Prognosis of Patients with Sepsis and Non-Hepatic Hyperammonemia: A Cohort Study.

BACKGROUND Hyperammonemia has been reported in some critically ill patients with sepsis who do not have hepatic failure. A significant proportion of patients with non-hepatic hyperammonemia have underlying sepsis, but the association between non-hepatic hyperammonemia and prognosis is unclear. MATERIAL AND METHODS Information about patients with sepsis and non-hepatic hyperammonemia was retrieved from the Medical Information Mart for Intensive Care-III database. Survival rates were analyzed using the Kaplan-Meier method. Multivariate logistic regression models were employed to identify prognostic factors. Receiver operating characteristic (ROC) curve analysis was used to measure the predictive ability of ammonia in terms of patient mortality. RESULTS A total of 265 patients with sepsis were enrolled in this study. Compared with the non-hyperammonemia group, the patients with hyperammonemia had significantly higher rates of hospital (59.8% vs. 43.0%, P=0.007), 30-day (47.7% vs. 34.8%, P=0.036), 90-day (61.7% vs. 43.7%, P=0.004), and 1-year mortality (67.3% vs. 49.4%, P=0.004). In the survival analysis, hyperammonemia was associated with these outcomes. Serum ammonia level was an independent predictor of hospital mortality. The area under the ROC curve for the ammonia levels had poor discriminative capacity. The hyperammonemia group also had significantly lower Glasgow Coma Scale scores (P=0.020) and higher incidences of delirium (15.9% vs. 8.2%, P=0.034) and encephalopathy (37.4% vs. 19.6%, P=0.001). Intestinal infection and urinary tract infection with organisms such as Escherichia coli may be risk factors for hyperammonemia in patients who have sepsis. CONCLUSIONS Higher ammonia levels are associated with poorer prognosis in patients with sepsis. Ammonia also may be associated with sepsis-associated encephalopathy. Therefore, we recommend that serum ammonia levels be measured in patients who are suspected of having sepsis.

The association between levosimendan and mortality in patients with sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: Levosimendan is increasingly being used in patients with sepsis or septic shock because of its potential to improve organ function and reduce mortality. We aimed to determine if levosimendan can reduce mortality in patients with sepsis or septic shock via meta-analysis. EVIDENCE SOURCES AND STUDY SELECTION: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane Library databases from inception through 1 October 2022. Literature evaluating the efficacy of levosimendan in patients with sepsis or septic shock was included. DATA EXTRACTION AND OUTCOME MEASUREMENTS: Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CI), and P -values for 28-day mortality (primary outcome). Secondary outcomes included changes in indexes reflecting cardiac function before and after treatment, changes in serum lactate levels in the first 24 h of treatment, and the mean SOFA score during the study period. Safety outcomes included rates of tachyarrhythmias and total adverse reactions encountered with levosimendan. RESULTS: Eleven randomized controlled trials were identified, encompassing a total of 1044 patients. After using levosimendan, there was no statistical difference between groups for 28-day mortality (34.9% and 36.2%; OR: 0.93; 95% CI [0.72-1.2]; P  = 0.57; I 2  = 0%; trial sequential analysis-adjusted CI [0.6-1.42]) and sequential organ failure assessment (SOFA) score, and more adverse reactions seemed to occur in the levosimendan group, although the septic shock patient's heart function and serum lactate level improved. CONCLUSION: There was no association between the use of levosimendan and 28-day mortality and SOFA scores in patients with septic shock, though there was statistically significant improvement in cardiac function and serum lactate.

Establishment and evaluation of animal models of sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a critical disease caused by sepsis. In addition to high mortality, SAE can also adversely affect life quality and lead to significant socioeconomic costs. This review aims to explore the development of evaluation animal models of SAE, giving insight into the direction of future research in terms of its pathophysiology and therapy. METHODS: We performed a literature search from January 1, 2000, to December 31, 2022, in MEDLINE, PubMed, EMBASE, and Web of Science using related keywords. Two independent researchers screened all the accessible articles based on the inclusion and exclusion criteria and collected the relevant data of the studies. RESULTS: The animal models for sepsis are commonly induced through cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) injection. SAE can be evaluated using nervous reflex scores and sepsis evaluation during the acute phase, or through Morris water maze (MWM), open-field test, fear condition (FC) test, inhibitory avoidance, and other tests during the late phase. CONCLUSION: CLP and LPS injection are the most common methods for establishing SAE animal models. Nervous reflexs cores, MWM, FC test, and inhibitory avoidance are widely used in SAE model analysis. Future research should focus on establishing a standardized system for SAE development and analysis.

