Surviving Sepsis Campaign Research Priorities 2023

Surviving Sepsis Campaign Research Priorities 2023

  • Post category:Expert Opinion
  • Reading time:31 mins read

Introduction

(Article introduction authored by ICU Editorial Team)

Sepsis, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection, affects millions worldwide annually and carries a high mortality risk.

The Surviving Sepsis Campaign (SSC) aims to reduce sepsis-related deaths and has issued guidelines for adult sepsis management since 2002. Despite advancements from studies and clinical trials, significant gaps persist in understanding sepsis pathobiology and management, complicating the development of targeted therapies.

The latest SSC guidelines highlight these gaps, with only a few strong recommendations among many weak ones and unanswered questions. To address these issues, the SSC established a research committee to identify research priorities encompassing all aspects of sepsis, not just those covered in guidelines.

In 2018, the committee outlined 26 priorities, including clinical and basic science areas. Subsequent research has tackled some of these questions but has also unveiled new gaps. Following the latest guidelines, a new research committee has been tasked with updating these priorities to enhance sepsis understanding, management, and outcomes.

Question 1: What is the best strategy for screening and identification of patients with sepsis? Can predictive modeling be used in real-time to assist recognition of sepsis? What Is Known.

What Is Known.

The 2021 Surviving Sepsis Campaign (SSC) guidelines emphasize the importance of health systems implementing performance improvement programs for sepsis, including screening, due to the critical nature of timely identification, which correlates with improved outcomes.

However, the guidelines do not specify a recommended screening approach. While sepsis diagnosis entails recognizing infection and acute organ dysfunction resulting from a dysregulated host response, various screening tools have been developed to predict clinical deterioration or poor outcomes.

Historically, systemic inflammatory response syndrome (SIRS) criteria were used for identification, but their efficacy was limited.

Subsequently, tools like the quick Sequential Organ Failure Assessment (qSOFA) and the National Early Warning Score (NEWS) were proposed, each showing varying levels of accuracy in predicting mortality or ICU admission.

Despite their utility in identifying risk, these tools lack specificity for sepsis diagnosis, serving primarily to raise suspicion rather than confirm diagnosis.

Gaps in Knowledge/Critique of Evidence.

The best screening tool(s) for sepsis is unknown. Without standards for diagnosing infection, sepsis, dysregulated host response, or organ dysfunction that are both accurate and generalizable, it will be difficult to create them.

Despite the interest and growth in automated sepsis screening models, high-quality evidence of benefit over routine care is lacking. A Cochrane review of automated monitoring vs. standard care identified only very low-quality evidence that precluded drawing any meaningful conclusions.

While two randomized controlled trial (RCT) have suggested benefit of automated sepsis screening, they were relatively small and should be viewed as exploratory.

Future Directions

Future directions in sepsis research necessitate studies to establish sepsis algorithms adaptable across various electronic health record (EHR) systems, ensuring adequate sensitivity, specificity, and positive predictive value for seamless integration into clinical practice. Evaluation of automated sepsis algorithms against standard care is imperative to determine their impact on patient outcomes.

These investigations should encompass not only large-scale observational studies for external validity but also randomized controlled trials (RCTs) assessing the algorithms’ efficacy prospectively. Ideally, cluster RCTs should be conducted to compare outcomes between units or hospitals with active versus passive algorithm alerts, considering both patient-related outcomes and healthcare system implications.

Algorithm refinement is crucial to expedite sepsis recognition while minimizing alarm fatigue. Key questions for future studies include defining dysregulated host responses, optimal algorithm training methods, implementation strategies, and efficacy in resource-limited settings.

Question 2: What Causes Organ Injury and Dysfunction in Sepsis, How Should It Be Defined and How Can It Be Detected?

2A: What Causes Organ Injury and Dysfunction in Sepsis?

What is known

Various factors contribute to the pathobiology of sepsis-induced organ injury and dysfunction, including immune and endothelial cell dysfunction, impaired neural mechanisms, cellular and metabolic dysregulation, microvascular dysfunction, compromised oxygen delivery or utilization, endocrinopathy, mitochondrial dysfunction, and abnormalities in transcellular signal transduction.

