Managing sepsis in the era of precision medicine: a narrative review

Ho Jin Yong; Sung Min Kim; Dohhyung Kim

doi:10.4266/acc.000884

Articles

Page Path: HOME > Acute Crit Care > Volume 41(2); 2026 > Article

ACC review series 2026: sepsis 1 Managing sepsis in the era of precision medicine: a narrative review: Acute and Critical Care 2026;41(2):189-200.
DOI: https://doi.org/10.4266/acc.000884
Published online: May 28, 2026

Ho Jin Yong

, Sung Min Kim

, Dohhyung Kim

Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea

Corresponding author: Dohhyung Kim Department of Internal Medicine, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, Korea Tel: +82-41-550-3870 Fax: +82-41-556-3256 Email: kimdh@dankook.ac.kr

• Received: January 28, 2026 • Revised: February 24, 2026 • Accepted: March 12, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2,412 Views
2,147,484,101 Download

Full Article

Download PDF

Abstract
Infographics
INTRODUCTION
PRECISION MEDICINE IN SEPSIS/SEPTIC SHOCK TREATMENT
CONCLUSION
KEY MESSAGES
NOTES
REFERENCES

Abstract

For decades, the management of sepsis has adopted protocolized care bundles. However, the plateau in global survival rates suggests that the "one-size-fits-all" paradigm exemplified by early goal-directed therapy has reached its limits. The physiological and biological heterogeneity of sepsis necessitates a fundamental shift toward precision medicine. This review examines the transition from empirical resuscitation to individualized care across four critical domains. First, fluid strategy is evolving from aggressive loading to dynamic stewardship. Current evidence favors balanced crystalloids over saline and advocates restrictive dosing guided by dynamic responsiveness indices and venous congestion assessments to prevent iatrogenic harm. Second, hemodynamic support is shifting toward a catecholamine‑sparing strategy. To mitigate the metabolic and immunologic toxicities of high-dose norepinephrine, multimodal vasopressors, such as vasopressin and angiotensin II, are used to target specific biological phenotypes, such as high-renin states. Third, antibiotic management balances rapid administration with rigorous stewardship through pharmacokinetic optimization, including continuous infusions, diagnostic pauses for stable patients, and short-course regimens. Finally, corticosteroid therapy is moving beyond universal debate toward targeted application. Emerging data support their use in specific responder phenotypes, notably severe community-acquired pneumonia and distinct transcriptomic endotypes. In conclusion, modern critical care is moving beyond rigid protocols toward a personalized framework. By integrating bedside biomarkers and clinical phenotypes, clinicians can deliver “the right drug, at the right dose, for the right patient," thereby optimizing outcomes in sepsis and septic shock.
Key Words: precision medicine; sepsis; septic shock

Infographics

INTRODUCTION

Sepsis and septic shock represent a dysregulated host response to infection. They cause life‑threatening organ dysfunction and remain a leading cause of mortality in intensive care units worldwide [1,2]. For over two decades, sepsis management has been driven by the paradigm of early recognition and protocolized resuscitation. In 2001, the landmark early goal-directed therapy (EGDT) study by Rivers et al. [3] revolutionized sepsis care by emphasizing aggressive fluid resuscitation and hemodynamic optimization within the first 6 hours, significantly reducing mortality at that time. However, subsequent large-scale randomized controlled trials (RCTs), such as ProCESS, ARISE, and ProMISe, challenged the rigid, target-driven elements of EGDT, demonstrating that protocolized care was not superior to usual care in settings where standard practice had already improved [4-6].

Despite these advances, the global sepsis survival rate has plateaued, suggesting that the limits of a "one-size-fits-all" approach have been reached [7]. The physiological and biological heterogeneity of sepsis patients means that a uniform strategy may benefit some while harming others. Consequently, modern critical care is undergoing a profound transformation from empirical broad-spectrum resuscitation to “individualized precision medicine” [8]. This new era focuses on tailoring interventions to specific clinical phenotypes, biological endotypes, and dynamic physiological states [9,10]. The therapeutic focus has shifted from maximizing macro-hemodynamics to preserving microcirculation, mitigating iatrogenic harm such as fluid overload and catecholamine toxicity, and optimizing drug delivery [11].

This review highlights the transition toward a more personalized framework in sepsis management by presenting current evidence and debates across four critical domains: fluid stewardship, catecholamine‑sparing strategy (decatecholaminization), antibiotic precision, and phenotype-guided corticosteroid therapy.

PRECISION MEDICINE IN SEPSIS/SEPTIC SHOCK TREATMENT

Individualized Fluid Strategy: from Liberal Loading to Dynamic Stewardship

Fluid resuscitation serves as the cornerstone of hemodynamic stabilization in sepsis-induced hypoperfusion, yet it remains one of the most contentious aspects of critical care. The traditional dogma of "hit hard and early" with aggressive volume expansion is being replaced by a safety-centric individualized approach [3,12]. This shift is driven by accumulating evidence that although hypovolemia leads to organ hypoperfusion, fluid overload is independently associated with increased mortality, pulmonary edema, and renal capsular congestion [12]. Clinicians must now navigate complex decisions over the type of fluid, volume, and administration strategy, as well as the precise timing of de-resuscitation, conceptualized through the ROSE model (Resuscitation, Optimization, Stabilization, Evacuation) [13].

After decades of debate, the choice between crystalloids and colloids, as well as between saline and balanced solutions, has finally reached a new consensus. A comprehensive 2025 network meta-analysis of 28 RCTs involving 8,770 patients provided additional evidence in favor of balanced crystalloids (BC) [14]. This analysis identified BC as the superior agent for reducing 90-day mortality compared to saline or low-molecular-weight hydroxyethyl starch (HES), with a surface under the cumulative ranking curve (SUCRA) value of 86.3% [14]. The physiological rationale supporting these findings was that saline administration results in a high chloride load, which induces hyperchloremic metabolic acidosis. This acidosis can trigger renal vasoconstriction, reduce glomerular filtration rates, and exacerbate immune dysregulation [15,16]. Furthermore, the analysis highlighted the role of albumin. Although no single fluid consistently prevents acute kidney injury across all patients, hyperoncotic albumin demonstrated the highest potential for renal protection (SUCRA 74.5%), followed closely by BC [14]. Therefore, current evidence supports BC as the standard first-line fluid, with albumin reserved for specific phenotypes, such as patients with hypoalbuminemia or those at high risk of renal injury who require significant volume sparing. Conversely, the use of synthetic colloids, such as HES, is strongly discouraged due to proven risks of nephrotoxicity and coagulopathy.

