Sex differences in sepsis outcomes across the lifespan: a population-based cohort study in Germany

Critical Care volume 29, Article number: 408 (2025) Published: 26 September 2025

 

Importance

Sepsis is a major global health concern influenced by both biological sex and socially constructed gender roles, which can affect disease susceptibility, progression, treatment and outcomes. Evidence on sex-specific differences in sepsis often lacks age-specific analysis, despite known interactions between sex, age, and immune function.

Objective

We aimed to investigate age-dependent associations between sex and mortality as well as long-term outcomes among sepsis survivors after hospitalization.

Design, setting, and participants

This retrospective, population-based cohort study based on nationwide health claims data from 2009 to 2017 of 23.0 million beneficiaries of a large German health insurance provider. Patients aged 15 years and older with incident hospital-treated sepsis identified by ICD-10-GM codes in 2013 to 2014 were included.

Exposures

Female and male sex.

Main outcomes and measures

Differences in 12-months mortality, medical, psychological and cognitive diagnoses, as well as dependency on nursing care by sex and age were analyzed using generalized additive models including sex*age interaction effects. We report average marginal effects (AME) for sex and age as estimates of the adjusted marginal increase or decrease of the event rate of outcomes.

Results

We included 159,684 sepsis patients in 2013/2014, of which 75,809 (47.5%) were female and 83,875 (52.5%) were male. The average marginal hospital and 12-months mortality over the observed age distribution was AME = − 2.8% (95% CI, − 3.2%, − 2.3%, P < .001) and AME = − 5.4% (95% CI, − 5.9%, − 4.9%, P < .001) lower in females, respectively. Significant female survival benefits were predominantly found beyond age 44 (hospital mortality) and age 47 (12-months mortality). Females were also less often affected by cognitive impairments, but more often experienced psychological and physical impairments as well as nursing care dependency with differential associations observable across the lifespan.

Conclusion and relevance

Sepsis long-term outcomes appear to be influenced by a complex interaction between age and sex. While our study focuses on these factors, it is important to acknowledge that observed associations cannot be attributed to biological sex alone, as numerous additional factors - directly or indirectly related to sex- may also contribute. These findings underscore the importance of incorporating sex-specific considerations into sepsis care and post-acute support strategies to improve long-term outcomes.

Critical Care Bulletin: August 2025

 

Immunosuppressive therapy management during sepsis in kidney transplant recipients: a prospective multicenter study

Annals of Intensive Care volume 15, Article number: 116, Published: 10 August 2025

Background

Sepsis is the leading cause of Intensive Care Unit (ICU) admissions in kidney transplant recipients (KTRs). However, the optimal immunosuppressive therapy (IST) management in this context is not well-defined. We aimed to evaluate the impact of IST management in the ICU on mortality rates and kidney graft function 6 months after inclusion in KTRs admitted for sepsis.

Methods

We conducted a multicenter, prospective, observational study over 1 year in 11 French ICUs. Inclusion criteria were all KTRs who have been transplanted for at least 3 months, admitted to the ICU for sepsis. All changes of IST (7 days prior to ICU admission or throughout the ICU stay) were collected. The primary outcome was MAKE 180 (Major Adverse Kidney Event), a composite outcome including mortality, kidney graft dysfunction and dialysis requirement at 180 days after inclusion.

Results

One hundred and twenty-four patients were included. The main cause of ICU admission was respiratory failure for 78 patients (62.9%). Predominant IST management was mycophenolic acid (MPA) discontinuation for 74 patients (59.7%) and calcineurin inhibitor (CNI) continuation for 63 patients (50.8%). By multivariable analysis, after adjustment for age, non-renal SOFA score at admission, kidney function at admission, sex, and history of cellular rejection we did not find any significant association between MAKE 180 and CNI discontinuation (adjusted OR = 1.05, 95% CI 0.87–1.26, p = 0.6). In contrast, MPA discontinuation was significantly associated with MAKE 180 (adjusted OR = 1.45, 95% CI 1.07–1.96, p = 0.018). No significant association was found between IST discontinuation and ICU-acquired infections (adjusted OR = 1.14, 95% CI 0.95–1.36, p = 0.157). Among ICU survivors, only 2 graft rejections occurred during the year following ICU discharge.