Endothelial dysfunction induced by sepsis is known to promote organ injury and failure, supported by evidence from studies in cells, animals, and humans. Cellular metabolic block and mitochondrial dysfunction have also been implicated in organ dysfunction and failure, with promising research suggesting the potential for restoring cytochrome C oxidase activation to improve mitochondrial dysfunction in sepsis.

Metabolomic profiles of patients have been found to be predictive of sepsis outcomes, demonstrating associations with immune status, endothelial function, and the development of multiple organ dysfunction syndrome (MODS).

Additionally, research has made progress in understanding the roles of the central and peripheral nervous systems in regulating inflammation and organ responses to sepsis.

Gaps in knowledge/critique of evidence

The roles of noncirculating cells, such as endothelial cells, pericytes, marginated leukocytes, tissue macrophages, neurons, microglia, and astrocytes, are not well understood in sepsis.

While much research has been conducted in vitro and in animal models, human studies often rely on blood biomarkers as proxies for organ functions.

Current research primarily focuses on immune cells and individual cell lineages, with limited understanding of the communication and interaction between different organ systems.

Despite two decades of experimental research suggesting the vagus nerve’s role in regulating inflammatory responses and sepsis outcomes, its clinical application, such as vagal nerve stimulation, remains largely unexplored.

The relationship between organ injury, dysfunction, and the distinction between adaptive and maladaptive responses to sepsis is poorly understood, along with the contribution of sepsis versus host comorbidities to organ dysfunction. This lack of clarity hampers the study of organ injury and dysfunction in sepsis.

Future directions

The development of methods to study human cellular and tissue responses to sepsis in real time would be enormously helpful to our understanding of how sepsis affects organs individually and collectively.

There is a need to devise better methods to explore the organ and tissue specific pathophysiology and to improve our understanding of the role of noncirculating cells.

Additionally, work is needed to determine how sepsis affects cells within organs, what constitutes an adaptive vs. maladaptive cellular and organ response to sepsis, and how organ and systems interactions contribute to healthy and maladaptive responses during sepsis.

2B: How Do We Identify Organ Dysfunction?

What is known

Patients with sepsis develop a constellation of laboratory and physiologic indices that track with disease severity and outcomes. Currently, the diagnoses of organ injury and/or dysfunction rely on proxies, such as commonly obtained laboratory tests (e.g., arterial blood gases, liver function tests, creatinine, and coagulation markers) and radiographic findings.

In 2016, the Sepsis-3 task force revised and clarified the definitions of sepsis and septic shock (1). In addition to clarifying that sepsis is defined as “life threatening organ dysfunction caused by a dysregulated host response to infection,” they focused on the use of the SOFA, which incorporates laboratory variables and interventions, to identify sepsis at the bedside.

Baseline elevations or increasing SOFA scores positively correlate with mortality.

Gaps in knowledge/critique of evidence

There remains a lack of clarity regarding the line separating adaptive and maladaptive function, in large part because of a lack of gold standard criteria.

Clinical research relies on organ failure proxies rather than the direct measurements of organ function. Differentiating organ injury from organ dysfunction remains problematic.

It should be noted that some elements of the SOFA score are no longer used clinically, alternative vasopressor agents are used, and some organs are not included in the SOFA score, which altogether suggests that the SOFA score should be revised.

Future directions

The definitions of organ injury and dysfunction need to be further clarified. Methods to assess organ function, either through biologic activity or closer proxies to function-related activities, would help to then identify dysfunction.

As organs usually have several metabolic pathways (e.g., kidneys, liver), the question is whether one functional or multiple pathways should be investigated, and how to prioritize these?

If such endpoints are to be helpful, they would need to be understood in the context of pathobiology, whether they are intrinsic or extrinsic, how they are elicited, and by what mechanisms.

The development of practical methods to directly assess organ function in humans, without relying on surrogate measurements, would help to drive forward the understanding of organ injury and dysfunction.

2C: Can Blood Biomarkers (e.g., Cytokines, Chemokines, Lipid Mediators, Metabolites) and/or Activation Profiles of Circulating Leukocytes and Platelets Be Used to Understand What Is Happening Within Specific Organs?

What is known

Biomarkers may be used to identify organ injury and dysfunction and to track responses to treatments. Some may roughly reflect the magnitude of the organ pathology—for example, liver injury (increasing transaminases levels), liver dysfunction (e.g., modestly increased bilirubin levels), liver failure (high bilirubin, profound coagulopathy), but there are, admittedly, many confounders.

