Sepsis remains a significant global health challenge, with high mortality rates despite advances in critical care. This review examines recent updates in sepsis management protocols, focusing on the evolution of early goal-directed therapy (EGDT), advancements in fluid resuscitation strategies, and the emergence of biomarker-driven diagnostic approaches. We critically analyse the impact of landmark studies such as Protocol-based care for early septic shock (ProCESS), Australasian resuscitation in sepsis evaluation (ARISE), and protocolized management in sepsis (ProMISe) on EGDT implementation, discuss the shift towards more individualized fluid management, and explore the potential of novel biomarkers in improving sepsis diagnosis and prognostication. The review also highlights current challenges in sepsis care and provides insights into future directions for research and clinical practice. By synthesizing the latest evidence, this article aims to provide clinicians with a comprehensive understanding of contemporary sepsis management strategies to optimize patient outcomes.

Sepsis, Fluid resuscitation, Biomarkers, Critical care, Individualized treatment.

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of morbidity and mortality worldwide.[1] Despite significant advances in critical care medicine, the management of sepsis continues to challenge clinicians due to its complex pathophysiology and heterogeneous clinical presentation. Over the past two decades, there has been a paradigm shift in sepsis care, moving from a one-size-fits-all approach to more personalized strategies based on individual patient characteristics and responses to treatment.[2]

This review aims to provide a comprehensive overview of recent updates in sepsis management protocols, with a particular focus on three key areas: the evolution of EGDT, advancements in fluid resuscitation strategies, and the emergence of biomarker-driven diagnostic approaches. By examining these developments, we seek to elucidate the current state of sepsis care and identify promising avenues for future research and clinical practice.

Historical context
The modern era of sepsis management can be traced back to the landmark study[3], which introduced the concept of EGDT. This protocol emphasized early recognition of sepsis and prompt initiation of a structured treatment algorithm within the first 6 hours of diagnosis. The EGDT approach included specific targets for central venous pressure (CVP), mean arterial pressure (MAP), and central venous oxygen saturation (ScvO₂), along with the use of fluid resuscitation, vasopressors, and blood transfusions as needed.

The publication of the Rivers study marked a turning point in sepsis care, leading to widespread adoption of EGDT principles and their incorporation into international guidelines, including the surviving sepsis campaign (SSC).[4] However, subsequent large-scale, multicenter trials, such as ProCESS, ARISE, and ProMISe, challenged the universal applicability of the original EGDT protocol, prompting a reevaluation of sepsis management strategies.[5-7]

This review was conducted through a comprehensive literature search using PubMed, Embase, and Cochrane Library databases. We included randomized controlled trials, meta-analyses, systematic reviews, and clinical practice guidelines published between 2001 and 2024. Search terms included “sepsis,” “septic shock,” ” EGDT,” “fluid resuscitation,” “biomarkers,” and “sepsis management.” Additional relevant articles were identified through reference lists of selected papers and expert recommendations.

Evolution of EGDT: The introduction of EGDT is a.[3] revolutionized sepsis management by providing a structured approach to early resuscitation. The original protocol aimed to achieve specific hemodynamic targets within the first 6 hours of sepsis recognition, including:

• CVP of 8-12 mmHg
• MAP ≥ 65 mmHg
• ScvO₂ ≥ 70%
• Urine output ≥ 0.5 mL/kg/hour

The initial single-center study reported a significant reduction in mortality (30.5% vs. 46.5%) with EGDT compared to standard care.[3] This led to widespread adoption of EGDT principles and their incorporation into international guidelines, including SSC.[4]

However, the universal applicability of EGDT was challenged by three large, multicenter randomized controlled trials: ProCESS (2014), ARISE (2014), and ProMISe (2015).[5-7] These studies, collectively known as the “trio of trials,” compared EGDT to usual care in different healthcare settings across multiple countries. Surprisingly, all three trials failed to demonstrate a mortality benefit with EGDT compared to standard care.

ProCESS

• No significant difference in 60-day mortality between EGDT, protocol-based standard therapy, and usual care.
• EGDT group received more intravenous fluids, vasoactive agents, and blood transfusions in the first 6 hours.[5]

ARISE

• No significant difference in 90-day mortality between EGDT and usual care.
• EGDT group received more fluids, vasopressors, and dobutamine in the first 6 hours.[6]

ProMISe

• No significant difference in 90-day mortality between EGDT and usual care.
• EGDT was associated with higher costs and increased length of stay in the intensive care unit.[7]

These results led to a reevaluation of the role of EGDT in sepsis management. A subsequent meta-analysis by the protocolized resuscitation in sepsis meta-analysis (PRISM) investigators, which included data from all three trials, confirmed the lack of mortality benefit with EGDT compared to usual care.[8]

The apparent discrepancy between the original rivers study and the trio of trials can be attributed to several factors.[9-11]

• Improvements in standard sepsis care over time include earlier recognition and antibiotic administration.
• Lower overall mortality rates in the more recent trials, reflecting general advancements in critical care.
• Differences in healthcare systems and resources across study sites.
• Potential overemphasis on achieving specific physiological targets rather than individualizing treatment.