CLINICAL PHENOTYPES OF SEPSIS-ASSOCIATED ENCEPHALOPATHY: A RETROSPECTIVE COHORT STUDY.

ABSTRACT: Background: Sepsis-associated encephalopathy (SAE) is a dysfunction of the central nervous system experienced during sepsis with variable clinical and pathophysiologic features. We sought to identify distinct SAE phenotypes in relation to clinical outcomes. Methods: The Medical Information Mart for Intensive Care IV (MIMIC-IV) database and the eICU database were used to conduct a retrospective cohort study. Adult sepsis patients were included and SAE was defined as having a Glasgow Coma Scale (GCS) score ˂15 or delirium. The following our clinical phenotypes were defined as: ischemic-hypoxic, metabolic, mixed (ischemic-hypoxic and metabolic), and unclassified. The primary outcome was in-hospital mortality. Results: The study enrolled 4,120 sepsis patients, 2,239 from MIMIC-IV (including 1,489 patients with SAE, 67%), and 1,881 from eICU (1,291, 69%). For the SAE cohort, 2,780 patients in total were enrolled (median age, 67 years; interquartile range, 56-76.8; 1,589 (57%) were male; median GCS score was 12 [8-14]; median Sequential Organ Failure Assessment score was 6 [4-9]). The SAE phenotype distributions between the MIMIC-IV and eICU cohorts were as follows (39% vs. 35% ischemic-hypoxic, P = 0.043; 38% vs. 40% metabolic, P = 0.239; 15% vs. 15% mixed, P = 0.972; 38% vs. 40% unclassified, P = 0.471). For the overall cohort, the in-hospital mortality for patients with ischemic-hypoxic, metabolic, mixed, or unclassified phenotypes was 33.9% (95% confidence interval, 0.3-0.37), 28.4% (0.26-0.31), 41.5% (0.37-0.46), and 14.2% (0.12-0.16), respectively. In the multivariable logistic analysis, the mixed phenotype was associated with the highest risk of in-hospital mortality after adjusting for age, sex, GCS, and modified Sequential Organ Failure Assessment score (adjusted odds ratio, 2.11; 95% confidence interval, 1.67-2.67; P < 0.001). Conclusions: Four SAE phenotypes had different clinical outcomes. The mixed phenotype had the worst outcomes. Further understanding of these phenotypes in sepsis may improve trial design and targeted SAE management.

Non-hepatic Hyperammonemia: A Potential Therapeutic Target for Sepsis-associated Encephalopathy.

Sepsis-Associated Encephalopathy (SAE) is a common complication in the acute phase of sepsis, and patients who develop SAE have a higher mortality rate, longer hospital stay, and worse quality of life than other sepsis patients. Although the incidence of SAE is as high as 70% in sepsis patients, no effective treatment is available for this condition. To develop an effective treatment for SAE, it is vital to explore its pathogenesis. It is known that hyperammonemia is a possible factor in the pathogenesis of hepatic encephalopathy as ammonia is a potent neurotoxin. Furthermore, our previous studies indicate that non-hepatic hyperammonemia seems to occur more often in sepsis patients; it was also found that >50% of sepsis patients with non-hepatic hyperammonemia exhibited encephalopathy and delirium. Substatistical analyses indicate that non-hepatic hyperammonemia is an independent risk factor for SAE. This study updates the definition, clinical manifestations, and diagnosis of SAE; it also investigates the possible treatment options available for non-hepatic hyperammonemia in patients with sepsis and the mechanisms by which non-hepatic hyperammonemia causes encephalopathy.

Norepinephrine use in cardiogenic shock patients is associated with increased 30 day mortality.