Human studies have demonstrated alterations in levels of numerous biomarkers in sepsis, and their correlation with organ failure and mortality, including markers of endothelial activation and injury, long noncoding RNAs, cancer protein biomarkers, and brain natriuretic peptide.

Markers of leukocyte activation and function are also associated with sepsis outcomes. RBC and platelet parameters may predict sepsis severity and outcomes.

Gaps in knowledge/critique of evidence

The utility of using biomarkers, cells and platelets to understand the pathobiology of sepsis at the tissue and organ levels remains unclear.

Circulating microparticles are increased in sepsis but their protective or detrimental effects should be clarified. An important limitation of many biomarkers is that they do not inform on the exact process explaining the rise in biomarker.

Some markers may be more specific or more informative of the process but direct mechanistic links between most biomarkers and organ pathologies have yet to be characterized. There continues to be a lack of data confirming that circulating biomarkers reflect what is going on at the tissue level (e.g., nervous system, adipose tissue, vasculature, interstitial spaces). Accordingly, there remains a lack of clarity in their utility in identifying and tracking organ dysfunction or directing therapies.

Future directions

Continued innovation in methods to use combination of clinical features, functional measurements, and laboratory endpoints (e.g., imaging, biomarkers, physiologic, neurocognitive) is required to understand the pathobiology and progression of organ injury and dysfunction and to guide human sepsis studies.

Further delineation of the relationship between specific biomarkers or patterns of biomarkers, single or multiple organ injury or dysfunction is needed.

Question 3: How Should Fluid Resuscitation Be Individualized, Initially and Beyond?

3A: What Is the Optimal Fluid Management in the First 24 Hours of the Septic Patient With Hypotension or Hypoperfusion?

What is known

The optimal fluid management strategy for patients with sepsis, especially regarding initial resuscitation and subsequent infusion, has long been debated. While it’s one of the most common interventions in critical care, evidence guiding fluid resuscitation in sepsis remains limited.

Current Surviving Sepsis Campaign (SSC) guidelines recommend an early fixed resuscitation of 30 mL/kg bolus of balanced crystalloids for septic patients with hypotension or hypoperfusion.

However, evidence supporting this recommendation is largely based on retrospective studies and observations from randomized controlled trials (RCTs) of hemodynamic management.

Guidance for fluid management in septic shock beyond initial resuscitation is sparse, with the SSC guidelines suggesting additional fluid infusion be guided by dynamic hemodynamic variables.

Recent large multicenter RCTs have failed to demonstrate a difference in outcomes between liberal and restrictive fluid strategies, indicating a need for further research in this area.

Gaps in knowledge/critique of evidence

Studies are needed to determine the optimal fluid resuscitation regimen for sepsis patients with hypotension and hypoperfusion, both initially and ongoing.

The current recommendation of fixed volume resuscitation is supported loosely, and its applicability to all patients regardless of individual factors like comorbidities and severity of illness is uncertain.

Quality improvement studies have shown that fluid resuscitation, along with early recognition and antibiotics, is associated with improved mortality, but the relative contribution of each element is unknown.

Early vasopressor administration may help limit fluid resuscitation volume and improve response to fluid boluses. The approach of modest fluid resuscitation and early vasopressor initiation has gained attention recently.

However, recent RCTs comparing liberal versus restrictive fluid strategies did not show significant differences in outcomes, but the trials may not directly inform on the early introduction of vasopressors. These studies highlight the need for personalized fluid management approaches in sepsis patients based on individual characteristics and conditions.

Future directions

The hemodynamic treatment of sepsis patients clearly would benefit from studies on early fluid resuscitation. One possible approach could include the comparison of a fixed volume of 30 mL/kg crystalloids to less or more fluid based on clinical context.

This would be important in settings where the availability of hemodynamic monitoring to guide fluid infusion is scarce.

Alternatively, an individualized management integrating clinical context and using dynamic variables or passive leg raising test (PLR) for the prediction of fluid responsiveness should be studied and compared with fixed volume initial resuscitation.

Also, strategies of early norepinephrine infusion to limit fluid administration would be important to study and determining whether to start hypotensive patients on fluids first, vasopressors first or both simultaneously.

