The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.

Heterogeneity of Benefit from Earlier Time-to-Antibiotics for Sepsis.

Rationale: Shorter time-to-antibiotics improves survival from sepsis, particularly among patients in shock. There may be other subgroups for whom faster antibiotics are particularly beneficial.Objectives: Identify patient characteristics associated with greater benefit from shorter time-to-antibiotics.Methods: Observational cohort study of patients hospitalized with community-onset sepsis at 173 hospitals and treated with antimicrobials within 12 hours. We used three approaches to evaluate heterogeneity of benefit from shorter time-to-antibiotics: 1) conditional average treatment effects of shorter (⩽3 h) versus longer (>3-12 h) time-to-antibiotics on 30-day mortality using multivariable Poisson regression; 2) causal forest to identify characteristics associated with greatest benefit from shorter time-to-antibiotics; and 3) logistic regression with time-to-antibiotics modeled as a spline.Measurements and Main Results: Among 273,255 patients with community-onset sepsis, 131,094 (48.0%) received antibiotics within 3 hours. In Poisson models, shorter time-to-antibiotics was associated with greater absolute mortality reduction among patients with metastatic cancer (5.0% [95% confidence interval; CI: 4.3-5.7] vs. 0.4% [95% CI: 0.2-0.6] for patients without cancer, P < 0.001); patients with shock (7.0% [95% CI: 5.8-8.2%] vs. 2.8% [95% CI: 2.7-3.5%] for patients without shock, P = 0.005); and patients with more acute organ dysfunctions (4.8% [95% CI: 3.9-5.6%] for three or more dysfunctions vs. 0.5% [95% CI: 0.3-0.8] for one dysfunction, P < 0.001). In causal forest, metastatic cancer and shock were associated with greatest benefit from shorter time-to-antibiotics. Spline analysis confirmed differential nonlinear associations of time-to-antibiotics with mortality in patients with metastatic cancer and shock.Conclusions: In patients with community-onset sepsis, the mortality benefit of shorter time-to-antibiotics varied by patient characteristics. These findings suggest that shorter time-to-antibiotics for sepsis is particularly important among patients with cancer and/or shock.

Geo-economic Influence on the Effect of Fluid Volume for Sepsis Resuscitation: A Meta-Analysis.

Rationale: Sepsis management relies on fluid resuscitation avoiding fluid overload and its related organ congestion. Objectives: To explore the influence of country income group on risk-benefit balance of fluid management strategies in sepsis. Methods: We searched e-databases for all randomized controlled trials on fluid resuscitation in patients with sepsis or septic shock up to January 2023, excluding studies on hypertonic fluids, colloids, and depletion-based interventions. The effect of fluid strategies (higher versus lower volumes) on mortality was analyzed per income group (i.e., low- and middle-income countries [LMICs] or high-income countries [HICs]). Measurements and Main Results: Twenty-nine studies (11,798 patients) were included in the meta-analysis. There was a numerically higher mortality in studies of LMICs as compared with those of HICs: median, 37% (interquartile range [IQR]: 26-41) versus 29% (IQR: 17-38; P = 0.06). Income group significantly interacted with the effect of fluid volume on mortality: Higher fluid volume was associated with higher mortality in LMICs but not in HICs: odds ratio (OR), 1.47; 95% confidence interval (95% CI): 1.14-1.90 versus 1.00 (95% CI: 0.87-1.16), P = 0.01 for subgroup differences. Higher fluid volume was associated with increased need for mechanical ventilation in LMICs (OR, 1.24 [95% CI: 1.08-1.43]) but not in HICs (OR, 1.02 [95% CI: 0.80-1.29]). Self-reported access to mechanical ventilation also significantly influenced the effect of fluid volume on mortality, which increased with higher volumes only in settings with limited access to mechanical ventilation (OR: 1.45 [95% CI: 1.09-1.93] vs. 1.09 [95% CI: 0.93-1.28], P = 0.02 for subgroup differences). Conclusions: In sepsis trials, the effect of fluid resuscitation approach differed by setting, with higher volume of fluid resuscitation associated with increased mortality in LMICs and in settings with restricted access to mechanical ventilation. The precise reason for these differences is unclear and may be attributable in part to resource constraints, participant variation between trials, or other unmeasured factors.

Stratification of Sepsis Patients on Admission into the Intensive Care Unit According to Differential Plasma Metabolic Phenotypes.