The administration of fluid has also evolved from fixed dosing to individualized titration. The "Surviving Sepsis Campaign" historically advocated a fixed initial bolus of 30 ml/kg [17]. However, the 2025 European Society of Intensive Care Medicine (ESICM) guidelines and recent landmark trials have challenged the rigidity of this recommendation [18]. Two major RCTs, the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) and the Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial (CLASSIC), compared restrictive and liberal fluid strategies in patients with sepsis or septic shock. The CLOVERS trial found no significant difference in 90-day mortality between a restrictive strategy and a liberal fluid strategy (14.0% vs. 14.9%, P=0.61) [19]. Similarly, the CLASSIC trial found no difference in 90‑day mortality between restricted intravenous fluid administration and standard care in patients with septic shock (42.3% vs. 42.1%, P=0.96) [20]. These results question the notion that 'more fluid is better'. Currently, the 2025 ESICM guidelines (Part 2) suggest that while an initial bolus may be reasonable, it should not be applied blindly. Instead, therapy must be adapted to the clinical context, particularly in resource-limited settings or in patients prone to congestion, such as those with heart failure or renal dysfunction [18].

This individualized approach is best operationalized using the ROSE framework [13]. The "Resuscitation" phase focuses on the rapid restoration of perfusion, where fluid boluses are most effective. However, continuing this aggressive behavior into the "Optimization" and "Stabilization" phases is a common error. In these later phases, fluid responsiveness often decreases, and the risk of accumulation increases. The "Evacuation" phase represents a critical unmet need in modern practice. The definition of when and how to actively remove accumulated fluid is still unclear. While the concept of "de-resuscitation" using diuretics or renal replacement therapy is gaining traction, the optimal triggers remain debated. Current recommendations suggest transitioning to de-escalation when the patient is no longer fluid responsive and hemodynamic stability is achieved [12,13]. To guide this, monitoring has shifted from static metrics such as central venous pressure, which fail to predict fluid responsiveness, to dynamic indices, including pulse pressure variation, stroke volume variation, and the passive leg raising test [21-23]. Furthermore, assessing fluid tolerance using bedside tools such as the venous excess ultrasound score [24], is increasingly recommended to prevent iatrogenic congestion before it manifests as organ failure.

The comparison between the traditional paradigm and the precision medicine approach in fluid strategy is summarized in Table 1.

Catecholamine‑Sparing Strategy: a Multimodal Approach to Hemodynamic Support

For decades, the hemodynamic management of septic shock has relied heavily on titrating catecholamines, primarily norepinephrine (NE), to maintain a mean arterial pressure (MAP) of at least 65 mm Hg [25,26]. While effective in restoring perfusion pressure, high-dose catecholamines are far from safe. They are associated with a spectrum of toxicities, including direct myocardial injury, induction of tachyarrhythmias, metabolic dysregulation such as hyperglycemia and hyperlactatemia, and significant immunomodulation [27]. Recognition of these adverse effects has led to the concept of a catecholamine‑sparing strategy, decatecholaminization, which advocates the early introduction of non-catecholaminergic vasopressors to reduce the total catecholamine load and target distinct physiological pathways [28].

The rationale for decatecholaminization is based on receptor physiology. In severe septic shock, particularly in the setting of severe acidosis, alpha-1 and beta-1 adrenergic receptors (the targets of NE) undergo desensitization and downregulation, leading to catecholamine refractoriness [29]. In contrast, vasopressin acts via V1a receptors, which are relatively preserved in acidic environments and do not rely on the same signaling pathways [30]. By activating V1a receptors, vasopressin causes vascular smooth muscle contraction without directly stimulating myocardial oxygen consumption or heart rate [31]. This mechanistic difference translates into distinct organ-specific benefits. In the heart, reduced catecholamine use minimizes beta-adrenergic stimulation, thereby significantly reducing the risk of tachyarrhythmias, particularly atrial fibrillation. A systematic review and meta-analysis showed that vasopressin-containing strategies lower the risk of arrhythmias compared to catecholamine monotherapy [28]. In the kidney, vasopressin preferentially constricts efferent arterioles while sparing afferent arterioles via nitric oxide release [31]. This unique hemodynamic profile can maintain glomerular filtration pressure more effectively than NE. While concerns about excessive peripheral vasoconstriction exist, data suggest that clinically significant ischemic events, such as digital ischemia, are rare when vasopressin doses are limited to 0.03 U/min [32].

Clinical evidence supporting this multimodal approach is ambiguous and points toward specific responder phenotypes. In the Vasopressin and Septic Shock Trial (VASST) trial, although a reduction in overall mortality was not demonstrated, a prespecified subgroup analysis suggested that early initiation of vasopressin may improve survival in patients with less severe shock (baseline NE dose <15 μg/min), with mortality rates of 26.5% in the vasopressin group versus 35.7% in the NE group (P=0.05). [32]. Similarly, the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, which focused on renal outcomes, found that although kidney failure-free days were not significantly different, vasopressin use significantly reduced the need for renal replacement therapy compared with NE (25.4% vs. 35.3%, P=0.04) [33]. This suggests that vasopressin may offer renal-protective benefits in specific patient groups.