3B: What Is the Best Hemodynamic Tool to Predict Fluid Responsiveness in the Septic Patient in the Early Resuscitation Phase?

What is known

The proportion of patients responding to fluids decreases as resuscitation progresses, despite ongoing perfusion abnormalities. Repeated fluid boluses increase the risk of fluid overload and are associated with worse outcomes in septic shock patients.

Therefore, after initial resuscitation, predicting fluid responsiveness becomes crucial to restrict fluid administration to patients likely to benefit. Dynamic indices and passive leg raising (PLR) are more accurate predictors of fluid responsiveness than static parameters.

Dynamic indices, based on heart-lung interaction, include respiratory variations in pulse pressure or stroke volume, variations in vena cava size, end-expiratory pause, tidal volume challenge, and positive end-expiratory pressure test.

However, these indices have limitations such as spontaneous breathing, low lung compliance, and arrhythmias. PLR-induced changes in cardiac output offer an alternative method to reliably predict fluid responsiveness, suitable for patients under spontaneous or mechanical ventilation, and can overcome most limitations of tests using heart-lung interactions.

Gaps in knowledge/critique of evidence

While passive leg raising (PLR) is appealing for predicting fluid responsiveness, it relies on measuring cardiac output (CO), which may not always be available.

Emerging techniques such as plethysmography or capillary refill time during PLR show promise but require further evaluation. In ventilated patients, changes in end-tidal CO2 may reflect CO changes, but these are typically small.

Ventilation using low tidal volume is a common limitation of tests using heart-lung interactions. Although the tidal volume challenge is conceptually appealing, its utility in unselected populations needs assessment.

Each test for fluid responsiveness has an indeterminate zone, complicating clinical decision-making. While different dynamic variables have varying diagnostic capacities, combining tests’ effects on diagnostic accuracy remain unclear.

In post-surgical patients, incorporating dynamic fluid responsiveness assessment into therapy improves outcomes, but its impact in septic shock patients is less certain, despite reduced fluid requirements observed in some studies.

Future directions

Large studies comparing the diagnostic accuracy of the different tests and indices to predict fluid responsiveness are required.

In addition, it is important to explore which tests are most valuable in specific settings, such as spontaneous breathing, low lung compliance, and right ventricular dysfunction, and whether a combination of tests provides added value.

Finally, studies assessing the impact on outcomes of resuscitative strategies using fluid responsiveness prediction should be performed.

3C: What Measures Predict Optimal Fluid Resuscitation?

What is known:

Optimal fluid resuscitation in septic shock relies on improving tissue perfusion in fluid-responsive patients without signs of poor fluid tolerance.

Peripheral perfusion-guided resuscitation, particularly using capillary refill time (CRT), has shown reduced mortality and organ dysfunction recovery compared to lactate-targeted resuscitation.

Biological indices like mixed venous oxygen saturation (SvO2/ScvO2), blood lactate, and venoarterial carbon dioxide (Pvaco2) are used to assess cardiac output adequacy.

Microcirculatory abnormalities are common and persistent hyperlactatemia may indicate tissue hypoperfusion, guiding resuscitation efforts.

However, assessing fluid intolerance remains complex and multifactorial.

Gaps in knowledge/critique of evidence:

While hypotension often triggers fluid administration, the effects on mean arterial pressure (MAP) vary and do not reliably reflect tissue perfusion.

Different tissue perfusion indices respond differently to fluid administration, and their optimal values and targets remain undefined.

Microcirculation-targeted therapy lacks standardized protocols and outcome studies.

Despite promising results, capillary refill time (CRT) lacks standardization, limiting its reliability and comparison with other strategies.

Future directions:

Further studies are needed to characterize tissue perfusion response to fluids and define optimal thresholds for various perfusion indices.

Investigating combined markers of tissue perfusion and their impact on fluid resuscitation and outcomes is essential.

Outcome studies should assess CRT-targeted resuscitation in different septic shock subtypes to improve standardization and reliability.

Question 4: What Is the Best Vasopressor Approach for Treating the Different Phases of Septic Shock?

4A: What Should Be the Target of Vasopressor Therapy (e.g., Mean Arterial Pressure, Organ-Specific Perfusion Pressure, Diastolic Blood Pressure)?

What is known:

Determining optimal hemodynamic targets for preserving or restoring microcirculatory blood flow and improving organ perfusion remains contentious.