Delayed diagnosis of patients with sepsis or septic shock is associated with increased mortality and morbidity. UPLC-MS and NMR spectroscopy were used to measure panels of lipoproteins, lipids, biogenic amines, amino acids, and tryptophan pathway metabolites in blood plasma samples collected from 152 patients within 48 h of admission into the Intensive Care Unit (ICU) where 62 patients had no sepsis, 71 patients had sepsis, and 19 patients had septic shock. Patients with sepsis or septic shock had higher concentrations of neopterin and lower levels of HDL cholesterol and phospholipid particles in comparison to nonsepsis patients. Septic shock could be differentiated from sepsis patients based on different concentrations of 10 lipids, including significantly lower concentrations of five phosphatidylcholine species, three cholesterol esters, one dihydroceramide, and one phosphatidylethanolamine. The Supramolecular Phospholipid Composite (SPC) was reduced in all ICU patients, while the composite markers of acute phase glycoproteins were increased in the sepsis and septic shock patients within 48 h admission into ICU. We show that the plasma metabolic phenotype obtained within 48 h of ICU admission is diagnostic for the presence of sepsis and that septic shock can be differentiated from sepsis based on the lipid profile.

Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.

INTRODUCTION: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging. OBJECTIVE: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality. METHODS: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) - the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact. RESULTS: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-L-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased. CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.

Biomarkers of endothelial glycocalyx damage are associated with microvascular dysfunction in resuscitated septic shock patients.

BACKGROUND: Microvascular dysfunction plays a central role in organ dysfunction during septic shock. Endothelial glycocalyx (eGC) damage could contribute to impaired microcirculation. The aim was to assess whether several eGC-damaged biomarkers are associated with microvascular dysfunction in resuscitated septic shock patients. METHODS: This cross-sectional study included resuscitated septic shock patients (N = 31), and a group of healthy individuals (N = 20). The eGC damage biomarkers measured were syndecan-1 (SDC-1), soluble CD44 (CD44s), hyaluronic acid (HYAL) in blood sample; sulfated glycosaminoglycans (GAGs) in urine sample; and thrombomodulin (TBML) in blood sample as biomarker of endothelial cell damage. Microcirculation was assessed through sublingual videocapillaroscopy using the GlycoCheck™, which estimated the perfused vascular density (PVD); the perfused boundary region (PBR), an inverse parameter of the eGC thickness; and the microvascular health score (MVHS). We defined a low MVHS (<50th percentile in septic patients) as a surrogate for more impaired microvascular function. RESULTS: The SDC-1, CD44s, TBML and GAGs levels were correlated with impaired microvascular parameters (PVD of vessels with diameter < 10 µm, MVHS and flow-adjusted PBR); p < 0.05 for all comparisons, except for GAGs and flow-adjusted PBR. The SDC-1 [78 ng/mL (interquartile range (IQR) 45-336) vs. 48 ng/mL (IQR 9-85); p = 0.052], CD44s [796ρg/mL (IQR 512-1995) vs. 526ρg/mL (IQR 287-750); p = 0.036], TBML [734ρg/mL (IQR 237-2396) vs. 95ρg/mL (IQR 63-475); p = 0.012] and GAGs levels [0.42 ρg/mg (IQR 0.04-1.40) vs. 0.07 ρg/mg (IQR 0.02-0.20); p = 0.024]; were higher in septic patients with more impaired sublingual microvascular function (low MVHS vs. high MVHS). CONCLUSION: SDC-1, CD44s, TBML and GAGs levels were associated with impaired microvascular function in resuscitated septic shock patients.

Midregional-proAdrenomedullin as a prognostic tool in sepsis and septic shock: A systematic review and meta-analysis.

