Early recognition and bundle-based management of pediatric sepsis in the emergency department: a narrative review

Introduction

Background

Pediatric sepsis remains a major cause of global morbidity and mortality and continues to impose a substantial burden on emergency and critical care systems (1,2). Although epidemiological estimates vary across definitions and settings, available data consistently indicate that sepsis remains associated with considerable short-term mortality, especially in severe presentations and resource-constrained environments (1,2). In emergency care, however, the practical problem is no longer simply to acknowledge the importance of sepsis; it is to identify which children require escalation early enough for bundle-based treatment to alter the clinical trajectory. This challenge is especially acute in general emergency departments (EDs), where pediatric case volume, pathway familiarity, and available resources vary substantially. Recent developments, including updated pediatric sepsis definitions, multicenter implementation collaboratives, and expanding digital screening tools, make a focused reassessment of the current evidence particularly timely.

Rationale and knowledge gap

Early identification of pediatric sepsis in the ED remains challenging because the syndrome is biologically and clinically heterogeneous (2,3). Age-dependent variation in baseline physiology, immune maturation, and compensatory reserve means that neonates, infants, and older children may present with markedly different patterns of illness. In addition, early manifestations are frequently nonspecific, including fever, tachycardia, irritability, poor feeding, or mild respiratory distress, which can overlap with many self-limited infectious conditions. As emphasized in the Surviving Sepsis Campaign pediatric guidelines, delays in recognition can postpone timely antimicrobial therapy, hemodynamic support, and escalation of care in a disease process that may deteriorate rapidly (3). The unresolved clinical questions are equally important: existing screening tools do not perform uniformly across settings, the evidence base supporting individual bundle elements is not equally strong, and implementation remains uneven between tertiary children’s hospitals and general EDs.

These challenges have driven continued efforts to develop more reliable recognition tools for pediatric sepsis. Organ dysfunction-based approaches such as the pediatric Sequential Organ Failure Assessment (pSOFA) and, more recently, the Phoenix criteria have strengthened the conceptual framework for pediatric sepsis by moving beyond older inflammation-based definitions toward risk stratification grounded in organ dysfunction (4,5). However, their roles should be distinguished carefully. The Phoenix criteria were derived primarily to standardize the definition of pediatric sepsis and septic shock rather than to function as a frontline early-warning recognition tool in the emergency department. Accordingly, performance remains context dependent. ED-based validation work has shown that tools derived from intensive care or classification-oriented settings may not translate perfectly to frontline emergency care, where data are limited at presentation and patients often represent an earlier stage of disease evolution (4). Likewise, contemporary multicenter data from general EDs suggest that care quality and sepsis outcomes vary substantially across institutions, highlighting the influence of case volume, workflow design, and local expertise on real-world recognition and treatment performance (6).

Because no single tool is sufficient for all pediatric ED settings, current practice increasingly relies on multimodal recognition strategies. These include structured clinical assessment, scoring systems, conventional and emerging biomarkers, and digital approaches based on electronic health records (EHRs) and predictive analytics (5,7,8). Biomarkers remain attractive because they may complement bedside assessment and support diagnostic or prognostic refinement, yet currently available markers still have important limitations in sensitivity, specificity, or clinical interpretability when used in isolation (7). Similarly, machine learning and EHR-based models have shown promise for earlier prediction and automated surveillance, but their broader implementation is constrained by issues of external validity, alert burden, and workflow integration (8). Accordingly, the key translational question is no longer whether any single marker or score can solve the problem, but how multiple sources of information can be integrated into a practical and timely ED recognition pathway.

Objective

In parallel with advances in recognition, bundle-based management has emerged as a central strategy for converting early suspicion into prompt action (3,9). Pediatric sepsis bundles emphasize rapid screening, early antimicrobial administration, timely fluid resuscitation, serial reassessment, and coordinated multidisciplinary response. Importantly, multicenter quality-improvement data indicate that bundled ED sepsis care can improve process measures and may also contribute to better clinical outcomes (9). Nevertheless, implementation remains inconsistent, and important gaps persist regarding which recognition tools are most useful in the ED, how bundle adherence can be sustained across different resource settings, and how nursing-led and team-based workflows can be optimized. In this context, the purpose of this narrative review is not merely to summarize pediatric sepsis care broadly, but to address three practical questions relevant to frontline emergency care: which recognition strategies are most useful at the point of initial evaluation, which bundle elements have the strongest support for time-sensitive implementation, and what organizational barriers most often prevent reliable delivery across different ED environments, as summarized in Figure 1. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0358/rc).

Figure 1 Operational emergency department pathway for early recognition and bundle-based management of pediatric sepsis. This figure presents an operational ED pathway for pediatric sepsis, beginning with initial suspicion based on symptoms, vital signs, perfusion abnormalities, or altered mental status. The pathway then proceeds through structured screening, integrated use of clinical judgment and adjunctive tools, pathway activation, first-hour bundle delivery, and repeated reassessment of treatment response. The purpose of the figure is to convert the narrative review into a practical process framework that highlights how recognition and bundle-based management are linked in real-world emergency care rather than existing as separate conceptual steps. ED, emergency department.

Methods

A structured narrative review was conducted using the PubMed database. The search was performed on March 15, 2026 and covered studies published from January 1, 2010 through March 15, 2026. Search terms were chosen to capture both pediatric sepsis recognition and bundle-based emergency management, including screening tools, biomarkers, quality-improvement pathways, and digital decision support. We focused on ED-relevant studies involving recognition strategies, pathway or bundle implementation, nursing or workflow processes, and emerging translational tools. Titles and abstracts were screened against predefined inclusion and exclusion criteria, and the included literature was synthesized narratively into major domains relevant to frontline emergency care. In accordance with journal guidance for narrative reviews, we report the search date, timeframe, selection process, language/access considerations, and synthesis approach transparently in Table 1.