The Surviving Sepsis Campaign (SSC) guidelines recommend an initial mean arterial pressure (MAP) target of 65 mm Hg, but observational data suggest mortality and acute kidney injury risks increase with lower MAP thresholds.

Organ blood flow depends on organ-specific perfusion pressure, influenced by factors like autoregulation thresholds and receptor type variations.

Septic AKI is associated with mean perfusion pressure (MPP) deficits, and individualized MPP targets based on pre-illness levels may reduce AKI incidence. Microcirculatory dysfunction can persist despite MAP above 65 mm Hg.

Gaps in knowledge/critique of evidence:

Targeting MAP alone may yield ambiguous results, necessitating consideration of other perfusion indices and vasopressor effects. Reliable indicators of microcirculatory health and organ-specific perfusion targets are needed for physiology-based resuscitation.

Trials are underway for tissue perfusion-guided strategies, but the relationship between skin perfusion and organ-specific microcirculation remains unclear. Specific biomarkers for microcirculation-guided vasopressor therapy and tailored perfusion targets for different sepsis subphenotypes require investigation.

Future directions:

Comparative studies between hemodynamic variables and direct organ perfusion evaluation are needed to understand their value and limitations. These studies should consider sepsis subtypes, comorbidities, and resuscitation phases.

The potential for sublingual videomicroscopy or other assessments to individualize blood pressure targets warrants evaluation. Knowledge about receptor type and density may guide vasopressor selection.

Research on preventing organ-specific dysfunction should consider unintended consequences on other organs. Tools indicating early perfusion/microcirculatory dysfunction are needed to modify resuscitation strategies promptly.

4B: What Strategies Optimize Vasopressor Therapy Outcomes?

4B1: When Should Vasopressors Be Initiated?

What is known

Delay in correcting hypotension is associated with increased mortality. While some patients may respond to fluid therapy alone, others need vasopressor support.

The SSC guidelines do not indicate timing nor guide prioritization of fluids vs. vasopressors. Experimental studies suggest early vasopressor introduction decreases the need for resuscitative fluids and improves tissue perfusion.

In an observational study using propensity matching, early initiation of norepinephrine was associated with lower fluid volumes administered, a less positive fluid balance and a lower 28-day mortality.

A small RCT demonstrated that the early use of a fixed dose of norepinephrine after the initial 30 mL/kg of crystalloids was associated with more shock control and less cardiogenic pulmonary edema and arrhythmia.

Gaps in knowledge/critique of evidence

There are no reliable tools to determine which patients require immediate vasopressor initiation and those who should receive fluid therapy first. Low DAP or low arterial elastance (165) suggests that the patient would fail to respond to fluid alone.

Further, it is unclear which patient-specific characteristics are most important to determine timing and whether any other factors (i.e., type of sepsis including offending pathogen, site of infection, or organ dysfunction patterns) contribute.

Future directions

It is crucial to develop tools (e.g., imaging techniques, biomarkers) that are readily available to identify patients who benefit from immediate vasopressor initiation and patients in whom vasopressor support can be deferred safely.

Future vasopressor timing studies should include the comparison of different subphenotypes of sepsis, evaluate the impact of vasopressor timing in patients with variable acute and chronic comorbidities, and evaluate the role of early vasopressor support in patients with sepsis-induced “organ stress.”

4B2: In What Circumstances Can Vasopressors Be Delivered Peripherally?

What is known

Vasopressors have been traditionally administered via central venous access. However, securing a central venous permit can be time-consuming, leading to delayed initiation of vasopressors.

Studies exploring the safety of vasopressors via peripheral catheters have shown variable results related to feasibility and adverse effects. Several patients initially receiving vasopressors via peripheral access never subsequently required a central line during their ICU stay.

However, failure rates for peripheral vein insertion reached 15%, and infectious complications were more frequent with peripheral access.

There are concerns about extravasation when giving vasopressors through a peripheral vein, but the incidence seems relatively low and the consequences are usually minimal when peripheral line are used for less than 6–12 hours.

Based upon this, the SSC guidelines concluded that administering vasopressors for a short period of time via a well-placed peripheral catheter proximal to the antecubital fossa is unlikely to cause local tissue injury.

However, it should be noted that information derived from central venous catheters cannot be accurately measured peripherally.