Although it is not currently available in Korea, the introduction of synthetic angiotensin II (Ang-II) has further expanded the reduction of catecholamine use. A Phase 3 Study of LJPC-501 in Patients With Catecholamine-Resistant Hypotension (ATHOS-3) trial demonstrated that Ang-II significantly increased MAP in patients with vasodilatory shock refractory to high-dose catecholamines (69.9% response vs. 23.4%, P<0.001) [34]. More importantly, post-hoc analyses of this trial provided a compelling example of precision medicine. Patients with a high-renin phenotype, indicating a dysregulated renin-angiotensin-aldosterone system and relative Ang-II deficiency, showed a significant survival benefit with Ang-II therapy, whereas patients with low renin levels did not [35]. This suggests that septic shock is biologically heterogeneous and that angiotensin-II-responsive patients can be identified via biomarkers.

Current practice is moving toward an initial use of multiple vasopressors, followed by a gradual reduction guided by clinical response or biomarker-guided selection. Identifying phenotypes, such as a vasopressin-responsive phenotype associated with low copeptin levels [30] or an angiotensin-II-responsive phenotype associated with high renin [35], enables targeted therapy. Copeptin, the stable C‑terminal fragment of the vasopressin precursor, is secreted in equimolar amounts with arginine vasopressin (AVP) and provides a reliable surrogate marker for endogenous AVP activity [36]. Low circulating copeptin levels, which reflect relative vasopressin deficiency, are a potential biomarker to identify vasopressin‑responsive patients, particularly in the early phases of septic shock [28]. The primary aim of reducing catecholamine exposure is not merely to raise blood pressure but also to achieve hemodynamic stability with the least possible adverse effects on the patient. The pharmacological mechanisms, target phenotypes, and clinical evidence for a multimodal vasopressor approach are summarized in Table 2.

Antibiotic Stewardship and Precision Dosing: Balancing Speed with Accuracy

Empirical antibiotic administration is the single most critical intervention in sepsis, and delays in antibiotic initiation in septic shock are associated with increased mortality [37]. However, the rising global crisis of antimicrobial resistance has forced a re-evaluation of the traditional "hit hard and early" paradigm. The modern approach seeks a delicate equilibrium between rapid, effective treatment and rigorous antibiotic stewardship [38]. This involves debates centered on four key areas: the method of delivery, the timing of administration, the spectrum of coverage, and the duration of therapy.

A major focus of recent research is optimizing antibiotic delivery based on pharmacokinetics and pharmacodynamics. Beta-lactam antibiotics, the workhorses of sepsis treatment, exhibit time-dependent killing, meaning their efficacy depends on the duration during which the free drug concentration remains above the minimum inhibitory concentration (fT > MIC) [39]. In critically ill patients, physiological changes such as increased distribution volume and augmented renal clearance (ARC) can lead to subtherapeutic concentrations with standard bolus dosing. Consequently, continuous or prolonged infusion has been proposed to maximize fT>MIC [40]. The 2024 The Beta-Lactam InfusioN Group Study (BLING III) trial, a massive RCT involving over 7,000 patients, tested this hypothesis. Although the trial did not meet its primary endpoint of reducing 90-day mortality (24.9% in the continuous group vs. 26.8% in the intermittent group, P=0.08), it demonstrated a statistically significant improvement in clinical cure rates (55.7% vs. 50.0%, P<0.001) [41]. Furthermore, a 2025 meta-analysis by Tejada et al. [42] suggested a trend toward reduced hospital mortality (relative risk [RR], 0.92; P<0.05). These results indicate that although continuous infusion may not be necessary for all patients, it may offer an advantage for certain high-risk phenotypes, specifically those with ARC or infections caused by pathogens with high MICs, in which standard dosing is likely to fail.

The timing of antibiotic administration has also been refined. For patients with septic shock, the consensus remains that antibiotics must be administered immediately, ideally within one hour of recognition [17]. However, for patients with sepsis without shock, the mechanical application of the "1-hour bundle" has been criticized for promoting overuse. Contemporary guidelines now endorse a diagnostic pause of up to 3 hours in stable patients [17]. This window allows clinicians to conduct thorough investigations, including imaging and microbiological sampling, to confirm infection and exclude non-infectious mimics. This shift prioritizes diagnostic accuracy over speed in stable patients, reducing unnecessary exposure to broad-spectrum agents.

Reflecting the modern imperative to balance rapid, effective treatment with microbiome preservation [38], carbapenem-sparing strategies have been continuously evaluated. Although carbapenem-sparing regimens are conceptually attractive, low-risk settings for carbapenem-sparing strategies should be explicitly defined. These include non-bacteremic urinary tract infections or infections caused by organisms with borderline susceptibility, for which observational data suggest comparable outcomes with non-carbapenem β-lactams [43]. In contrast, extended-spectrum beta-lactamase bacteremia, as demonstrated in the RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp. (MERINO) trial, requires carbapenem therapy due to significantly higher mortality with piperacillin–tazobactam [44]. Conversely, in the context of de‑escalation, a retrospective multicenter cohort study of 4,967 patients with monomicrobial Enterobacteriaceae bloodstream infection found no difference in 30‑day mortality between patients who received oral step‑down therapy and those who continued parenteral therapy [45]. These findings suggest that transitioning to oral step‑down therapy may be an effective approach for patients who have achieved source control and shown an appropriate clinical response, and that early transition may be associated with a shorter hospital stay. Thus, current evidence supports a precision approach by prioritizing carbapenems during the critical phase to ensure survival, while cautiously pursuing oral step-down therapy in the recovery phase to reduce prolonged antibiotic use and the duration of hospital stay. Additionally, the role of combination therapy (e.g., adding an aminoglycoside to a beta-lactam) for Gram-negative sepsis is being reconsidered. The 2023 Infectious Diseases Society of America guidance suggests that routine double coverage does not improve survival but significantly increases the risk of nephrotoxicity [46]. Therefore, optimized high-dose monotherapy is increasingly preferred, with combination therapy reserved for select cases, such as neutropenia or the high prevalence of multidrug-resistant organisms.