As a result of these findings, recent sepsis guidelines have moved away from strict adherence to EGDT protocols. The 2021 SSC guidelines now recommend a more flexible approach to early sepsis management, emphasizing the rapid identification, early administration of antibiotics, and individualized fluid resuscitation.[12]

Advancements in fluid resuscitation strategies: Fluid resuscitation remains a cornerstone of early sepsis management, but recent research has highlighted the importance of a more nuanced approach. The traditional “one-size-fits-all” strategy of aggressive fluid administration has been challenged by evidence suggesting potential harm from fluid overload.[13]

Key developments in fluid resuscitation strategies
Dynamic assessment of fluid responsiveness: Use of passive leg raise test, pulse pressure variation, and stroke volume variation to predict fluid responsiveness. These techniques help identify patients who are likely to benefit from additional fluid administration.[14]

Balanced crystalloid solutions: Growing evidence supports the use of balanced crystalloids (e.g., Ringer’s lactate) over normal saline for resuscitation. Balanced solutions may reduce the risk of hyperchloremic metabolic acidosis and acute kidney injury.[15]

Conservative fluid management: Increasing recognition of the potential harms of fluid overload, including prolonged mechanical ventilation and increased mortality. Shift towards a more restrictive fluid strategy after initial resuscitation.[16]

Albumin in severe sepsis: The albumin Italian outcome sepsis (ALBIOS) trial suggested potential benefits of albumin administration in patients with severe sepsis and septic shock, particularly in those with hypoalbuminemia. However, the optimal role of albumin in sepsis management remains controversial.[17]

Timing and rate of fluid administration: Emphasis on early, rapid fluid resuscitation within the first hour of sepsis recognition. Subsequent fluid administration is guided by frequent reassessment of hemodynamic status and tissue perfusion.[18]

The 2021 SSC guidelines reflect these advancements, recommending:

• Initial fluid resuscitation with 30 mL/kg of crystalloid within the first 3 hours.
• Subsequent fluid administration is guided by frequent reassessment of hemodynamic status.
• Use of dynamic variables to assess fluid responsiveness when available.
• Balanced crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement.[19,20]

Biomarker-driven diagnostic approaches: The search for reliable biomarkers to improve sepsis diagnosis, prognostication, and treatment guidance has been an active area of research. While numerous biomarkers have been investigated, few have demonstrated sufficient accuracy and clinical utility to be widely adopted. However, recent advances show promise in enhancing sepsis management through biomarker-driven approaches.[20,21]

Key developments in sepsis biomarkers
Procalcitonin (PCT): Widely studied for its ability to differentiate bacterial from viral infections and guide antibiotic therapy. PCT-guided algorithms have been shown to reduce antibiotic exposure without increasing adverse outcomes.[22]

C-reactive protein (CRP): Although less specific than PCT, CRP remains a useful marker of inflammation and infection. Serial CRP measurements can help monitor treatment response.[23]

Lactate: Elevated lactate levels are associated with increased mortality in sepsis. Lactate clearance has been proposed as an alternative to ScvO₂ monitoring in sepsis resuscitation.[24]

Presepsin: A novel biomarker showing promise in early sepsis diagnosis and prognostication. May offer advantages over PCT in certain clinical scenarios.[24,25]

Cell-free deoxyribonucleic acid (DNA): Emerging evidence suggests that circulating cell-free DNA levels correlate with sepsis severity and mortality. Potential applications in early sepsis detection and risk stratification.[26]

Multi-biomarker panels: Combining multiple biomarkers may improve diagnostic and prognostic accuracy. Machine learning algorithms are being developed to interpret complex biomarker patterns.[27]

The integration of biomarkers into sepsis management protocols has the potential to improve early sepsis recognition and diagnosis, guide antibiotic stewardship efforts, assist in risk stratification and prognostication, and monitor treatment response and inform clinical decision-making.[28,29]

However, challenges remain in standardizing biomarker measurement techniques, establishing optimal cut-off values, and demonstrating clear improvements in patient outcomes. Ongoing research aims to address these issues and validate the clinical utility of biomarker-driven approaches in sepsis care.[30,31]

Current state of the field: The management of sepsis has evolved significantly over the past two decades, moving towards a more individualized approach that combines rapid recognition, early intervention, and targeted therapy.[31]
Key aspects of current sepsis management include:

Early recognition and diagnosis: Implementation of sepsis screening tools and early warning systems. Increased awareness and education among healthcare providers.[32]

Prompt antibiotic administration: Emphasis on administering broad-spectrum antibiotics within 1 hour of sepsis recognition. De-escalation of antibiotic therapy based on culture results and clinical response.[34]

Source control: Rapid identification and control of the infection source (e.g., drainage of abscesses, removal of infected devices).[34]

Hemodynamic support: Individualized fluid resuscitation guided by a dynamic assessment of fluid responsiveness. Use of vasopressors to maintain adequate tissue perfusion.