BACKGROUND: Midregional-proAdrenomedullin (MR-proADM) has been recently proposed as a tool in patients with sepsis and septic shock. Our aim was to evaluate the prognostic role of MR-proADM in hospitalized patients with sepsis and septic shock. METHODS: PRISMA guideline was followed. MEDLINE and EMBASE were searched up to June 2023. Primary outcome was mean difference in MR-proADM among survivors and nonsurvivors, secondary outcome mean difference in MR-proADM according to infection severity and type. Risk of bias was evaluated using Newcastle-Ottawa scale for observational studies and Cochrane tool for randomized trials. Pooled mean differences (MD) with corresponding 95% confidence intervals (CIs) were calculated in a random-effects model. RESULTS: Twenty-four studies included 6730 adult patients (1208 nonsurvivors and 5522 survivors) and three studies included 195 paediatric patients (30 nonsurvivors and 165 survivors). A total of 10, 4 and 13 studies included, respectively, patients with sepsis (3602 patients), septic shock (386 patients) and a mixed population (2937 patients). Twenty-one studies included patients with different source of infection, three with pneumonia and one with a catheter-related infection. Most studies (n = 12) had a follow-up of 28 days. In adult cohort, pooled mean difference between nonsurvivors and survivors of MR-proADM was 2.55 mmol/L (95% CI: 1.95-3.15) with higher values in patients with septic shock (4.25 mmol/L; 95% CI, 2.23-6.26 mmol/L) than in patients with sepsis (1.77 mmol/L; 95% CI: 1.11-2.44 mmol/L). In paediatric cohort, pooled mean difference was 3.11 mmol/L (95% CI: -0.02-6.24 mmol/L). CONCLUSIONS: Higher values of MR-proADM are detectable in nonsurvivors adult and paediatric-hospitalized patients with sepsis or septic shock.

Efficacy and Safety of Hydrocortisone, Ascorbic Acid, and Thiamine Combination Therapy for the Management of Sepsis and Septic Shock: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

INTRODUCTION: This systematic review aimed to assess the efficacy and safety of hydrocortisone, ascorbic acid, and thiamine (HAT) combination therapy in patients with sepsis and septic shock. METHODS: We conducted a database search in MEDLINE, Embase, CENTRAL, Web of Science, and CNKI for randomised controlled trials (RCTs) comparing HAT against placebo/standard of care or against hydrocortisone in sepsis/septic shock patients. Outcomes included mortality, ICU/hospital length of stay (LOS), vasopressor durations, mechanical ventilation durations, change in SOFA at 72 h, and adverse events. RCT results were pooled in random-effects meta-analyses. Quality of evidence was assessed using GRADE. RESULTS: Fifteen RCTs (N = 2,594) were included. At 72 h, HAT reduced SOFA scores from baseline (mean difference [MD] -1.16, 95% confidence interval [CI]: -1.58 to -0.74, I2 = 0%) compared to placebo/SoC, based on moderate quality of evidence. HAT also reduced the duration of vasopressor use (MD -18.80 h, 95% CI: -23.67 to -13.93, I2 = 64%) compared to placebo/SoC, based on moderate quality of evidence. HAT increased hospital LOS (MD 2.05 days, 95% CI: 0.15-3.95, I2 = 57%) compared to placebo/SoC, based on very low quality of evidence. HAT did not increase incidence of adverse events compared to placebo/SoC. CONCLUSIONS: HAT appears beneficial in reducing vasopressor use and improving organ function in sepsis/septic shock patients. However, its advantages over hydrocortisone alone remain unclear. Future research should use hydrocortisone comparators and distinguish between sepsis-specific and comorbidity- or care-withdrawal-related mortality.

Marked hyperferritinemia in critically ill cancer patients.

OBJECTIVES: To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS: A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 µg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS: A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 µg/L (range: 10.300-426.073 µg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION: Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.

Sepsis and Septic Shock in Patients Undergoing Thyroidectomy: Incidence, Risk Factors, and Outcomes.

INTRODUCTION: Postoperative sepsis represents a rare complication following thyroidectomy. We aimed to explore the incidence, risk factors, sources, and outcomes of postoperative sepsis and septic shock among adult patients undergoing thyroidectomy. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program were used in this retrospective cohort study. Patients aged ≥18 y who underwent elective thyroidectomy between 2005 and 2019 were included. Multivariable binary logistic regression models were computed to explore risk factors and outcomes of 30-d sepsis and septic shock. RESULTS: Among the 180,373 included patients, 0.1% developed sepsis or septic shock. Male gender, low body mass index, American Society of Anesthesiologists classes 3-5, functional dependence, smoking, diabetes mellitus, pulmonary disease, inpatient surgery, malignant indication, clean-contaminated wound classification, and operation time ≥150 min were significant risk factors for development of sepsis or septic shock. Common infectious sources of sepsis included surgical site infections (29.6%), pneumonia (18.6%), urinary tract infections (16.2%), and multiple infections (6.9%). Patients with postoperative sepsis or septic shock were significantly more likely to develop complications, including wound disruption, stroke, cardiac and renal complications, thromboembolism, prolonged length of stay, unplanned reoperation, and mortality. CONCLUSIONS: Sepsis is rare following thyroidectomy. Our study provides insight into risk factors and procedural characteristics which may contribute to the development of postoperative sepsis or septic shock in this population.