The duration of antimicrobial therapy is increasingly being reduced through short-course regimens. Multiple clinical trials have shown that a 7‑day course is as effective as a 14-day course for uncomplicated Gram-negative bacteremia and pneumonia, without increasing recurrence or mortality [47,48]. Procalcitonin (PCT) algorithms are valuable tools for guiding antibiotic discontinuation. A recent network meta-analysis involving 5,023 patients demonstrated that both PCT‑guided and C-reactive protein‑guided strategies shortened antibiotic treatment (–1.89 days [95% CI, –2.30 to –1.47] and –2.56 days [95% CI, –4.21 to –0.91], respectively), with low to moderate certainty of evidence. In this analysis, PCT‑guided strategies consistently showed benefit, including among patients with shorter baseline antimicrobial durations (7–10 days) and those meeting Sepsis‑3 criteria. The greatest effect was observed when using a PCT cutoff of 0.5 μg/L combined with an 80% reduction. Moreover, PCT‑guided strategies were associated with reduced mortality (–27 per 1,000 patients [95% CI, –45 to –7]), an effect that was particularly pronounced in Sepsis‑3 populations [49]. Practical strategies for optimizing antibiotic therapy across the domains of delivery, timing, spectrum, and duration are presented in Table 3.

Corticosteroid Therapy: Targeting Biological Phenotypes and Genomic Signatures

For over 50 years, corticosteroids have been a subject of intense debate in sepsis. Their use reflects the concept of critical illness-related corticosteroid insufficiency (CIRCI) and their ability to modulate the dysregulated inflammatory response [50,51]. The clinical landscape has been shaped by conflicting results from major trials, shifting the focus from questioning "whether" to use steroids to determining "who" is most likely to benefit [50]. This evolution highlights the move toward precision medicine guided by clinical and genomic phenotypes.

The mechanisms of corticosteroids are pleiotropic, involving both genomic and non-genomic pathways. Through genomic pathways, corticosteroids bind to cytosolic glucocorticoid receptors, translocate to the nucleus, and modulate gene transcription to suppress pro-inflammatory cytokines (e.g., by inhibiting NF-κB) and upregulate anti-inflammatory mediators. The non-genomic pathway provides rapid effects on membrane stability and vascular reactivity [52]. Despite these theoretical benefits, clinical trials have yielded heterogeneous results. The ADRENAL trial, which is the largest RCT to date, found no significant difference in 90-day mortality between hydrocortisone and placebo (27.9% vs. 28.8%, P=0.50), although it did show faster shock reversal [53]. In contrast, the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHS) trial demonstrated a significant reduction in mortality with hydrocortisone plus fludrocortisone compared with placebo (43.0% vs. 49.1%, P=0.03) [54].

These divergent outcomes have spurred a search for responder phenotypes. A recent systematic review and meta-analysis of 45 RCTs concluded that corticosteroids are likely to reduce short-term mortality (RR, 0.93) and increase the likelihood of shock reversal (RR, 1.24) with high certainty [55]. However, these benefits must be weighed against risks such as hyperglycemia, hypernatremia, and neuromuscular weakness. The most compelling evidence for precision medicine comes from transcriptomic analyses. A secondary analysis of the ADRENAL trial identified distinct Sepsis Response Signatures (SRS)1 and 2 based on gene expression profiles. Patients with the SRS2 endotype (characterized by relative immunosuppression) appeared to derive a mortality benefit from hydrocortisone, whereas those with the SRS1 endotype (characterized by higher inflammation) did not and may have experienced harm [56]. This suggests that the underlying biological state determines steroid responsiveness.

In the absence of routine genomic testing, clinical phenotypes serve as practical guides, though recent evidence presents a mixed picture. The Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE COD) trial identified severe community-acquired pneumonia (sCAP) as a highly steroid-responsive phenotype, demonstrating a profound reduction in 28-day mortality with hydrocortisone (6.2% vs. 11.9%, P=0.006) without septic shock at enrollment [57]. Conversely, the recent Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial failed to show a 90-day mortality benefit in sCAP patients (mortality 15% in the hydrocortisone group vs. 9.8% in the control group), although the duration of shock was shorter in the hydrocortisone group [58]. These conflicting results suggest that while sCAP is a distinct entity, the benefit of corticosteroids may be influenced by specific patient characteristics or trial designs, necessitating a careful, personalized approach rather than a universal mandate.

Current guidelines recommend low-dose IV hydrocortisone (200 mg/day) for adult patients with septic shock who are refractory to adequate fluid resuscitation and vasopressor therapy (NE dose >0.25 μg/kg/min) [17]. The addition of fludrocortisone (50 μg) remains an option based on the APROCCHSS protocol, particularly for those with severe persistent hypotension [54]. The future of corticosteroid therapy lies in the development of point-of-care (POC) biomarkers or rapid genomic assays that can distinguish responders (e.g., SRS2 phenotype, CIRCI) from non-responders, enabling targeted immunomodulation that maximizes survival while minimizing adverse effects. Table 4 categorizes specific clinical and genomic phenotypes to guide the personalized administration of corticosteroids.

Practical Constraints to Implementing Precision Medicine in Sepsis

While precision medicine is emerging as a new paradigm in sepsis treatment, its translation into routine clinical practice faces significant practical hurdles. The most fundamental barrier is the lack of rapid diagnostic tools available at the bedside. Sepsis is a medical emergency in which immediate intervention within hours determines survival; however, current omics technologies, such as transcriptomics, often have long turnaround times, making them unsuitable for real-time decision-making [59]. Therefore, without the development of standardized POC assays capable of identifying phenotypes within 1 to 3 hours, the application of precision medicine remains limited.

Economic and structural barriers cannot be ignored either. High-cost targeted therapies and biomarker tests must overcome the thresholds of cost-effectiveness validation and insurance reimbursement. In low-resource healthcare settings lacking artificial intelligence (AI)-based data integration systems or advanced laboratories, accessing these benefits is difficult, posing a significant risk of exacerbating healthcare disparities [60]. Methodologically, the high heterogeneity of sepsis complicates the application of traditional RCTs. To overcome this, adaptive platform trials or predictive enrichment strategies are required, yet they entail substantial costs, complex designs, and challenges in patient recruitment [61]. Finally, ethical issues and educational gaps must be addressed. The handling of sensitive genetic and molecular information raises concerns regarding privacy protection and consent. Moreover, the professional competency required for clinicians to interpret probabilistic genomic data and complex biomarkers is not yet sufficiently covered in standard medical curricula [62].

