious adverse events. A total of 35 trials randomising 4682 patients were assessed and reviewed in full text. All trials but two had high risk of bias. No statistically significant effect was found for any dose of steroids versus placebo or no intervention on mortality at maximal follow-up [relative risk (RR) 0.89; TSA adjusted confidence interval (CI) 0.74–1.08]. Two trials with low risk of bias also showed no statistically significant difference (random-effects model RR 0.38, 95 % CI 0.06–2.42). Similar results were obtained in subgroups of trials stratified according to high (>500 mg) or low (≤500 mg) dose hydrocortisone (or equivalent) (RR 0.87; TSA-adjusted CI 0.38–1.99; and RR 0.90; TSA-adjusted CI 0.49–1.67, respectively). There were also no statistically significant effects on serious adverse events other than mortality (RR 1.02; TSA-adjusted CI 0.7–1.48). The effects did not vary according to the degree of sepsis. TSA showed that many more randomised patients are needed before definitive conclusions may be drawn. Evidence to support or negate the use of steroids in any dose in sepsis patients is lacking. The results of ongoing and future well-designed, large randomised clinical trials are needed.

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Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis.

Importance Although corticosteroids are widely used for adults with sepsis, both the overall benefit and potential risks remain unclear. Objective To conduct a systematic review and meta-analysis of the efficacy and safety of corticosteroids in patients with sepsis. Data Sources and Study Selection MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until March 20, 2018, and updated on August 10, 2018. The termscorticosteroids,sepsis,septic shock,hydrocortisone,controlled trials, andrandomized controlled trialwere searched alone or in combination. Randomized clinical trials (RCTs) were included that compared administration of corticosteroids with placebo or standard supportive care in adults with sepsis. Data Extraction and Synthesis Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs) and mean differences (MDs) with corresponding 95% CIs. Two independent reviewers completed citation screening, data abstraction, and risk assessment. Main Outcomes and Measures Twenty-eight–day mortality. Results This meta-analysis included 37 RCTs (N = 9564 patients). Eleven trials were rated as low risk of bias. Corticosteroid use was associated with reduced 28-day mortality (RR, 0.90; 95% CI, 0.82-0.98;I2 = 27%) and intensive care unit (ICU) mortality (RR, 0.85; 95% CI, 0.77-0.94;I2 = 0%) and in-hospital mortality (RR, 0.88; 95% CI, 0.79-0.99;I2 = 38%). Corticosteroids were significantly associated with increased shock reversal at day 7 (MD, 1.95; 95% CI, 0.80-3.11) and vasopressor-free days (MD, 1.95; 95% CI, 0.80-3.11) and with ICU length of stay (MD, −1.16; 95% CI, −2.12 to −0.20), the sequential organ failure assessment score at day 7 (MD, −1.38; 95% CI, −1.87 to −0.89), and time to resolution of shock (MD, −1.35; 95% CI, −1.78 to −0.91). However, corticosteroid use was associated with increased risk of hyperglycemia (RR, 1.19; 95% CI, 1.08-1.30) and hypernatremia (RR, 1.57; 95% CI, 1.24-1.99). Conclusions and Relevance The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo use or standard supportive care. More research is needed to associate personalized medicine with the corticosteroid treatment to select suitable patients who are more likely to show a benefit.

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Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis.

Multiple corticosteroids and treatment regimens have been used as adjuncts in the treatment of septic shock. Qualitative and quantitative differences exist at cellular and tissular levels between the different drugs and their patterns of delivery. The objective of this study was to elucidate any differences between the drugs and their treatment regimens regarding outcomes for corticosteroid use in adult patients with septic shock. Network meta-analysis of the data used for the recently conducted Cochrane review was performed. Studies that included children and were designed to assess respiratory function in pneumonia and acute respiratory distress syndrome, as well as cross-over studies, were excluded. Network plots were created for each outcome, and all analyses were conducted using a frequentist approach assuming a random-effects model. Complete data from 22 studies and partial data from 1 study were included. Network meta-analysis provided no clear evidence that any intervention or treatment regimen is better than any other across the spectrum of outcomes. There was strong evidence of differential efficacy in only one area: shock reversal. Hydrocortisone boluses and infusions were more likely than methylprednisolone boluses and placebo to result in shock reversal. There was no clear evidence that any one corticosteroid drug or treatment regimen is more likely to be effective in reducing mortality or reducing the incidence of gastrointestinal bleeding or superinfection in septic shock. Hydrocortisone delivered as a bolus or as an infusion was more likely than placebo and methylprednisolone to result in shock reversal.