Conclusion

This study is the first prospective investigation to suggest an association between MPA discontinuation and adverse outcomes during sepsis in critically-ill KTRs. These findings must be interpreted with caution given the potential confounding introduced by SARS-Cov-2–specific treatment protocols. Further interventional trials are necessary to optimize immunosuppressive drug strategies in KTRs during sepsis.

 

Effectiveness of targeted post-acute interventions and follow-up services for sepsis survivors: a systematic review

Critical Care volume 29, Article number: 351, Published: 08 August 2025

Background

The majority of sepsis survivors suffer from significant long-term consequences, including cognitive, psychological, and physical impairments. Despite growing recognition of these challenges, there is a lack of robust evidence regarding effective post-acute interventions to improve long-term outcomes. This systematic review aims to compile the present evidence on the effectiveness of post-acute interventions and follow-up services on patient-relevant long-term outcomes of sepsis survivors.

Methods

PubMed, Web of Science and ClinicalTrials.gov were searched for relevant publications from 01/2013 until 08/2024. Studies evaluating the effect of targeted post-acute interventions and follow-up services compared to usual care were included. Risk of bias was assessed using the RoB2- and ROBINS-I tool.

Results

Fourteen studies including 383,680 patients from high-income-countries were identified. All included studies showed either a moderate risk of bias (non-randomized studies) or some concerns (randomized trials), primarily due to residual confounding, suboptimal blinding and outcome assessment. Interventions varied substantially in terms of measures, implementation time and outcomes addressed. Rehabilitation interventions were associated with long-term survival benefits until 10 years after sepsis according to three observational studies. Additionally, one randomized controlled trial with minimization found that an 8-week exercise-based intervention improved the anaerobic threshold in sepsis survivors. Interventions (n = 7) targeting care coordination and follow-up bundles led to reductions in rehospitalization rates and mortality until 12 months post-discharge and were associated with improvements in long-term physical function and PTSD symptoms. An ICU-specific virtual reality-based intervention may reduce symptoms of PTSD and depression up to six months after exposure.

Conclusion

Post-acute interventions, such as care coordination, bundle approaches, and rehabilitation can improve patient-relevant outcomes in sepsis survivors. However, the overall number of existing studies is small, all studies may be affected by certain forms of bias and for some domains of post-sepsis impairment no specific interventions have yet been identified. Therefore, further high-quality prospective follow-up studies are needed to strengthen the evidence regarding the effectiveness and acceptability of interventions across all domains of post-sepsis impairments, particularly cognitive impairments.

 

Targeting high circulating dipeptidyl peptidase 3 in circulatory failure

Critical Care volume 29, Article number: 340, Published: 31 July 2025

Abstract

Circulating dipeptidyl peptidase 3 is a new biomarker linked to circulatory failure prognosis and pathophysiology and is a potential actionable therapeutic target. In this short review intended for the clinician, a question-and-answer format provides key insights on the nature of this biomarker and the therapeutical potential of its targeted inhibition in critically ill patients.

 

Post-extubation dysphagia in the ICU−a narrative review: epidemiology, mechanisms and clinical management (Update 2025)

Critical Care volume 29, Article number: 244 (2025) 

Abstract

Dysphagia (i.e. an impairment in swallowing function that impacts on safety or efficiency) is present in many intensive care unit (ICU) survivors, in particular following extubation (“post-extubation dysphagia”, PED). Despite the fact that pathomechanisms leading to PED are currently incompletely understood, local as well as central neurological and neuromuscular dysfunctions may be key to development of PED. Data from prospective large-scale clinical investigations with systematic screening demonstrate that PED affects about one out of five (about 20%) of mixed medical-surgical unplanned (emergency) ICU admissions. PED is associated with an increased risk for aspiration, aspiration-induced pneumonia, malnutrition, increased ICU resource use, decreased quality of life, prolonged ICU- and hospital length of stay and increased overall morbidity and mortality. Data demonstrate that PED is an independent predictor of 90-day mortality with increased risk of death up to about one year after ICU admission. PED may be a somewhat overlooked medical problem since in many ICUs, PED is currently not routinely screened for in all patients at risk (i.e. all ICU patients) following extubation. In this review, we update the available data on PED with a focus on epidemiology, risk factors, potential aetiology and treatment approaches, as well as clinical management on ICUs.