To overcome these challenges, technological and institutional innovations are essential. The timeliness of diagnosis must be secured through the clinical implementation of next-generation POC technologies, such as lab-on-a-chip or rapid polymerase chain reaction [63]. In the context of research methodology, adaptive platform trials like REMAP-CAP should be promoted, and global data-sharing collaborations established to enhance the efficiency of generating evidence for rare endotypes [61]. Additionally, to bridge the knowledge gap in the clinical field, data science must be integrated into medical curricula, and the adoption of AI-based clinical decision support systems (CDSS) capable of intuitively interpreting complex omics data should be accelerated [64]. If these multifaceted efforts are successful, precision medicine will become the new standard in the intensive care unit in the near future.

Table 5 summarizes practical constraints and future directions for precision sepsis care.

CONCLUSION

The management of sepsis is shifting from rigid protocols to a precision medicine framework. Current evidence favors individualized, phenotype-guided strategies, including fluid therapy, catecholamine-sparing strategy, pharmacokinetic optimization of antibiotics, and targeted immunomodulation, over traditional empirical approaches. However, a significant gap remains between identifying biological endotypes and bedside application, primarily due to the lack of rapid POC diagnostics and infrastructural barriers. Overcoming these hurdles requires technological innovations, such as rapid omics assays and AI-driven CDSS, alongside adaptive platform trials. Ultimately, integrating these tools into routine practice will enable clinicians to deliver "the right treatment to the right patient at the right time” [65]. This evolution promises to overcome the current plateau in survival rates, redefining the standard of critical care through biological precision.

KEY MESSAGES

▪ Sepsis management is shifting from strict protocols to precision medicine. This change aims to better account for patient differences and to overcome plateaued survival rates.

▪ Interventions, such as fluids, hemodynamic support, antibiotics, and corticosteroids, are now tailored to unique traits and biomarkers to deliver “the right drug, at the right dose, for the right patient.”

NOTES

CONFLICT OF INTEREST

Dohhyung Kim is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

FUNDING

None.

ACKNOWLEDGMENTS

None.

AUTHOR CONTRIBUTIONS

Conceptualization: DK. Data curation: HJY, SMK. Project administration: DK. Visualization: DH. Writing – original draft: HJY, SMK. Writing – review & editing: DK. All authors read and agreed to the published version of the manuscript.

Table 1.

Individualized fluid strategy

Domain	Traditional paradigm	Precision medicine approach	Rationale & evidence
Fluid choice	NS (0.9% NaCl) or colloids (HES)	BC (1st-line)	BCs reduce mortality and AKI compared with normal saline.
Fluid choice	NS (0.9% NaCl) or colloids (HES)	Albumin for specific phenotypes	HES is contraindicated due to nephrotoxicity.
Dosing strategy	Fixed "hit hard and early" (e.g., 30 ml/kg bolus for all)	Restrictive and titrated (ROSE framework)	A restrictive strategy is safe.
Dosing strategy	Fixed "hit hard and early" (e.g., 30 ml/kg bolus for all)	Restrictive and titrated (ROSE framework)	Fluid overload is independently associated with mortality.
Monitoring	Static metrics (e.g., CVP)	Dynamic indices (PPV, SVV, PLR), Fluid tolerance (VExUS)	CVP fails to predict fluid responsiveness.
Monitoring	Static metrics (e.g., CVP)	Dynamic indices (PPV, SVV, PLR), Fluid tolerance (VExUS)	VExUS score helps prevent iatrogenic congestion.
De-resuscitation	Often overlooked	Active evacuation	Removal of accumulated fluid when hemodynamic stability is achieved and the patient is no longer fluid responsive.

NS: normal saline; HES: hydroxyethyl starch; BC: balanced crystalloid; AKI: acute kidney injury; ROSE: Resuscitation, Optimization, Stabilization, Evacuation; CVP: central venous pressure; PPV: pulse pressure variation; SVV: stroke volume variation; PLR: passive leg raising; VExUS: venous excess ultrasound score.

Table 2.

Multimodal hemodynamic support

Agent	Target mechanism	Target phenotype / Indication	Clinical benefit	Practical considerations / limitations
Norepinephrine	α-1, β-1 agonist	Standard 1st-line	Effective for MAP	High doses cause metabolic/immunologic toxicity.
Vasopressin	V1a receptor agonist	Vasopressin-responsive phenotype (low copeptin / early shock)	Spares catecholamines	Risk of digital ischemia at high doses; cost higher than NE
			Reduces atrial fibrillation
			Preserves renal GFR
Angiotensin II	RAAS activation	High-renin phenotype (vasodilatory shock)	Increase MAP and survival in high-renin patients	High cost; not globally available (e.g., limited in some Asian/African regions); requires renin biomarker (not routine)

MAP: mean arterial pressure; GFR: glomerular filtration rate; NE: norepinephrine; RAAS: Renin-Angiotensin-Aldosterone System.

Table 3.

Antibiotic stewardship and precision dosing

Domain	Recommendation	Rationale & key evidence
Delivery (PK/PD)	Continuous or prolonged infusion (beta-lactams)	Maximizes fT>MIC
Delivery (PK/PD)	Continuous or prolonged infusion (beta-lactams)	Crucial for patients with ARC or high-MIC pathogens
Timing	Immediate (shock)	Immediate for septic shock
Timing	Diagnostic Pause (stable)	A 3-hour pause allows confirmation of infection and prevents overuse in stable patients.
Spectrum	Carbapenem-sparing	Carbapenem-sparing regimens are noninferior to carbapenem regimens in low-risk cases, such as non-bacteremic urinary tract infection or infection caused by organisms with borderline susceptibility.
Spectrum	Monotherapy	Combination therapy increases nephrotoxicity without a survival benefit.
Duration	Short course (7 days)	7 days are as effective as 14 days for G (-) bacteremia and pneumonia.