Organ support: Mechanical ventilation for respiratory failure. Renal replacement therapy for acute kidney injury. Glycemic control and nutritional support.

Adjunctive therapies: Corticosteroids in refractory septic shock. Consideration of immunomodulatory therapies in selected cases.

Ongoing monitoring and reassessment: Frequent evaluation of clinical status, hemodynamics, and organ function. Adjustment of treatment based on patient response and biomarker trends. The current approach to sepsis management emphasizes the importance of early intervention, while also recognizing the need for individualized treatment based on patient characteristics and their response to therapy. This shift has been reflected in recent guidelines, including the 2021 SSC recommendations.[35-37]

The evolution of sepsis management protocols over the past two decades has led to significant improvements in patient care and outcomes. However, several challenges and areas of ongoing debate remain.[32-40]

Balancing standardization and individualization: While protocolized care can improve consistency and reduce variability, there is a growing recognition of the need to tailor treatment to individual patient characteristics and responses. Finding the right balance between standardized approaches and personalized medicine remains a key challenge in sepsis management.

Optimal fluid resuscitation strategies: The ideal approach to fluid management in sepsis remains a topic of debate. Questions remain regarding the optimal type, amount, and timing of fluid administration, as well as the most effective methods for assessing fluid responsiveness and preventing fluid overload.

Role of biomarkers in clinical decision-making: While biomarkers show promise in improving sepsis diagnosis and management, their integration into routine clinical practice faces several challenges. These include the standardization of measurement techniques, the establishment of clinically relevant cut-off values, and the demonstration of clear improvements in patient outcomes.

Antibiotic stewardship in the era of multidrug-resistant organisms: Balancing the need for early, broad-spectrum antibiotic therapy with the risks of promoting antimicrobial resistance remains a significant challenge. The development of rapid diagnostic tests and biomarker-guided algorithms may help optimize the use of antibiotics in sepsis.

Addressing sepsis in resource-limited settings: Many of the advances in sepsis care have been developed and validated in high-resource healthcare systems. Adapting these approaches to resource-limited settings, where the burden of sepsis is often highest, requires innovative solutions and context-specific research.

Heterogeneity of sepsis populations: The diverse nature of sepsis, with variations in causative pathogens, host responses, and organ dysfunctions, complicates the development of universally effective treatments. Future research may focus on identifying distinct sepsis endotypes and developing targeted therapies.

Long-term outcomes and post-sepsis syndrome: As short-term mortality from sepsis has decreased, there is growing recognition of the long-term consequences of sepsis, including cognitive impairment, functional disability, and increased risk of recurrent infections. Addressing these long-term sequelae represents an important area for future research and clinical focus.

The management of sepsis has undergone significant evolution over the past two decades, driven by advances in our understanding of sepsis pathophysiology and the results of large-scale clinical trials. The shift from rigid protocols to more flexible, individualized approaches reflects the complex and heterogeneous nature of sepsis.

Key developments in sepsis care include 1) Re-evaluation of EGDT, with a move towards more flexible resuscitation strategies, 2) Advancements in fluid management, 3) Emphasizing dynamic assessment of fluid responsiveness and recognition of potential harms from fluid overload, and 4) Emergence of biomarker-driven approaches to improve sepsis diagnosis, prognostication, and treatment guidance.

While these advances have contributed to improved outcomes in sepsis, significant challenges remain. Future research should focus on developing and validating personalized treatment algorithms that account for individual patient characteristics and responses, refining biomarker-based approaches to enhance early sepsis recognition and guide therapy. Additionally, it should address the long-term consequences of sepsis and improve the quality of life for survivors, as well as adapt sepsis management strategies for resource-limited settings.

As we move forward, integrating cutting-edge research with clinical expertise and patient values will be crucial in further improving outcomes for patients with sepsis. Continued collaboration between clinicians, researchers, and policymakers is essential to translate scientific advances into meaningful improvements in sepsis care worldwide.[38-40]

Not reported

Not reported

Sumaiya Amin Adrita
Department of Emergency Medicine
Maidstone & Tunbridge Wells NHS Trust, UK
Email: sumaiya.adrita@nhs.net

The author contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles and was involved in the writing – original draft preparation and writing – review & editing to refine the manuscript.

Not applicable

Not reported

None

https://doi.org/10.63096/medtigo3092112

Sumaiya AA. Recent Advances in Sepsis Management: From Early Goal-Directed Therapy to Biomarker-Driven Approaches. medtigo J Emerg Med. 2024;1(1):e3092112. doi:10.63096/medtigo3092112 Crossref