 

Severe listeriosis in intensive care units: insights from a retrospective multicentric study

Critical Care volume 29, Article number: 201 Published: 19 May 2025

Background

Listeriosis is a rare but severe foodborne infection, particularly affecting immunocompromised individuals and older adults. Severe cases may lead to neurolisteriosis and sepsis, necessitating intensive care unit (ICU) admission. This study aims to analyze the demographic characteristics, clinical presentation, microbiological findings, treatments, and outcomes of critically ill patients with Listeria infections in the ICU.

Methods

A retrospective multicenter study was conducted across 23 French hospitals over a 10-year period, including ICU patients with culture-confirmed Listeria monocytogenes infections. Data on demographics, comorbidities, ICU admission characteristics, biological and microbiological parameters, treatments, and outcomes were collected. The primary outcome was ICU mortality. A multivariable logistic regression model was used to identify factors associated with mortality in patients with neurological manifestations.

Results

A total of 110 patients were included, with a median age of 68 years; 61% were male, and 71% were immunocompromised. Neurological involvement was present in most cases. Invasive mechanical ventilation was required in 58% of patients, and vasopressor support in 44%. ICU and in-hospital mortality rates were 25% and 32%, respectively. Among patients with neurolisteriosis, each 1-point decrease in Glasgow Coma Scale score at admission was associated with increased mortality (OR, 1.22; 95% CI 1.05–1.45; p = 0.009), as were higher cerebrospinal fluid (CSF) protein levels (OR, 1.56; 95% CI 1.15–2.41; p = 0.028). Steroid use was not significantly associated with reduced mortality (OR, 0.30; 95% CI 0.07–1.05; p = 0.076).

Conclusion

Listeriosis requiring ICU admission is associated with high morbidity and mortality, particularly in older and immunocompromised patients. The severity of these infections is reflected by the frequent need for organ support. Further research is needed to clarify the potential role of steroids in neurolisteriosis.

 

Identifying a unique signature of sepsis in patients with pre-existing cirrhosis

Critical Care volume 29, Article number: 199 Published: 19 May 2025

Background

The pre-existing diagnosis of cirrhosis is a complicating factor in the progression and prognosis of sepsis; however, the unique epidemiology, sepsis characteristics, and underlying mechanisms of immune dysregulation in sepsis among patients with cirrhosis remain incompletely understood. Our primary objective was to identify clinical outcomes and biological characteristics that differ between patients with and without cirrhosis among critically ill patients with sepsis.

Methods

We analyzed data from a prospective cohort of critically ill patients presenting to single center with sepsis. Subjects were followed for 6 days for the development of acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), and 30 days for mortality. Inflammatory, endothelial, and coagulopathic proteins were measured in plasma collected at ICU admission in a subset of patients. We determined associations of cirrhosis with outcomes using multivariable logistic regression adjusting for pre-specified confounders. We tested differences in plasma protein levels by cirrhosis diagnosis using the Wilcoxon Rank-sum test.

Results

We enrolled 2962 subjects, 371 (13%) of whom had a pre-existing diagnosis of cirrhosis. Patients with cirrhosis had higher severity of illness scores, were more likely to have an abdominal source of sepsis, and had more significant clinically measured coagulation abnormalities relative to patients without cirrhosis. In multivariate analysis, cirrhosis was associated with higher AKI risk (adjusted OR 1.65; 95% CI 1.21 to 2.26; P = 0.002), and 30-day mortality (adjusted OR 1.38; 95% CI 1.05 to 1.82; P = 0.022). There was no significant difference in risk for ARDS (adjusted OR 1.02; 95% CI 0.69 to 1.50; P = 0.92). Cirrhosis was associated with higher plasma levels of angiopoietin-2 (P < 0.001), von Willebrand factor (P < 0.001), and soluble thrombomodulin (P < 0.001), as well as lower levels of interleukin (IL)-10 (P < 0.001), IL-1β (P = 0.008), and IL-1RA (P = 0.036). There were no significant differences in levels of IL-6 (P = 0.30).

Conclusions

We identified associations between pre-existing cirrhosis and endothelial injury, AKI, and mortality in sepsis. Patients with pre-existing cirrhosis who develop sepsis may display a unique phenotype of endothelial dysfunction that requires unique targeted approaches.

 

Extremely early initiation of vasopressors might not decrease short-term mortality for adults with septic shock: a systematic review and meta-analysis

Annals of Intensive Care volume 15, Article number: 18 (2025)

Published: 27 January 2025

Background

The optimal timing for initiating vasopressor therapy in patients with septic shock remains unclear. This study aimed to assess the impact of early versus late vasopressor initiation on clinical outcomes.