PK: pharmacokinetics; PD: pharmacodynamics; fT: time that the free-drug concentration remains above the MIC; MIC: minimal inhibitory concentration; ARC: augmented renal clearance.

Table 4.

Corticosteroid therapy and phenotype-guided immunomodulation

Clinical/genomic phenotype	Implementation status	Recommendation	Evidence/mechanism
Refractory septic shock	Current practice	IV hydrocortisone 200 mg/day (±fludrocortisone)	Recommended when NE dose >0.25 μg/kg/min
Refractory septic shock	Current practice	IV hydrocortisone 200 mg/day (±fludrocortisone)	Reduces the duration of shock.
Severe CAP	Current practice	Strongly recommended	Significant mortality reduction without septic shock (CAPE COD)
SRS2 endotype	Research/future	Likely beneficial	The transcriptomic signature of immunosuppression was associated with benefit.
SRS2 endotype	Research/future	Likely beneficial	Requires a rapid genomic assay
SRS1 endotype	Research/future	Avoid	The transcriptomic signature of high inflammation was associated with potential harm.

IV: intravenous; NE: norepinephrine; CAP: community-acquired pneumonia; CAPE COD: Community-Acquired Pneumonia: Evaluation of Corticosteroids; SRS: Sepsis Response Signature.

Table 5.

Practical constraints and future directions for precision sepsis care

Domain	Key constraints	Potential solutions & future directions
Diagnostics	Lack of rapid (<3 hr) point-of-care tests for endotyping (e.g., transcriptomics)	Development of bedside rapid PCR or microfluidic devices
Diagnostics	Lack of standardized biomarker validation	Standardization of assay platforms across institutions
Infrastructure & economics	High cost of novel therapies (e.g., Ang-II) and molecular assays	Cost-effectiveness studies justify reimbursement
	Limited insurance reimbursement	Integration of AI/ML into EHR for real-time phenotype alert systems
	Data silos preventing real-time integration of EHR and omics data	Global equity initiatives for low-resource settings
Research methodology	Heterogeneity makes traditional RCTs inefficient	Adoption of adaptive platform trials (e.g., REMAP-CAP)
Research methodology	Difficulty in recruiting for enriched small subgroups	Large-scale collaborative networks for data sharing
Clinical adoption	Knowledge gap in interpreting genomic/probabilistic data	Updated critical care curricula, including omics/data science
Clinical adoption	Ethical concerns regarding data privacy	Robust ethical frameworks for genetic data usage

PCR: polymerase chain reaction; Ang-II: angiotensin II; EHR : electronic health record; AI: artificial intelligence; ML: machine learning; RCT: randomized controlled trial; REMAP-CAP: Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia.