AIMS: Norepinephrine is recommended as a first-line vasopressor agent in the haemodynamic stabilization of cardiogenic shock. The survival benefit of norepinephrine therapy has not been demonstrated in clinical practice, however. This study aimed to explore the relationship between norepinephrine use and outcomes in cardiogenic shock patients in real-world conditions. METHODS AND RESULTS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care III (MIMIC-III) database. Cardiogenic shock patients were enrolled and categorized into a norepinephrine group or a non-norepinephrine group. Propensity score matching (PSM) was used to control for confounders. Cox proportional-hazards models and multivariable logistic regression were used to investigate the relationship between norepinephrine treatment and mortality. A total of 927 eligible patients were included: 552 patients in the norepinephrine group and 375 patients in the non-norepinephrine group. After PSM, 222 cases from each group were matched using a 1:1 matching algorithm. Thirty day mortality for patients treated with norepinephrine was significantly higher than for those in the non-norepinephrine group (41% vs. 30%, OR 1.61, 95% CI 1.09-2.39, P = 0.017; HR 1.50, 95% CI 1.09-2.06, P = 0.013). In the multivariable analysis, there was no significant difference between norepinephrine therapy and long-term (90 day, 180 day, or 1 year) mortality (90 day (OR 1.19, 95% CI 0.82-1.74, P = 0.363), 180 day (OR 1.17, 95% CI 0.80-1.70, P = 0.418), 1 year (OR 1.14, 95% CI 0.79-1.66, P = 0.477). Patients in the norepinephrine group required more mechanical ventilation (84% vs. 67%, OR 2.67, 95% CI 1.70-4.25, P < 0.001) and experienced longer ICU stays (median 7 vs. 4 days, OR 7.92, 95% CI 1.40-44.83, P = 0.020) than non-norepinephrine group. CONCLUSIONS: Cardiogenic shock patients treated with norepinephrine were associated with significantly increased short-term mortality, while no significant difference was found on long-term survival rates. Future trials are needed to validate and explore this association.

Is rosuvastatin protective against sepsis-associated encephalopathy? A secondary analysis of the SAILS trial.

BACKGROUND: Sepsis is a common cause of death in emergency departments and sepsis-associated encephalopathy (SAE) is a major complication. Rosuvastatin may play a neuroprotective role due to its protective effects on the vascular endothelium and its anti-inflammatory functions. Our study aimed to explore the potential protective function of rosuvastatin against SAE. METHODS: Sepsis patients without any neurological dysfunction on admission were prospectively enrolled in the "Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome" study (SAILS trial, ClinicalTrials.gov number: NCT00979121). Patients were divided into rosuvastatin and placebo groups. This is a secondary analysis of the SAILS dataset. Baseline characteristics, therapy outcomes, and adverse drug events were compared between groups. RESULTS: A total of 86 patients were eligible for our study. Of these patients, 51 were treated with rosuvastatin. There were significantly fewer cases of SAE in the rosuvastatin group than in the placebo group (32.1% vs. 57.1%, P=0.028). However, creatine kinase levels were significantly higher in the rosuvastatin group than in the placebo group (233 [22-689] U/L vs. 79 [12-206] U/L, P=0.034). CONCLUSION: Rosuvastatin appears to have a protective role against SAE but may result in a higher incidence of adverse events.

Development of an intensive simulating training program in emergency medicine for medical students in China.

BACKGROUND: A national standardized emergency medicine (EM) curriculum for medical students, including specific competencies in procedural skills, are absent in many countries. The development of an intensive simulating training program in EM, based on a tight schedule, is anticipated to enhance the competency of medical students. METHODS: A 3-day intensive EM training program, consisting of four procedural skills and 8-hour case-based learning (CBL), was developed by experienced physicians from the EM department in Peking Union Medical College Hospital (PUMCH). Medical students from Peking Union Medical College (PUMC) and Tsinghua University (THU) participated in the training. Three written tests were cautiously designed to examine the short-term (immediately after the program) and long-term (6 months after the program) efficacy of the training. After completion of the training program, an online personal appraisal questionnaire was distributed to the students on WeChat (a mobile messaging App commonly used in China) to achieve anonymous self-evaluation. RESULTS: Ninety-seven out of 101 students completed the intensive training and took all required tests. There was a significant increase in the average score after the intensive simulating training program (pre-training 13.84 vs. 15.57 post-training, P<0.001). Compared with the pre-training test, 63 (64.9%) students made progress. There was no significant difference in scores between the tests taken immediately after the program and 6 months later (15.57±2.22 vs. 15.38±2.37, P=0.157). Students rated a higher score in all diseases and procedural skills, and felt that their learning was fruitful. CONCLUSIONS: The introduction of a standardized intensive training program in EM focusing on key competencies can improve clinical confidence, knowledge, and skills of medical students toward the specialty. In addition, having such a program can also enhance student's interest in EM as a career choice which may enhance recruitment into the specialty and workplace planning.