Methods

A systematic review and meta-analysis were conducted by searching PubMed, Embase, and Cochrane databases. Studies comparing early and late vasopressor administration in septic shock patients were included. The primary outcome was short-term mortality, and subgroup analyses were performed based on different initiation timings.

Results

Eleven studies with 6,661 patients were included. Different studies define the ‘early administration’ timeframe variously, ranging from one to seven hours. No significant difference in short-term mortality was observed between early and late administration in the combined analysis of 3,757 patients from two RCTs and three quasi-experimental studies (OR: 0.66, 95% CI: [0.36, 1.19], I²: 82%). However, lower mortality was found in subgroups with early but not extremely early initiation (one to three hours, OR: 0.70, 95% CI: [0.60, 0.82], I²: 0%), and those using septic shock diagnosis as time zero (OR: 0.64, 95% CI: [0.48, 0.85], I²: 39%).

Conclusion

Our findings found that earlier initiation of vasopressor therapy, particularly within one to three hours after the diagnosis of septic shock, may be associated with reduced short-term mortality in certain subgroups. However, due to the heterogeneity in study definitions and potential confounding factors, these results should be interpreted cautiously. Further standardized investigations are warranted to precisely determine the optimal timing for vasopressor initiation to maximize survival outcomes in patients with septic shock.

 

The role of phospholipid transfer protein in sepsis-associated acute kidney injury

Critical Care volume 29, Article number: 33 (2025) 

Published: 20 January 2025

Background

Phospholipid transfer protein (PLTP), a glycoprotein widely expressed in the body, is primarily involved in plasma lipoprotein metabolism. Previous research has demonstrated that PLTP can exert anti-inflammatory effects and improve individual survival in patients with sepsis and endotoxemia by neutralizing LPS and facilitating LPS clearance. However, the role of PLTP in sepsis-associated acute kidney injury (SA-AKI) and the specific mechanism of its protective effects are unclear. This study aimed to assess the potential role of PLTP in SA-AKI.

Methods

This is a population-based prospective observational study of patients with sepsis admitted to the intensive care unit. Blood samples were collected on days 1, 3, 5, and 7 after admission to the ICU. Plasma PLTP lipotransfer activity was measured to assess outcomes, including the incidence of SA-AKI and 30-day major adverse kidney events (MAKE 30). The correlation between PLTP lipotransfer activity and SA-AKI and MAKE 30 was evaluated through logistic regression modeling. Receiver operating characteristic curves were used to assess the diagnostic value of PLTP lipotransfer activity for SA-AKI and MAKE 30. The PLTP lipotransfer activity was categorized into high and low groups based on the optimal cut-off values. The differences between the high and low PLTP lipotransfer activity groups in terms of MAKE 30 were evaluated using Kaplan–Meier analysis. The SA-AKI mouse model was established via cecum ligation and puncture (CLP) in the animal experimental phase. The impact of PLTP on renal function was then investigated in wild-type and PLTP ± mice. The wild-type mice were given recombinant human PLTP (25 μg, 200 μL each/dose) via the tail vein at 1-, 7-, and 23-h intervals on the day preceding CLP. The control group received an equal volume of solvent. The 10-day survival and kidney function among the treatment groups were then evaluated.

Results

A total of 93 patients were enrolled in this clinical trial, of which 52 developed acute kidney injury (AKI). A total of 32 patients died over the course of the 30-day follow-up period, 34 underwent kidney replacement therapy, 37 developed persistent acute kidney injury, and 55 patients met the composite endpoint. The plasma PLTP lipotransfer activity was identified as an independent predictor of SA-AKI (crude OR = 0.96, 95% CI 0.95–0.98, p < 0.001; adjusted OR = 0.92, 95% CI 0.86–0.96, p = 0.001) and MAKE 30 (crude OR = 0.97, 95% CI 0.96–0.98, p < 0.001; adjusted OR = 0.96, 95% CI 0.93–0.98, p = 0.001). The area under the curve (AUC) of plasma PLTP lipotransfer activity within 24 h of ICU admission could predict the occurrence of SA-AKI and MAKE 30 in septic patients (AUC values; 0.87 (95% CI 0.79–0.94) and 0.87 (95% CI 0.80–0.94), respectively). The cumulative incidence of main kidney adverse events was significantly lower in the high group than in the low group (p < 0.001). Compared with the controls, creatinine levels were significantly elevated in the CLP mice, while PLTP lipotransfer activity was significantly decreased at 24 h postoperatively. Moreover, the PTLP ± mice exhibited significantly impaired renal function and markedly elevated plasma levels of inflammatory mediators compared with the wild-type CLP mice. Notably, human recombinant PTLP significantly prolonged 10-day survival, improved renal function, and attenuated mitochondrial structural damage in wild-type CLP mice.