REFERENCES

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10.Article PubMed PMC
2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet 2020;395:200-11.Article PubMed PMC
3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.Article PubMed
4. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93.Article PubMed PMC
5. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506.Article PubMed
6. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-11.Article PubMed
7. Vincent JL, van der Poll T, Marshall JC. The end of "one size fits all" sepsis therapies: toward an individualized approach. Biomedicines 2022;10:2260.Article PubMed PMC
8. Carvey MM, Glauser J. The management of severe sepsis and septic shock: a novel update and bedside reference guide. Curr Emerg Hosp Med Rep 2025;13:7.Article PDF
9. Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019;321:2003-17.Article PubMed PMC
10. Stanski NL, Wong HR. Prognostic and predictive enrichment in sepsis. Nat Rev Nephrol 2020;16:20-31.Article PubMed PDF
11. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 2015;19 Suppl 3:S8.Article PubMed PMC PDF
12. Mekontso Dessap A, Cecconi M. Stepwise fluid management in critical illness. Intensive Care Med 2025 Dec 22 [Epub]. https://doi.org/10.1007/s00134-025-08263-8. Article
13. Malbrain ML, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, et al. Principles of fluid management and stewardship in septic shock: it is time to consider the four D's and the four phases of fluid therapy. Ann Intensive Care 2018;8:66.Article PubMed PMC PDF
14. Long J, Chen Z, Luo X, Zhen L, Chi X. Fluid resuscitation management in patients with sepsis and septic shock: a network meta-analysis. Am J Emerg Med 2025;96:80-90.Article PubMed
15. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012;256:18-24.Article PubMed
16. Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest 2006;130:962-7.Article PubMed
17. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med 2021;49:e1063-143.Article PubMed
18. Mekontso Dessap A, AlShamsi F, Belletti A, De Backer D, Delaney A, Møller MH, et al. European Society of Intensive Care Medicine (ESICM) 2025 clinical practice guideline on fluid therapy in adult critically ill patients: part 2-the volume of resuscitation fluids. Intensive Care Med 2025;51:461-77.Article PubMed
19. Shapiro NI, Douglas IS, Brower RG, Brown SM, Exline MC, Ginde AA, et al. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med 2023;388:499-510.Article PubMed PMC
20. Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, et al. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med 2022;386:2459-70.Article PubMed
21. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest 2008;134:172-8.Article PubMed
22. Michard F, Boussat S, Chemla D, Anguel N, Mercat A, Lecarpentier Y, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med 2000;162:134-8.Article PubMed PDF
23. Monnet X, Marik P, Teboul JL. Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis. Intensive Care Med 2016;42:1935-47.Article PubMed PDF
24. Beaubien-Souligny W, Rola P, Haycock K, Bouchard J, Lamarche Y, Spiegel R, et al. Quantifying systemic congestion with Point-Of-Care ultrasound: development of the venous excess ultrasound grading system. Ultrasound J 2020;12:16.Article PubMed PMC PDF
25. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89.Article PubMed
26. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370:1583-93.Article
27. Andreis DT, Singer M. Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum. Intensive Care Med 2016;42:1387-97.Article PDF
28. Lajoye Q, Orieux A, Boyer A, Prevel R, Jozwiak M. Vasopressin and its analogues in patients with septic shock: holy Grail or unfulfilled promise? Crit Care 2025;29:333.Article PubMed PDF
29. Gonçalves A, Gonçalves Pereira F, Fernandes S, Gonçalves Pereira J. Insights Into the pathophysiology of catecholamine-refractory shock: a narrative review. Cureus 2025;17:e86224. Article PMC
30. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588-95.Article PubMed
31. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest 2001;120:989-1002.Article PubMed
32. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.Article PubMed
33. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial. JAMA 2016;316:509-18.Article PubMed
34. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-30.Article PubMed
35. Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, et al. Renin and survival in patients given angiotensin II for catecholamine-resistant vasodilatory shock. A clinical trial. Am J Respir Crit Care Med 2020;202:1253-61.Article PubMed PDF
36. Khattri Bhandari S, Fan SL. Copeptin as a marker for vasopressin dysregulation and diagnosis. J Appl Lab Med 2026;11:143-54.Article PubMed PDF
37. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96.Article PubMed
38. Klompas M, Calandra T, Singer M. Antibiotics for sepsis-finding the equilibrium. JAMA 2018;320:1433-4.Article PubMed
39. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1-10.Article PubMed
40. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014;58:1072-83.
41. Dulhunty JM, Brett SJ, De Waele JJ, Rajbhandari D, Billot L, Cotta MO, et al. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA 2024;332:629-37.Article PubMed PMC
42. Tejada DA, García HC, Tomás-Alvarado E, Yangali-Vicente J, Rivera-Lozada O, Barboza JJ, et al. Continuous versus intermittent infusion of β-lactams in patients with sepsis and septic shock: a systematic review and meta-analysis. BMC Infect Dis 2025;25:1138.Article PubMed PMC PDF
43. Cariou E, Griffier R, Orieux A, Silva S, Faguer S, Seguin T, et al. Efficacy of carbapenem vs non carbapenem β-lactam therapy as empiric antimicrobial therapy in patients with extended-spectrum β-lactamase-producing Enterobacterales urinary septic shock: a propensity-weighted multicenter cohort study. Ann Intensive Care 2023;13:22.Article PubMed PMC PDF
44. Harris PN, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018;320:984-94.Article PubMed PMC
45. Tamma PD, Conley AT, Cosgrove SE, Harris AD, Lautenbach E, Amoah J, et al. Association of 30-day mortality with oral step-down vs continued intravenous therapy in patients hospitalized with enterobacteriaceae bacteremia. JAMA Intern Med 2019;179:316-23.Article PubMed PMC
46. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ, et al. Infectious Diseases Society of America 2023 Guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis 2023 Jul 18 [Epub]. https://doi.org/10.1093/cid/ciad428. Article
47. Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, et al. Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial. Clin Infect Dis 2019;69:1091-8.Article PubMed
48. Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003;290:2588-98.Article PubMed
49. Kubo K, Sakuraya M, Sugimoto H, Takahashi N, Kano KI, Yoshimura J, et al. Benefits and harms of procalcitonin- or C-reactive protein-guided antimicrobial discontinuation in critically ill adults with sepsis: a systematic review and network meta-analysis. Crit Care Med 2024;52:e522-34.Article PubMed
50. Annane D, Briegel J, Seymour CW. Corticosteroids in sepsis: certainties and shadows. Intensive Care Med 2025;51:1890-3.Article PubMed PDF
51. Fredrick FC, Meda AK, Singh B, Jain R. Critical illness-related corticosteroid insufficiency: latest pathophysiology and management guidelines. Acute Crit Care 2024;39:331-40.Article PubMed PDF
52. Heming N, Sivanandamoorthy S, Meng P, Bounab R, Annane D. Immune effects of corticosteroids in sepsis. Front Immunol 2018;9:1736.Article PubMed PMC
53. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378:797-808.Article PubMed
54. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018;378:809-18.Article PubMed
55. Pitre T, Drover K, Chaudhuri D, Zeraaktkar D, Menon K, Gershengorn HB, et al. Corticosteroids in sepsis and septic shock: a systematic review, pairwise, and dose-response meta-analysis. Crit Care Explor 2024;6:e1000. Article PubMed PMC
56. Venkatesh B, Rey DA, Evans DM, Yao L, Finfer S, Bellomo R, et al. A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial. Crit Care Resusc 2025;27:100109.Article PubMed PMC
57. Dequin PF, Meziani F, Quenot JP, Kamel T, Ricard JD, Badie J, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 2023;388:1931-41.Article PubMed
58. Angus DC. Effect of hydrocortisone on mortality in patients with severe community-acquired pneumonia: The REMAP-CAP corticosteroid domain randomized clinical trial. Intensive Care Med 2025;51:665-80.Article PubMed PMC
59. Sweeney TE, Perumal TM, Henao R, Nichols M, Howrylak JA, Choi AM, et al. A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun 2018;9:694.Article PubMed PMC
60. Li DM, Parikh S, Costa A. A critical look into artificial intelligence and healthcare disparities. Front Artif Intell 2025;8:1545869.Article PubMed PMC
61. Kalil AC, Povoa P, Leone M. Subphenotypes and phenotypes to resolve sepsis heterogeneity: hype or hope? Intensive Care Med 2025;51:582-4.Article PubMed PDF
62. Vayena E, Blasimme A, Cohen IG. Machine learning in medicine: addressing ethical challenges. PLoS Med 2018;15:e1002689. Article PubMed PMC
63. Oeschger T, McCloskey D, Kopparthy V, Singh A, Erickson D. Point of care technologies for sepsis diagnosis and treatment. Lab Chip 2019;19:728-37.Article PubMed PMC
64. Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal AA. The artificial intelligence clinician learns optimal treatment strategies for sepsis in intensive care. Nat Med 2018;24:1716-20.Article PubMed PDF
65. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793-5.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite

CITE: export Copy Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Managing sepsis in the era of precision medicine: a narrative review