Gaps in knowledge/critique of evidence

Although vasopressors are initiated earlier when given peripherally rather than centrally, studies evaluating the comparative safety of various agents, as well different dose ranges and concentrations, still need to be performed. Further, there is some evidence that larger catheters placed more proximal are safer, but the ideal caliber and preferable site of the peripheral catheter has yet to be discovered.

Future directions:

Adequately powered prospective studies are needed to provide better evidence on the adequacy and safety of peripheral lines for administering vasopressors in sepsis.

In particular, the maximum dose and duration of vasopressor therapy that can be safely administered peripherally and the characteristics of patients benefiting most need to be identified. Future studies should also include specific analyses of high-risk groups.

4B3: What Is the Role of Epinephrine/Adrenaline in Septic Shock?

What is known:

Epinephrine is used in septic shock for its vasopressor and inotropic properties. It has greater β1- and β2-adrenergic activity than norepinephrine, resulting in higher heart rate and lactate levels.

However, it may not increase cardiac output significantly due to limited diastolic time. Trials comparing first-line epinephrine to norepinephrine show similar increases in mean arterial pressure (MAP) but more adverse effects with epinephrine, without differences in mortality.

In pediatric septic shock, norepinephrine plus dobutamine was associated with shorter time to shock resolution and fewer cases of refractory shock compared to epinephrine.

Gaps in knowledge/critique of evidence:

Trials have not evaluated epinephrine as an adjunct or replacement for norepinephrine in septic shock patients with cardiac dysfunction.

It’s unclear how to identify patients who may benefit from inotropic support or how epinephrine impacts specific organ function differently. The transient effects of epinephrine on lactate and arterial pH and their impact on major outcomes remain unknown.

Future directions:

An adequately powered trial should compare first-line epinephrine to norepinephrine without mandatory dobutamine addition.

Studies should evaluate treatment strategies in septic shock patients with cardiac dysfunction, incorporating organ-specific biomarkers and microcirculation evaluation.

The benefit of epinephrine compared to dobutamine or other inotropes in patients with escalating norepinephrine dosages or persistent hypoperfusion needs investigation.

4B4: For Patients With Septic Shock Receiving Norepinephrine and Vasopressin, Which Drug Should Be Weaned First and How?

What is known:

Vasopressin is recommended as an adjunct to norepinephrine for patients with inadequate mean arterial pressure (MAP) levels. Endogenous vasopressin levels rise in early septic shock but decline rapidly, leading to relative deficiency.

The optimal cessation order of norepinephrine and vasopressin is debated, with conflicting evidence on hypotension rates and mortality. Copeptin, a stable peptide released with vasopressin, may predict hypotension after vasopressin discontinuation.

Gaps in knowledge/critique of evidence:

The optimal cessation order and strategy for norepinephrine and vasopressin are uncertain. It’s unclear if hypotension post-cessation affects outcomes. Copeptin’s role in predicting hypotension requires further exploration.

Future directions:

Trials should assess optimal timing for combination vasopressor cessation, including dosage thresholds and duration of therapy.

The effects of cessation order and strategies on mortality and organ function need evaluation. Tools to predict readiness for vasopressor cessation, including biomarkers like copeptin, should be identified and investigated further.

Question 5: Can a Personalized/Precision Medicine Approach Identify Optimal Therapies to Improve Patient Outcomes?

What is known:

Personalized medicine aims to tailor therapy to individual patients, while precision medicine focuses on effective approaches in patient groups with similar characteristics. Precision may involve factors like the source of sepsis, comorbidities, immune status, or organ dysfunction.

Sepsis triggers both hyper-inflammatory and hypo-inflammatory immune responses, impacting hemodynamics and organ function. Subphenotyping eptic patients based on various criteria has revealed differing risks and treatment responses.

Gaps in Knowledge/Critique of Evidence:

Understanding the complex immune and hemodynamic responses in sepsis, as well as the onset of early organ dysfunction, remains challenging. Many therapies targeting the hyper-inflammatory phase have failed to improve short-term survival. Subphenotyping methods vary, and their clinical utility is uncertain.

Future Directions:

Identifying biomarkers for early organ stress and defining patients likely to benefit from specific interventions are priorities. Targeting therapies to specific subphenotypes & understanding the pro-inflammatory/anti-inflammatory state are crucial. Bedside diagnostics and artificial intelligence may aid in this endeavor.