/pdf/corticosteroids-in-septic-shock-a-systematic-review-and-44qd5hyssl.pdf

Corticosteroids in septic shock: a systematic review and network meta-analysis.

Objective To observe the effect of low-dose hydrocortisone on the requirement of norepinephrine and lactate clearance in patients with refractory septic shock, and to investigate the effect of stress dose corticosteroids in reversing septic shock and improving tissue oxygen supply. Methods Seventy-seven septic shock patients with hypotension refractory to fluids and administration of norepinephrine were randomly divided into control and treatment groups. In treatment group intravenous injection of low-dose hydrocortisone was given on top of the treatment given in control group for 14 days. The mean arterial pressure (MAP), lactate clearance and the data of norepinephrine use were compared between two groups during the course of treatment. Results The number of patients requiring norepinephrine was significantly lower and the MAP was significantly higher in 24 hours, 7 days, 14 days than those at the beginning of treatment in both groups (all P<0.01). Compare to the control group, the course of using norepinephrine was shorter and the number of using norepinephrine was smaller in 7 days in treatment group (both P<0.05); the MAP and lactate clearance were higher in 24 hours and 7 days in treatment group (P<0.05 or P<0.01). But there were no differences in mortality and the length of stay in intensive care unit (ICU). Conclusion For the patients with septic shock with refractory hypotension, low-dose hydrocortisone can decrease the time course and dosage of vasopressors, improve tissue oxygen supply, thus can reverse septic shock more rapidly.

Key words: 
hydrocortisone;  septic shock;  norepinephrine;  lactate clearance

[The effect of low-dose hydrocortisone on requirement of norepinephrine and lactate clearance in patients with refractory septic shock].

This study aimed to develop and validate an interpretable machine-learning model based on clinical features for early predicting in-hospital mortality in critically ill patients with sepsis.We enrolled all patients with sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV, v.1.0) database from 2008 to 2019. Lasso regression was used for feature selection. Seven machine-learning methods were applied to develop the models. The best model was selected based on its accuracy and area under curve (AUC) in the validation cohort. Furthermore, we employed the SHapley Additive exPlanations (SHAP) method to illustrate the effects of the features attributed to the model, and to analyze how the individual features affect the output of the model, and to visualize the Shapley value for a single individual.In total, 8,817 patients with sepsis were eligible for participation, the median age was 66.8 years (IQR, 55.9-77.1 years), and 3361 of 8817 participants (38.1%) were women. After selection, 25 of a total 57 clinical parameters collected on day 1 after ICU admission remained associated with prognosis and were used for developing the machine-learning models. Among seven constructed models, the eXtreme Gradient Boosting (XGBoost) model achieved the best performance with an AUC of 0.884 and an accuracy of 89.5% in the validation cohort. Feature importance analysis showed that Glasgow Coma Scale (GCS) score, blood urea nitrogen, respiratory rate, urine output, and age were the top 5 features of the XGBoost model with the greatest impact. Furthermore, SHAP force analysis illustrated how the constructed model visualized the individualized prediction of death.We have demonstrated the potential of machine-learning approaches for predicting outcome early in patients with sepsis. The SHAP method could improve the interpretability of machine-learning models and help clinicians better understand the reasoning behind the outcome. 

/pdf/interpretable-machine-learning-for-early-prediction-of-2m84icr6.pdf

Interpretable Machine Learning for Early Prediction of Prognosis in Sepsis: A Discovery and Validation Study

Burnout has gained increasing attention worldwide; however, there is a lack of relevant research in China. This study investigated the prevalence and factors associated with burnout in physicians of the intensive care unit (ICU) in mainland China. This cross-sectional multicenter study included critical care physicians from all provinces in mainland China (except Tibet). A self-administered survey questionnaire was conducted. It included three parts: demographic information, lifestyle and work information, and the Maslach Burnout Inventory. The levels of burnout were calculated. The factors independently associated with burnout were analyzed by logistic regression. Finally, 1813 intensivists participated in the survey. The participation rate was 90.7%. The prevalence of burnout and severe burnout was 82.1% (1489/1813) and 38.8% (704/1813), respectively. According to the logistic regression analysis, “difficulty in making treatment decisions” was independently associated with burnout [OR = 1.365, CI (1.060, 1.757)]. “Higher number of children” [OR = 0.714, CI (0.519, 0.981)] and higher “income satisfaction” [OR = 0.771, CI (0.619, 0.959)] were independent protective factors against severe burnout. The burnout rate in ICU physicians in China is high. Difficult treatment decisions, the number of children, and income satisfaction are independently associated with burnout rates among ICU physicians in China. Trial registration: Burnout syndrome of the Chinese personnel working in intensive care units: a survey in China, ChiCTR-EOC-17013044, registered October 19, 2017. http://www.chictr.org.cn/showproj.aspx?proj=22329
 .