Conclusions

These findings indicate that PLTP is a potential therapeutic target in sepsis-associated acute kidney injury.

 

Left ventricular diastolic dysfunction is prevalent but not associated with mortality in patients with septic shock

Intensive Care Medicine: Volume 51, pages 94-105, (2025)

Published: 07 January 2025

Purpose

Prognostic impact of left ventricular diastolic dysfunction (LVDD) in septic shock patients has not been determined using current diagnostic guidelines. We assessed the relation between LVDD during the first 3 days following intensive care unit (ICU) admission for septic shock and Day-28 mortality.

Methods

This prospective, multicenter, observational study enrolled 402 patients (age: 63 ± 13 year; 59% male; SAPS II: 59 ± 20; SOFA: 9.4 ± 3.6; mechanical ventilation: 74%) with septic shock (Sepsis-3 definition). Patients were echocardiographically assessed within 12 h after admission (Day 1), on Day 2, Day 3, at ICU and at hospital discharge (or Day 28 whichever occurred first), using 2016 American-European guidelines.

Results

LVDD was present at least once between Day 1 and 3 in 304 patients (76%), and in 56% and 44% of patients at ICU discharge and on Day 28 (or hospital discharge), respectively (43% of patients with follow-up). Seventy-eight of 172 patients (45%) exhibited similar LV diastolic properties throughout the study period while 58 patients (34%) improved their LVDD at follow-up (lower grade: n = 9, regression: n = 49). Day-28 mortality was not statistically different between patients with and without LVDD (80/304 [26%] vs. 25/88 [28%]; OR: 0.900 [0.530–1.527]; p = 0.696). Similar results were obtained when adjusting the multivariate model on SAPSII or SOFA score on admission, together with fluid balance during the first three days of ICU stay (OR: 0.838 [0.471–1.491]: p = 0.547 and OR: 0.887 [0.513–1.534]: p = 0.668, respectively).

Conclusion

LVDD was highly prevalent in patients with septic shock but not associated with mortality. It appeared improving in one-third of survivors.

 

Sex matters: Is it time for a SOFA makeover?

by Emma Larsson 

Critical Care 28, Article number: 268 (2024) Published 8 August 2024

While sepsis affects individuals regardless of sex, emerging research has highlighted notable differences in how women and men experience, respond to, and recover from sepsis treated in intensive care units (ICU). These differences are influenced by a complex interplay of biological, hormonal, and sociocultural factors. As we explore sepsis management in ICU settings, it becomes evident that understanding the factors contributing to these sex-based variations is important for tailoring therapeutic approaches and improving overall patient outcomes. Moreover, for a nuanced interpretation of current evidence, it is worth noting the distinction between the terms gender and sex: gender refers to the socially constructed roles and behaviors that a given society considers appropriate, while sex pertains to biological characteristics...

 

Impaired angiotensin II signaling in septic shock

 

by Adrien Picod, Bruno Garcia, Dirk Van Lier, Peter Pickkers, Antoine Herpain, Alexandre Mebazaa and Feriel Azibani 

 

Annals of Intensive Care volume 14, Article number: 89 Published: 14 June 2024

 

Abstract

Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II—angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin–angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin–angiotensin–aldosterone system alterations in septic shock should help to decipher patients’ phenotypes and to implement targeted interventions.

 

Prognostic differences in sepsis caused by gram-negative bacteria and gram-positive bacteria: a systematic review and meta-analysis

 

by Aling Tang, Yi Shi, Qingqing Dong, Sihui Wang, Yao Ge, Chenyan Wang, Zhimin Gong, Weizhen Zhang and Wei Chen 

 

Critical Care volume 27, Article number: 467 (2023) Published: 30 November 2023

 

Background

Bacteria are the main pathogens that cause sepsis. The pathogenic mechanisms of sepsis caused by gram-negative and gram-positive bacteria are completely different, and their prognostic differences in sepsis remain unclear.