Key summary of German national guideline for adult patients with nosocomial pneumonia- Update 2024 Funding number at the Federal Joint Committee (G-BA): 01VSF22007.

PURPOSE: This executive summary of a German national guideline aims to provide the most relevant evidence-based recommendations on the diagnosis and treatment of nosocomial pneumonia. METHODS: The guideline made use of a systematic assessment and decision process using evidence to decision framework (GRADE). Recommendations were consented by an interdisciplinary panel. Evidence analysis and interpretation was supported by the German innovation fund providing extensive literature searches and (meta-) analyses by an independent methodologist. For this executive summary, selected key recommendations are presented including the quality of evidence and rationale for the level of recommendation. RESULTS: The original guideline contains 26 recommendations for the diagnosis and treatment of adults with nosocomial pneumonia, thirteen of which are based on systematic review and/or meta-analysis, while the other 13 represent consensus expert opinion. For this key summary, we present 11 most relevant for everyday clinical practice key recommendations with evidence overview and rationale, of which two are expert consensus and 9 evidence-based (4 strong, 5 weak and 2 open recommendations). For the management of nosocomial pneumonia patients should be divided in those with and without risk factors for multidrug-resistant pathogens and/or Pseudomonas aeruginosa. Bacterial multiplex-polymerase chain reaction (PCR) should not be used routinely. Bronchoscopic diagnosis is not considered superior to´non-bronchoscopic sampling in terms of main outcomes. Only patients with septic shock and the presence of an additional risk factor for multidrug-resistant pathogens (MDRP) should receive empiric combination therapy. In clinically stabilized patients, antibiotic therapy should be de-escalated and focused. In critically ill patients, prolonged application of suitable beta-lactam antibiotics should be preferred. Therapy duration is suggested for 7-8 days. Procalcitonin (PCT) based algorithm might be used to shorten the duration of antibiotic treatment. Patients on the intensive care unit (ICU) are at risk for invasive pulmonary aspergillosis (IPA). Diagnostics for Aspergillus should be performed with an antigen test from bronchial lavage fluid. CONCLUSION: The current guideline focuses on German epidemiology and standards of care. It should be a guide for the current treatment and management of nosocomial pneumonia in Germany.

Rare case of septic shock combined with meningitis caused by Pasteurella multocida without a history of cat and dog bites.

BACKGROUND: Pasteurella multocida is a zoonotic pathogen that mainly causes local skin and soft tissue infections in the human body through cat and dog bites. It rarely causes bacteraemia (or sepsis) and meningitis. We reported a case of septic shock and meningitis caused by P. multocida in a patient without a history of cat and dog bites. CASE PRESENTATION: An 84-year-old male patient was urgently sent to the emergency department after he was found with unclear consciousness for 8 h, accompanied by limb tremors and urinary incontinence. In the subsequent examination, P. multocida was detected in the blood culture and wound secretion samples of the patient. However, it was not detected in the cerebrospinal fluid culture, but its DNA sequence was detected. Therefore, the patient was clearly diagnosed with septic shock and meningitis caused by P. multocida. The patient had no history of cat or dog contact or bite. The patient was subsequently treated with a combination of penicillin G, doxycycline, and ceftriaxone, and he was discharged after 35 days of hospitalisation. CONCLUSION: This report presented a rare case of septic shock and meningitis caused by P. multocida, which was not related to a cat or dog bite. Clinical doctors should consider P. multocida as a possible cause of sepsis or meningitis and should be aware of its potential seriousness even in the absence of animal bites.

The prognostic importance of the pan-immune-inflammation value in patients with septic shock.