Acute Crit Care. 2026;41(2):189-200. Published online May 28, 2026

DOI: https://doi.org/10.4266/acc.000884

XML Download

Figure

Managing sepsis in the era of precision medicine: a narrative review

Graphical abstract

Graphical abstract

Managing sepsis in the era of precision medicine: a narrative review

Domain	Traditional paradigm	Precision medicine approach	Rationale & evidence
Fluid choice	NS (0.9% NaCl) or colloids (HES)	BC (1st-line)	BCs reduce mortality and AKI compared with normal saline.
Fluid choice	NS (0.9% NaCl) or colloids (HES)	Albumin for specific phenotypes	HES is contraindicated due to nephrotoxicity.
Dosing strategy	Fixed "hit hard and early" (e.g., 30 ml/kg bolus for all)	Restrictive and titrated (ROSE framework)	A restrictive strategy is safe.
Dosing strategy	Fixed "hit hard and early" (e.g., 30 ml/kg bolus for all)	Restrictive and titrated (ROSE framework)	Fluid overload is independently associated with mortality.
Monitoring	Static metrics (e.g., CVP)	Dynamic indices (PPV, SVV, PLR), Fluid tolerance (VExUS)	CVP fails to predict fluid responsiveness.
Monitoring	Static metrics (e.g., CVP)	Dynamic indices (PPV, SVV, PLR), Fluid tolerance (VExUS)	VExUS score helps prevent iatrogenic congestion.
De-resuscitation	Often overlooked	Active evacuation	Removal of accumulated fluid when hemodynamic stability is achieved and the patient is no longer fluid responsive.

Agent	Target mechanism	Target phenotype / Indication	Clinical benefit	Practical considerations / limitations
Norepinephrine	α-1, β-1 agonist	Standard 1st-line	Effective for MAP	High doses cause metabolic/immunologic toxicity.
Vasopressin	V1a receptor agonist	Vasopressin-responsive phenotype (low copeptin / early shock)	Spares catecholamines	Risk of digital ischemia at high doses; cost higher than NE
			Reduces atrial fibrillation
			Preserves renal GFR
Angiotensin II	RAAS activation	High-renin phenotype (vasodilatory shock)	Increase MAP and survival in high-renin patients	High cost; not globally available (e.g., limited in some Asian/African regions); requires renin biomarker (not routine)

Domain	Recommendation	Rationale & key evidence
Delivery (PK/PD)	Continuous or prolonged infusion (beta-lactams)	Maximizes fT>MIC
Delivery (PK/PD)	Continuous or prolonged infusion (beta-lactams)	Crucial for patients with ARC or high-MIC pathogens
Timing	Immediate (shock)	Immediate for septic shock
Timing	Diagnostic Pause (stable)	A 3-hour pause allows confirmation of infection and prevents overuse in stable patients.
Spectrum	Carbapenem-sparing	Carbapenem-sparing regimens are noninferior to carbapenem regimens in low-risk cases, such as non-bacteremic urinary tract infection or infection caused by organisms with borderline susceptibility.
Spectrum	Monotherapy	Combination therapy increases nephrotoxicity without a survival benefit.
Duration	Short course (7 days)	7 days are as effective as 14 days for G (-) bacteremia and pneumonia.

Clinical/genomic phenotype	Implementation status	Recommendation	Evidence/mechanism
Refractory septic shock	Current practice	IV hydrocortisone 200 mg/day (±fludrocortisone)	Recommended when NE dose >0.25 μg/kg/min
Refractory septic shock	Current practice	IV hydrocortisone 200 mg/day (±fludrocortisone)	Reduces the duration of shock.
Severe CAP	Current practice	Strongly recommended	Significant mortality reduction without septic shock (CAPE COD)
SRS2 endotype	Research/future	Likely beneficial	The transcriptomic signature of immunosuppression was associated with benefit.
SRS2 endotype	Research/future	Likely beneficial	Requires a rapid genomic assay
SRS1 endotype	Research/future	Avoid	The transcriptomic signature of high inflammation was associated with potential harm.

Domain	Key constraints	Potential solutions & future directions
Diagnostics	Lack of rapid (<3 hr) point-of-care tests for endotyping (e.g., transcriptomics)	Development of bedside rapid PCR or microfluidic devices
Diagnostics	Lack of standardized biomarker validation	Standardization of assay platforms across institutions
Infrastructure & economics	High cost of novel therapies (e.g., Ang-II) and molecular assays	Cost-effectiveness studies justify reimbursement
	Limited insurance reimbursement	Integration of AI/ML into EHR for real-time phenotype alert systems
	Data silos preventing real-time integration of EHR and omics data	Global equity initiatives for low-resource settings
Research methodology	Heterogeneity makes traditional RCTs inefficient	Adoption of adaptive platform trials (e.g., REMAP-CAP)
Research methodology	Difficulty in recruiting for enriched small subgroups	Large-scale collaborative networks for data sharing
Clinical adoption	Knowledge gap in interpreting genomic/probabilistic data	Updated critical care curricula, including omics/data science
Clinical adoption	Ethical concerns regarding data privacy	Robust ethical frameworks for genetic data usage

Table 1. Individualized fluid strategy

Table 2. Multimodal hemodynamic support

MAP: mean arterial pressure; GFR: glomerular filtration rate; NE: norepinephrine; RAAS: Renin-Angiotensin-Aldosterone System.

Table 3. Antibiotic stewardship and precision dosing

PK: pharmacokinetics; PD: pharmacodynamics; fT: time that the free-drug concentration remains above the MIC; MIC: minimal inhibitory concentration; ARC: augmented renal clearance.

Table 4. Corticosteroid therapy and phenotype-guided immunomodulation

IV: intravenous; NE: norepinephrine; CAP: community-acquired pneumonia; CAPE COD: Community-Acquired Pneumonia: Evaluation of Corticosteroids; SRS: Sepsis Response Signature.

Table 5. Practical constraints and future directions for precision sepsis care