Methods

The PubMed, Web of Science, Cochrane Library, and Embase databases were searched for Chinese and English studies (January 2003 to September 2023). Observational studies involving gram-negative (G (−))/gram-positive (G (+)) bacterial infection and the prognosis of sepsis were included. The stability of the results was evaluated by sensitivity analysis. Funnel plots and Egger tests were used to check whether there was publication bias. A meta-regression analysis was conducted on the results with high heterogeneity to identify the source of heterogeneity. A total of 6949 articles were retrieved from the database, and 45 studies involving 5586 subjects were included after screening according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-seven high-quality studies and 18 moderate-quality studies were identified according to the Newcastle‒Ottawa Scale score. There was no significant difference in the survival rate of sepsis caused by G (−) bacteria and G (+) bacteria (OR 0.95, 95% CI 0.70–1.28). Subgroup analysis according to survival follow-up time showed no significant difference. The serum concentrations of C-reactive protein (CRP) (SMD = 0.39, 95% CI 0.02–0.76), procalcitonin (SMD = 1.95, 95% CI 1.32–2.59) and tumor necrosis factor-alpha (TNF-α) (MD = 0.31, 95% CI 0.25–0.38) in the G (−) bacterial infection group were significantly higher than those in the G (+) bacterial infection group, but there was no significant difference in IL-6 (SMD = 1.33, 95% CI − 0.18–2.84) and WBC count (MD = − 0.15, 95% CI − 0.96–00.66). There were no significant differences between G (−) and G (+) bacteria in D dimer level, activated partial thromboplastin time, thrombin time, international normalized ratio, platelet count, length of stay or length of ICU stay. Sensitivity analysis of the above results indicated that the results were stable.

Conclusion

The incidence of severe sepsis and the concentrations of inflammatory factors (CRP, PCT, TNF-α) in sepsis caused by G (−) bacteria were higher than those caused by G (+) bacteria. The two groups had no significant difference in survival rate, coagulation function, or hospital stay. The study was registered with PROSPERO (registration number: CRD42023465051).

 

 

 

 

 

 

 

 

Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial

 

by Chevret Sylvie, Bouadma Lila, Dupuis Claire, Burdet Charles and Timsit Jean-François 

 

Annals of Intensive Care volume 13, Article number: 75 (2023)

 

Background

The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC).

Methods

We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects.

Results

Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not.

Conclusions

In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings.

 

Time to treatment and mortality for clinical sepsis subtypes

 

by Anne Yang, Jason N. Kennedy, Katherine M. Reitz, Gary Phillips, Kathleen M. Terry, Mitchell M. Levy, Derek C. Angus and Christopher W. Seymour 

 

Critical Care volume 27, Article number: 236 Published: 15 June 2023

 

Background

Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations.

Methods

Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, β, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality.

Results

55,169 hospitalizations from 155 hospitals were included (34% α, 30% β, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02–1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02–1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05–1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99–1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97–1.01]) and did not differ among subtypes (p-interaction = 0.41).

Conclusion

Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype.

 

Influence of gender on age-associated in-hospital mortality in patients with sepsis and septic shock: a prospective nationwide multicenter cohort study

by Ryoung-Eun Ko, Danbee Kang, Juhee Cho, Soo Jin Na, Chi Ryang Chung, Sung Yoon Lim, Yeon Joo Lee, Sunghoon Park, Dong Kyu Oh, Su Yeon Lee, Mi Hyeon Park, Haein Lee, Chae-Man Lim and Gee Young Suh 

Critical Care volume 27, Article number: 229 Published: 11 June 2023

 

Background

Numerous epidemiological studies investigating gender-dependent clinical outcomes in sepsis have shown conflicting evidence. This study aimed to investigate the effect of gender on in-hospital mortality due to sepsis according to age group.

Methods

This study used data from the Korean Sepsis Alliance, an ongoing nationwide prospective multicenter cohort from 19 participating hospitals in South Korea. All adult patients diagnosed with sepsis in the emergency departments of the participating hospitals between September 2019 and December 2021 were included in the analysis. Clinical characteristics and outcomes were compared between male and female. Eligible patients were stratified by age into 19–50 years, 50–80 years, and ≥ 80 years old individuals.