Mechanical Learning for Prediction of Sepsis-Associated Encephalopathy.

Objective: The study aims to develop a mechanical learning model as a predictive model for predicting the appearance of sepsis-associated encephalopathy (SAE). Materials and Methods: The prediction model was developed in a primary cohort of 2,028 sepsis patients from June 2001 to October 2012, retrieved from the Medical Information Mart for Intensive Care (MIMIC III) database. Least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction and feature selection. The model was developed using multivariable logistic regression analysis. The performance of the nomogram has been evaluated in terms of calibration, discrimination, and clinical utility. Results: There were nine particular features in septic patients that were significantly associated with SAE. Predictors of individualized prediction nomograms included age, rapid sequential evaluation of organ failure (qSOFA), and drugs including carbapenem antibiotics, quinolone antibiotics, steroids, midazolam, H2-antagonist, diphenhydramine hydrochloride, and heparin sodium injection. The area under the curve (AUC) was 0.743, indicating good discrimination. The prediction model showed calibration curves with minor deviations from the ideal predictions. Decision curve analysis (DCA) suggested that the nomogram was clinically useful. Conclusion: We propose a nomogram for the individualized prediction of SAE with satisfactory performance and clinical utility, which could aid the clinician in the early detection and management of SAE.

Development and Validation of a Nomogram for the Prediction of Hospital Mortality of Patients With Encephalopathy Caused by Microbial Infection: A Retrospective Cohort Study.

BACKGROUND: Hospital mortality is high for patients with encephalopathy caused by microbial infection. Microbial infections often induce sepsis. The damage to the central nervous system (CNS) is defined as sepsis-associated encephalopathy (SAE). However, the relationship between pathogenic microorganisms and the prognosis of SAE patients is still unclear, especially gut microbiota, and there is no clinical tool to predict hospital mortality for SAE patients. The study aimed to explore the relationship between pathogenic microorganisms and the hospital mortality of SAE patients and develop a nomogram for the prediction of hospital mortality in SAE patients. METHODS: The study is a retrospective cohort study. The lasso regression model was used for data dimension reduction and feature selection. Model of hospital mortality of SAE patients was developed by multivariable Cox regression analysis. Calibration and discrimination were used to assess the performance of the nomogram. Decision curve analysis (DCA) to evaluate the clinical utility of the model. RESULTS: Unfortunately, the results of our study did not find intestinal infection and microorganisms of the gastrointestinal (such as: Escherichia coli) that are related to the prognosis of SAE. Lasso regression and multivariate Cox regression indicated that factors including respiratory failure, lactate, international normalized ratio (INR), albumin, SpO2, temperature, and renal replacement therapy were significantly correlated with hospital mortality. The AUC of 0.812 under the nomogram was more than that of the Simplified Acute Physiology Score (0.745), indicating excellent discrimination. DCA demonstrated that using the nomogram or including the prognostic signature score status was better than without the nomogram or using the SAPS II at predicting hospital mortality. CONCLUSION: The prognosis of SAE patients has nothing to do with intestinal and microbial infections. We developed a nomogram that predicts hospital mortality in patients with SAE according to clinical data. The nomogram exhibited excellent discrimination and calibration capacity, favoring its clinical utility.

Corrigendum: Development and Validation of a Nomogram for the Prediction of Hospital Mortality of Patients With Encephalopathy Caused by Microbial Infection: A Retrospective Cohort Study.

[This corrects the article DOI: 10.3389/fmicb.2021.737066.].

Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: Thiamine and vitamin C have been increasingly used in patients with sepsis or septic shock because of their potential for improving metabolism and reducing mortality. OBJECTIVE: We aim to determine if thiamine combined vitamin C can reduce mortality in patients with sepsis or septic shock. EVIDENCE SOURCES AND STUDY SELECTION: We comprehensively searched the PubMed, Embase, Cochrane Library, and Web of Science databases from their inception dates through 1 January 2021. Literature works evaluating the efficacy of thiamine combined vitamin C in patients with sepsis or septic shock were considered. DATA EXTRACTION AND OUTCOME MEASUREMENTS: Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CIs), and P values for in-hospital mortality (primary outcome). Secondary outcomes included duration of ICU stay, duration of hospital stay, duration of vasopressor use, and change in sequential organ failure assessment (SOFA) scores. RESULTS: Seven randomized controlled trials were identified, encompassing a total of 868 patients. There was no statistical difference between groups for in-hospital mortality (OR: 1.11; 95% CI [0.79-1.56]; P = 0.55). Other than improving SOFA score during the first 72 h after enrollment and duration of vasopressor use, we found no other significant associations. CONCLUSIONS: Despite widespread enthusiasm for thiamine combined with vitamin C for sepsis and septic shock, we only found an association with reduced SOFA score and time of vasopressor use. There was no association with in-hospital mortality.

Prognostic Role of Ammonia in Critical Care Patients Without Known Hepatic Disease.

Background and Aims: Hyperammonemia usually develops because of hepatic disease, but it may occur in patients with non-hepatic hyperammonemia (NHH). But, studies on the prognosis and possible risk factors of this disorder are lacking. The aim of this study was to find possible prognostic and risk factors for NHH in critically ill patients. Methods: Data were extracted from MIMIC III Database. Survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify prognostic factors. Results: Valproic acid, carbamazepine, corticosteroids, recent orthopedic surgery, epilepsy, disorders of urea cycle metabolism, and obesity were found to be risk factors for NHH. Patients in the hyperammonemia group had a higher 30 day mortality than those in the non-hyperammonemia group. After final regression analysis, ammonia was found to be independent predictors of mortality. Conclusion: Ammonia was an independent prognostic predictor of 30 day mortality for critical care patients without liver disease.

N-acetylcysteine as a treatment for amatoxin poisoning: a systematic review.

Introduction: Amatoxin leads to the majority of deaths by mushroom poisoning around the world. Amatoxin causes gastrointestinal disturbances and multiple organ dysfunction, including liver and renal failure. As a potential treatment for amatoxin poisoning, N-acetylcysteine (NAC) has been used for decades but its benefit is still unproven.Objectives: We undertook a systematic review to evaluate the performance and safety of N-acetylcysteine on patients suffering amatoxin intoxication.Methods: We searched Pubmed, EMBASE, CENTRAL and SinoMed databases, from inception to August 31, 2019. Articles were eligible if there were five or more patients with amatoxin poisoning and N-acetylcysteine was included in the therapeutic regimen. Mortality rate including liver transplant cases (MRLTi) was the primary outcome. Mortality rate not including liver transplant cases, liver and renal function, clinical complications, as well as any adverse reactions to intravenous NAC were secondary outcomes.Results: Thirteen studies with a total of 506 patients were included. The MRLTi of amatoxin-poisoning patients with NAC treatment was 11% (57/506), and a MRLTe of 7.9% (40/506) and a liver transplantation rate of 4.3% (22/506). Transaminase concentrations generally peaked around 3 days after ingestion, prothrombin time/International Normalized Ratio (PT/INR) generally worsened during the first 3-4 days after ingestion before returning to normal four to 7 days after ingestion, and Factor V levels normalized in about 4-5 days after ingestion in patients treated with NAC. Renal failure was reported in 3% (3/101) and acute kidney injury was reported in 19% (5/27). Gastrointestinal bleeding occurred in 21% (15/71). Anaphylactoid reactions were the principle adverse reaction to NAC treatment in amatoxin-poisoning patients with an incidence of 5% (4/73).Conclusions: NAC treatment combined with other therapies appears to be beneficial and safe in patients with amatoxin poisoning. Until further data emerge, it is reasonable to use NAC in addition to other treatments for amatoxin poisoning.