/pdf/prevalence-of-burnout-among-intensivists-in-mainland-china-a-4ztq8l69m0.pdf

Prevalence of burnout among intensivists in mainland China: a nationwide cross-sectional survey.

PURPOSE: We used lung ultrasonography to identify features of COVID-19 pneumonia and to evaluate the prognostic value. PATIENTS AND METHODS: We performed lung ultrasonography on 48 COVID-19 patients in an intensive care unit (ICU) (Wuhan, China) using a 12-zone method. The associations between lung ultrasonography score, PaO2/FiO2, APACHE II, SOFA, and PaCO2 with 28-day mortality were analyzed and the receiver operator characteristic curve was plotted. RESULTS: 25.9% areas in all scanning zones presented with B7 lines and 23.5% with B3 lines (B-pattern) on lung ultrasonography; 13% areas with confluent B lines (B-pattern), 24.9% in areas with consolidations, and 9.9% in areas with A lines. Pleural effusion was observed in 2.8% of areas. Lung ultrasonography score was negatively correlated with PaO2/FiO2 (nâ=â48, râ=â-0.498, Pâ<â0.05) and positively correlated with APACHE II (nâ=â48, râ=â0.435, Pâ<â0.05). Lung ultrasonography score was independently associated with 28-day mortality. The areas under receiver operator characteristic curves of lung ultrasonography score were 0.735 (95% CI: 0.586-0.844). The sensitivity, specificity, and cutoff values were 0.833, 0.722, and 22.5, respectively. CONCLUSIONS: Lung ultrasonography could be used to assess the severity of COVID-19 pneumonia, and it could also reveal the pathological signs of the disease. The lung ultrasonography score on ICU admission was independently related to the ICU 28-day mortality.

Findings and Prognostic Value of Lung Ultrasonography in Coronal Virus Disease 2019(COVID-19) Pneumonia.

Septic patients requiring intensive care unit (ICU) readmission are at high risk of mortality, but research focusing on the association of ICU readmission due to sepsis and mortality is limited. The aim of this study was to develop and validate a machine learning (ML) model for predicting in-hospital mortality in septic patients readmitted to the ICU using routinely available clinical data. The data used in this study were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV, v1.0) database, between 2008 and 2019. The study cohort included patients with sepsis requiring ICU readmission. The data were randomly split into a training (75%) data set and a validation (25%) data set. Nine popular ML models were developed to predict mortality in septic patients readmitted to the ICU. The model with the best accuracy and area under the curve (A.C.) in the validation cohort was defined as the optimal model and was selected for further prediction studies. The SHAPELY Additive explanations (SHAP) values and Local Interpretable Model-Agnostic Explanation (LIME) methods were used to improve the interpretability of the optimal model. A total of 1117 septic patients who had required ICU readmission during the study period were enrolled in the study. Of these participants, 434 (38.9%) were female, and the median (interquartile range [IQR]) age was 68.6 (58.4–79.2) years. The median (IQR) ICU interval duration was 2.60 (0.64–5.78) days. After feature selection, 31 of 47 clinical factors were ultimately chosen for use in model construction. Of the nine ML models tested, the best performance was achieved with the random forest (RF) model, with an A.C. of 0.81, an accuracy of 85% and a precision of 62% in the validation cohort. The SHAP summary analysis revealed that Glasgow Coma Scale score, urine output, blood urea nitrogen, lactate, platelet count and systolic blood pressure were the top six most important factors contributing to the RF model. Additionally, the LIME method demonstrated how the RF model works in terms of explaining risk of death prediction in septic patients requiring ICU readmission. The ML models reported here showed a good prognostic prediction ability in septic patients requiring ICU readmission. Of the features selected, the parameters related to organ perfusion made the largest contribution to outcome prediction during ICU readmission in septic patients. 

https://link.springer.com/content/pdf/10.1007/s40121-022-00671-3.pdf

Lu Li

Papers

[The effect of low-dose hydrocortisone on requirement of norepinephrine and lactate clearance in patients with refractory septic shock].

Interpretable Machine Learning for Early Prediction of Prognosis in Sepsis: A Discovery and Validation Study

Prevalence of burnout among intensivists in mainland China: a nationwide cross-sectional survey.

Findings and Prognostic Value of Lung Ultrasonography in Coronal Virus Disease 2019(COVID-19) Pneumonia.

Explainable Machine-Learning Model for Prediction of In-Hospital Mortality in Septic Patients Requiring Intensive Care Unit Readmission