INTRODUCTION: The purpose of this study was to determine whether the pan-immune-inflammation value (PIV), a novel biomarker combining neutrophil platelet, monocyte, and lymphocyte counts, some of the most widespread indicators of systemic inflammation, can predict mortality and prognosis in patients admitted to the intensive care unit (ICU) with septic shock. METHOD: This prospective study was performed with 82 patients aged 18 or over admitted to a tertiary ICU with diagnoses of septic shock. Patients with hematological disease and neutropenia were excluded. PIV was calculated with the formula [neutrophil count (103/µL) × platelet count (103/µL) × monocyte count (103/µL)]/lymphocyte count (103/µL). RESULTS: Median age, presence of hypertension, Acute Physiology and Chronic Health Evaluation II (APACHE II) levels, and neutrophil, monocyte, and platelet counts were lower in the low-PIV group than in the high-PIV group (p < 0.05). The highest area under ROC curve (AUC) was determined for Sequential Organ Failure Assessment (SOFA) (0.94 (0.89 - 0.99)), followed by Glasgow Coma Scale (GCS) (0.81 (0.70 - 0.91)), APACHE II (0.80 (0.69 - 0.91)) and lactate (0.77 (0.67 - 0.88)). Median survival was longer in the low-PIV group than in the high-PIV group (28 (15.25 - 40.76) vs 16 (9.46 - 22.55) days, respectively, p < 0.05). The univariate Cox proportional hazards (CPH) model showed that high PIV (HR = 2.13 (1.03-4.38)), low GCS (HR = 3.31 (1.34 - 8.15)), high SOFA (HR = 9.41 (2.86 - 30.95)), high APACHE II (HR = 3.08 (1.47 - 6.45)), high lactate (HR = 6.56 (2.73 - 15.75)), and high procalcitonin (PCT) (HR = 2.73 (1.11 - 6.69)) values were associated with a decreased survival time among ICU patients (p < 0.05). The multivariate CPH model showed the age-adjusted risk estimates for these six laboratory parameters. High lactate (HR = 7.97 (2.19 - 29.08)) and high SOFA scores (HR = 4.85 (1.22 - 19.32)) were significantly associated with shorter survival in ICU patients (p < 0.05). CONCLUSION: The findings of this research suggest that PIV could predict the longer survival in patients with septic shock. Despite PIV score's capability to show inflammation, it is not significantly associated with mortality in the multivariate analysis.

Persistent bacteremia caused by Ralstonia pickettii and Microbacterium: a case report.

BACKGROUND: Ralstonia pickettii is a low virulent, gram-negative bacillus that is rarely associated with human infections and may cause bacteremia. Microbacterium species are gram-positive coryneforms that are generally considered as a contaminant in Gram staining of blood cultures, especially when the time to positivity is longer than 48 h. Both these bacterial species are emerging opportunistic pathogens that may occasionally cause serious infections and even life-threatening health conditions. CASE PRESENTATION: Here, we report the case of a patient with bacteremia caused by both R. pickettii and Microbacterium. We advocate for providers to order rapid antibiotic susceptibility testing, since our patient's suffered two kinds of rare pathogens with the opposite of drug sensitivity results to imipenem. CONCLUSIONS: Our case present a patient suffered septic shock caused by R. pickettii and Microbacterium. Improving the antibiotic management based on the result of antimicrobial susceptibility tests is the key of successful treatment.

The prehospital NEW score to assess septic shock in-hospital, 30-day and 90-day mortality.

BACKGROUND: The early identification of sepsis presenting a high risk of deterioration is a daily challenge to optimise patient pathway. This is all the most crucial in the prehospital setting to optimize triage and admission into the appropriate unit: emergency department (ED) or intensive care unit (ICU). We report the association between the prehospital National Early Warning Score 2 (NEWS-2) and in-hospital, 30 and 90-day mortality of SS patients cared for in the pre-hospital setting by a mobile ICU (MICU). METHODS: Septic shock (SS) patients cared for by a MICU between 2016, April 6th and 2021 December 31st were included in this retrospective cohort study. The NEWS-2 is based on 6 physiological variables (blood pressure, heart rate, respiratory rate, temperature, oxygen saturation prior oxygen supplementation, and level of consciousness) and ranges from 0 to 20. The Inverse Probability Treatment Weighting (IPTW) propensity method was applied to assess the association with in-hospital, 30 and 90-day mortality. A NEWS-2 ≥ 7 threshold was chosen for increased clinical deterioration risk definition and usefulness in clinical practice based on previous reports. RESULTS: Data from 530 SS patients requiring MICU intervention in the pre-hospital setting were analysed. The mean age was 69 ± 15 years and presumed origin of sepsis was pulmonary (43%), digestive (25%) or urinary (17%) infection. In-hospital mortality rate was 33%, 30 and 90-day mortality were respectively 31% and 35%. A prehospital NEWS-2 ≥ 7 is associated with an increase in-hospital, 30 and 90-day mortality with respective RRa = 2.34 [1.39-3.95], 2.08 [1.33-3.25] and 2.22 [1.38-3.59]. Calibration statistic values for in-hospital mortality, 30-day and 90-day mortality were 0.54; 0.55 and 0.53 respectively. CONCLUSION: A prehospital NEWS-2 ≥ 7 is associated with an increase in in-hospital, 30 and 90-day mortality of septic shock patients cared for by a MICU in the prehospital setting. Prospective studies are needed to confirm the usefulness of NEWS-2 to improve the prehospital triage and orientation to the adequate facility of sepsis.