Results

During the study period, 6442 patients were included in the analysis, and 3650 (56.7%) were male. The adjusted odds ratio (OR) [95% confidence interval (CI)] for in-hospital mortality for male compared with female was 1.15 (95% CI = 1.02–1.29). Interestingly, in the age 19–50 group, the risk of in-hospital mortality for males was significantly lower than that of females [0.57 (95% CI = 0.35–0.93)]. For female, the risk of death remained relatively stable until around age 80 (P for linearity = 0.77), while in males, there was a linear increase in the risk of in-hospital death until around age 80 (P for linearity < 0.01). Respiratory infection (53.8% vs. 37.4%, p < 0.01) was more common in male, whereas urinary tract infection (14.7% vs. 29.8%, p < 0.01) was more common in female. For respiratory infection, male had significantly lower in-hospital mortality than female in the age 19–50 groups (adjusted OR = 0.29, 95% CI = 0.12–0.69).

Conclusions

Gender may influence age-associated sepsis outcomes. Further studies are needed to replicate our findings and fully understand the interaction of gender and age on the outcomes of patients with sepsis.

 

 

 

 

Critical Care Bulletin - April 2023

 

Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis

by Silei Sun, Daosheng Wang, Danfeng Dong, Lili Xu, Mengqi Xie, Yihui Wang, Tongtian Ni, Weisong Jiang, Xiaojuan Zhu, Ning Ning, Qian Sun, Shuyuan Zhao, Mengjiao Li, Peili Chen, Meiling Yu, Jian Li.

Critical Care volume 27, Article number: 127 (2023) Published: 28 March 2023

Background

The gut microbiome plays a pivotal role in the progression of sepsis. However, the specific mechanism of gut microbiota and its metabolites involved in the process of sepsis remains elusive, which limits its translational application.

Method

In this study, we used a combination of the microbiome and untargeted metabolomics to analyze stool samples from patients with sepsis enrolled at admission, then microbiota, metabolites, and potential signaling pathways that might play important roles in disease outcome were screened out. Finally, the above results were validated by the microbiome and transcriptomics analysis in an animal model of sepsis.

Results

Patients with sepsis showed destruction of symbiotic flora and elevated abundance of Enterococcus, which were validated in animal experiments. Additionally, patients with a high burden of Bacteroides, especially B. vulgatus, had higher Acute Physiology and Chronic Health Evaluation II scores and longer stays in the intensive care unit. The intestinal transcriptome in CLP rats illustrated that Enterococcus and Bacteroides had divergent profiles of correlation with differentially expressed genes, indicating distinctly different roles for these bacteria in sepsis. Furthermore, patients with sepsis exhibited disturbances in gut amino acid metabolism compared with healthy controls; namely, tryptophan metabolism was tightly related to an altered microbiota and the severity of sepsis.

Conclusion

Alterations in microbial and metabolic features in the gut corresponded with the progression of sepsis. Our findings may help to predict the clinical outcome of patients in the early stage of sepsis and provide a translational basis for exploring new therapies.

 

Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis

by Huang, Yu-Hsuan; Chen, Ching-Jung; Shao, Shih-Chieh; Li, Chih‑Huang; Hsiao, Chien-Han; Niu, Kuang-Yu; Yen, Chieh-Ching 

Critical Care Medicine ():10.1097/CCM.0000000000005820, March 06, 2023.

Objectives: 

We performed a systemic review and meta‐analysis to evaluate the diagnostic accuracy of monocyte distribution width (MDW) and to compare with procalcitonin and C‐reactive protein (CRP), in adult patients with sepsis.

Data Sources: 

A systematic literature search was performed in PubMed, Embase, and the Cochrane Library to identify all relevant diagnostic accuracy studies published before October 1, 2022.

Study Selection: 

Original articles reporting the diagnostic accuracy of MDW for sepsis detection with the Sepsis-2 or Sepsis-3 criteria were included.

Data Extraction: 

Study data were abstracted by two independent reviewers using a standardized data extraction form.

Data Synthesis: 

Eighteen studies were included in the meta‐analysis. The pooled sensitivity and specificity of MDW were 84% (95% CI [79–88%]) and 68% (95% CI [60–75%]). The estimated diagnostic odds ratio and the area under the summary receiver operating characteristic curve (SROC) were 11.11 (95% CI [7.36–16.77]) and 0.85 (95% CI [0.81–0.89]). Significant heterogeneity was observed among the included studies. Eight studies compared the diagnostic accuracies of MDW and procalcitonin, and five studies compared the diagnostic accuracies of MDW and CRP. For MDW versus procalcitonin, the area under the SROC was similar (0.88, CI = 0.84–0.93 vs 0.82, CI = 0.76–0.88). For MDW versus CRP, the area under the SROC was similar (0.88, CI = 0.83–0.93 vs 0.86, CI = 0.78–0.95).