Basic and Translational Science Questions

BTS.1: How Can We Improve Animal Models So That They More Closely Resemble Sepsis in Humans?

Sepsis is a highly complex condition affecting multiple organs and systems, posing challenges for understanding and treatment. Identifying and addressing cellular-level abnormalities may offer the most effective approach to prevent organ dysfunction. However, logistical constraints hinder direct organ function evaluation in patients, often relying on plasma biomarkers as proxies.

Sepsis also disrupts interactions between organ systems, complicating analysis.

Understanding the balance between normal and dysregulated host responses is crucial but challenging.

New technologies like multiomic approaches and functional MRI scanning may aid in studying tissue and cellular responses.

Ultimately, animal models are likely to provide accessible and applicable data, consistent with approaches taken in multiple disease states where animal models have led to fundamental changes in therapeutic approaches.

Unfortunately, currently used animal models of sepsis have limitations and strengths that require careful consideration when performing preclinical studies of sepsis

BTS.2: What Outcome Variables Maximize Correlations Between Human Sepsis and Animal Models and Are Therefore Most Appropriate to Use in Both?

A second global concern in both human and animal interventions involves the choice of appropriate outcome variables.

While mortality is easily measured, it is a narrow endpoint that does not in isolation account for other host factors such as quality of life.

Further, organ support systems make it possible to stave off death in septic humans almost indefinitely, while many regulatory bodies prohibit use of death as an outcome variable in animal experiments.

Additionally, mortality fails to address adverse but potentially modifiable outcomes in sepsis survivors (e.g., neurocognitive dysfunction, respiratory insufficiency, malnutrition, weakness).

BTS.3: How Does Sepsis Affect Specific Regions of the Brain That Modulate Pulmonary, Cardiovascular, Hepatic, Renal, and Gastrointestinal Function? How Does Sepsis Affect Interactions Between Neural, Endocrine, and Immune Systems?

Various cellular and extracellular processes are implicated in sepsis pathobiology, including cell cycle arrest, neutrophil extracellular traps, autophagy/mitophagy, release of extracellular vesicles, and endothelial and glycocalyx changes. However, distinguishing between normal and dysregulated host responses is challenging, hindering our ability to understand sepsis fully.

Sepsis disrupts organ-organ interactions, mediated by the immune, endocrine, and neural systems. While white cell and hormone levels have been extensively studied, compartmentalization within these systems complicates analysis.

BTS.4: How Does the Microbiome Affect Sepsis Pathobiology? How Does Sepsis Pathobiology Contribute to the “Pathobiome,” ?

Animal models of sepsis indicate that microbiota metabolites modulate outcomes and implicate the gut microbiome in injury in multiple organs. Further, targeting the microbiome for therapeutic gain by probiotics, prebiotics, synbiotics, microbial spores, fecal microbial transplantation, or selective decontamination of the digestive system-has been helpful in disorders such as dementia and cognitive disorders, inflammatory bowel disease, and lupus and may have therapeutic benefit in sepsis.

BTS.5: How Do Genetics and Epigenetics Influence the Development of Sepsis, the Course of Sepsis and the Response to Treatments for Sepsis?

Despite years of research in this domain, we do not yet fully understand the link between genetic factors and susceptibility, severity and evolution of sepsis.

Some cohort data or post hoc analyses of intervention studies suggest a link between genetic or metabolomic factors and response to therapy.

Epigenetic factors play a crucial role in various processes in sepsis from the coordination of the response to infection to inflammatory response but also particularly contributes to the induction of immunoparalysis. The pattern may vary on a daily basis after admission, suggesting that repeated measurements may be required.

CONCLUSIONS

Each successive version of the SSC guidelines is based upon the most up-to-date data available to the panel. Increases in knowledge have allowed for upgrading and downgrading guideline recommendations using GRADE methodology and evidence to decision framework.

Nevertheless, multiple knowledge gaps remain precluding the possibility of strong recommendations in most domains, and at times preventing any recommendation at all.

Our hope is that this document will spur international research on sepsis – both to change clinical guidelines in the near future and also to answer more basic questions that will hopefully spur discovery and innovation that can be translated to fundamental breakthroughs in sepsis.