The Effect of Albumin Replacement on Vasopressor Duration in Septic Shock in Patients With Hypoalbuminemia.

BACKGROUND: The use of albumin resuscitation in septic shock is only recommended in patients who have received large volumes of crystalloid resuscitation regardless of serum albumin concentration. The role of albumin is still largely debated and evidence to support its use still lacking. OBJECTIVE: The objective of this study was to evaluate whether albumin replacement increases the number of vasopressor-free days in patients with septic shock and hypoalbuminemia. METHODS: A retrospective analysis was conducted to assess the effect of albumin replacement in septic shock. Hypoalbuminemic patients with septic shock who received albumin were retrospectively compared with a cohort who did not. The primary outcome was number of vasopressor-free days at day 14 from shock presentation, which was analyzed using an adjusted linear regression model to adjust for confounders. RESULTS: There was no difference in vasopressor-free days at day 14 in patients who received albumin versus those who did not, after adjusting for confounders of exposure (0.50, 95% CI = -0.97 to 1.97; P = 0.502). There also was no difference in secondary outcomes except for need for invasive mechanical ventilation (MV), which was significantly lower in patients who received albumin (61 [54.4%] vs 88 [67.7%]; P = 0.035). CONCLUSIONS AND RELEVANCE: We observed no difference in vasopressor-free days at day 14 in patients with hypoalbuminemia who received albumin compared with those who did not. However, patients who received albumin required significantly less MV although further studies are warranted to assess this effect.

Clinical Response to Third-Line Angiotensin-II vs Epinephrine in Septic Shock: A Propensity-Matched Cohort Study.

BACKGROUND: The appropriate third-line vasopressor in septic shock patients receiving norepinephrine and vasopressin is unknown. Angiotensin-II (AT-II) offers a unique mechanism of action to traditionally used vasopressors in septic shock. OBJECTIVE: The objective of this study was to compare the clinical efficacy and safety of third-line AT-II to epinephrine in patients with septic shock. METHODS: A single-center, retrospective cohort study of critically ill patients was performed between April 1, 2019 and July 31, 2022. Propensity-matched (2:1) analysis compared adults with septic shock who received third-line AT-II to controls who received epinephrine following norepinephrine and vasopressin. The primary outcome was clinical response 24 hours after third-line vasopressor initiation. Additional efficacy and safety outcomes were investigated. RESULTS: Twenty-three AT-II patients were compared with 46 epinephrine patients. 47.8% of AT-II patients observed a clinical response at hour 24 compared with 28.3% of epinephrine patients (P = 0.12). In-hospital mortality (65.2% vs 73.9%, P = 0.45), cardiac arrhythmias (26.1% vs 26.1%, P = 0.21), and thromboembolism (4.3% vs 2.2%, P = 0.61) were not observed to be statistically different between groups. CONCLUSIONS AND RELEVANCE: Administration of AT-II as a third-line vasopressor agent in septic shock patients was not associated with significantly improved clinical response at hour 24 compared with epinephrine. Although underpowered to detect meaningful differences, the clinical observations of this study warrant consideration and further investigation of AT-II as a third-line vasopressor in septic shock.

Administration of methylene blue in septic shock: pros and cons.

Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

Fluid management for sepsis-induced hypotension in patients with advanced chronic kidney disease: a secondary analysis of the CLOVERS trial.

BACKGROUND: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD. METHODS: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90. RESULTS: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1). CONCLUSIONS: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy. TRIAL REGISTRATION: NCT03434028 (2018-02-09), BioLINCC 14149.