Conclusions: 

The results of the meta-analysis indicate that MDW is a reliable diagnostic biomarker for sepsis as procalcitonin and CRP. Further studies investigating the combination of MDW and other biomarkers are advisable to increase the accuracy in sepsis detection.

 

The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials

by Baofang Liang, Jianwei Su, Hanquan Shao, Huiying Chen and Baocheng Xie 

Critical Care volume 27, Article number: 109 (2023) Published: 13 March 2023

Background

To update a meta-analysis of randomized controlled trials (RCTs) and further explore the outcome of IV vitamin C (IVVC) administration in sepsis or septic shock patients.

Methods

This study is a meta-analysis of RCTs. The RCTs of vitamin C therapy in sepsis or septic shock were searched in PubMed, EMBASE and Clinical Trials.gov from inception to January 16, 2023. We registered the protocol with PROSPERO (CRD42022354875). The primary outcome was delta Sequential Organ Failure Assessment (SOFA) score at 72–96 h. Two reviewers independently assessed RCTs according to eligibility criteria: (1) study type: RCT; (2) patient population: patients ≥ 18 years with sepsis or septic shock; (3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention or placebo (defined as control group); (4) the RCT described short-term mortality or SOFA score. Then, two authors independently extracted related information from RCTs.

Results

Eighteen RCTs (n = 3364 patients) were identified in this meta-analysis. There were significant effects in the delta SOFA score from baseline to 72–96 h (MD, − 0.62; 95% CI, − 1.00 to − 0.25; p = 0.001) and the duration of vasopressor use (MD, − 15.07; 95% CI, − 21.59 to − 8.55; p < 0.00001) with IVVC therapy. Treatment with IVVC was not shown to improve short-term mortality (OR, 0.89; 95% CI, 0.77 to 1.04; p = 0.14); nevertheless, dose at 25–100 mg/kg/d subgroup associated with a significant reduction in short-term mortality (OR, 0.80; 95% CI, 0.65 to 0.97; p = 0.03). An increase adverse event was observed in IVVC therapy (OR, 1.98; 95% CI, 1.06 to 3.68; p = 0.03).

Conclusion

In this meta-analysis, IVVC in sepsis or septic shock patients significantly improved delta SOFA score and reduced the duration of vasopressor use, whereas it was not associated with reduction in short-term mortality and had higher adverse events.

 

Embracing complexity in sepsis

by Alex R. Schuurman, Peter M. A. Sloot, W. Joost Wiersinga and Tom van der Poll 

Critical Care volume 27, Article number: 102 (2023) Published: 11 March 2023

Abstract

Sepsis involves the dynamic interplay between a pathogen, the host response, the failure of organ systems, medical interventions and a myriad of other factors. This together results in a complex, dynamic and dysregulated state that has remained ungovernable thus far. While it is generally accepted that sepsis is very complex indeed, the concepts, approaches and methods that are necessary to understand this complexity remain underappreciated. In this perspective we view sepsis through the lens of complexity theory. We describe the concepts that support viewing sepsis as a state of a highly complex, non-linear and spatio-dynamic system. We argue that methods from the field of complex systems are pivotal for a fuller understanding of sepsis, and we highlight the progress that has been made over the last decades in this respect. Still, despite these considerable advancements, methods like computational modelling and network-based analyses continue to fly under the general scientific radar. We discuss what barriers contribute to this disconnect, and what we can do to embrace complexity with regards to measurements, research approaches and clinical applications. Specifically, we advocate a focus on longitudinal, more continuous biological data collection in sepsis. Understanding the complexity of sepsis will require a huge multidisciplinary effort, in which computational approaches derived from complex systems science must be supported by, and integrated with, biological data. Such integration could finetune computational models, guide validation experiments, and identify key pathways that could be targeted to modulate the system to the benefit of the host. We offer an example for immunological predictive modelling, which may inform agile trials that could be adjusted throughout the trajectory of disease. Overall, we argue that we should expand our current mental frameworks of sepsis, and embrace nonlinear, system-based thinking in order to move the field forward.