Challenges and current approaches to early recognition of pediatric sepsis

Clinical heterogeneity and diagnostic challenges in pediatric sepsis

Early recognition of pediatric sepsis in the emergency department is inherently difficult because sepsis in children is not a single, uniform clinical entity but a syndrome with substantial biological and phenotypic heterogeneity (2,10). Across the pediatric age spectrum, baseline vital signs, immune maturation, cardiovascular compensation, and organ-specific responses to infection differ considerably, which complicates the interpretation of early clinical findings. As a result, the same physiological abnormality may have different implications in a neonate, an infant, and an older child, while the absence of overt hypotension or obvious organ failure at presentation does not reliably exclude evolving severe sepsis or septic shock (3,11,12). This age-dependent variability is one of the principal reasons why pediatric sepsis remains more difficult to recognize promptly than many other time-sensitive emergency conditions.

A further challenge is that the earliest manifestations of sepsis are often nonspecific and overlap extensively with common self-limited infectious illnesses. Fever, tachycardia, delayed capillary refill, tachypnea, lethargy, poor feeding, or altered behavior may all represent early sepsis, but each of these signs is also frequently encountered in less severe pediatric infections (11,12). In younger infants, especially neonates, the presentation may be even more subtle, with temperature instability, apnea, feeding intolerance, or reduced interaction preceding more recognizable circulatory deterioration (11). Conversely, older children may maintain blood pressure and apparent hemodynamic stability until a relatively late stage because of robust compensatory vasoconstriction and tachycardia, thereby masking the severity of disease during initial assessment (3,12). This narrow window between nonspecific early illness and rapid decompensation is a defining problem in pediatric emergency sepsis care.

The diagnostic difficulty is compounded by the absence of a universally accepted bedside gold standard for early sepsis identification in children presenting to the ED (4,10). Historically, pediatric sepsis definitions were largely adapted from systemic inflammatory response syndrome (SIRS) criteria, which offered sensitivity but limited specificity. More recent organ dysfunction-based frameworks, including pSOFA and the Phoenix criteria, better align pediatric sepsis with contemporary pathobiological understanding, but even these approaches are affected by setting-specific limitations, especially in the ED where complete laboratory data may not yet be available and patients may present before overt organ dysfunction has fully declared itself (4,5,10). The scoping review by Oruganti et al. found marked heterogeneity across pediatric ED sepsis identification studies in terms of age groups, reference standards, index tools, and outcome definitions, underscoring the difficulty of directly comparing diagnostic performance across studies and institutions (10). From a translational perspective, this heterogeneity weakens standardization and makes it harder to define a single optimal recognition pathway for all pediatric emergency settings.

The relatively low prevalence of severe sepsis among the overall pediatric ED population creates an additional operational problem: clinicians must identify a small number of critically ill children within a much larger pool of febrile or physiologically abnormal patients (10,13,14). This ‘needle in a haystack’ problem has important implications for screening performance. Tools designed to maximize sensitivity often generate a substantial number of false positives, which can increase alert fatigue, unnecessary escalation, and inefficient resource use; by contrast, tools designed to improve specificity may miss children in the earliest phase of disease (10,13). In practice, this tradeoff helps explain why no single screening model has emerged as universally superior. In one pediatric ED study, the introduction of a vital sign-based electronic alert improved recognition when combined with bedside clinical assessment, but the alert alone had limited positive predictive value because abnormal vital signs are common in children for reasons other than sepsis (13). Similarly, direct comparison of physician judgment and an algorithmic alert showed that human clinical concern and electronic screening each captured different at-risk patients, suggesting that clinician assessment and automated tools should be viewed as complementary rather than competing strategies (14).

Recognition is also shaped by workflow and systems factors, not simply by disease biology. Pediatric sepsis identification in the ED depends on rapid triage, repeated reassessment, timely access to laboratory testing, and effective communication between nurses, physicians, and escalation teams (3,11,12). Under real-world emergency conditions, crowding, incomplete clinical information, variable pediatric expertise, and competing high-acuity demands can all delay recognition and treatment activation (11,12). This is especially relevant in general EDs, where pediatric sepsis may be encountered less frequently than in specialized children’s hospitals and where case volume, local pathway familiarity, and resource availability can influence care quality and outcomes (6). Accordingly, early recognition should be understood not merely as a diagnostic exercise, but as a dynamic systems process that integrates symptom interpretation, risk stratification, serial observation, and protocolized response.

Taken together, current evidence indicates that the challenge of pediatric sepsis recognition arises from the interaction of three factors: biological heterogeneity, nonspecific early presentation, and variable care environments (2,10-14). These realities explain why reliance on isolated clinical signs or single screening tools is insufficient in most ED settings. They also provide the rationale for a layered recognition strategy that combines structured bedside assessment, age-appropriate scoring systems, biomarkers, and workflow-integrated digital support.

Clinical scoring systems for early recognition of pediatric sepsis

Clinical scoring systems are central to the early recognition of pediatric sepsis because they provide a structured method for translating heterogeneous bedside findings into actionable estimates of risk (3,15). In the emergency department, where clinicians must identify a relatively small number of critically ill children among a much larger population of febrile or physiologically abnormal patients, scoring tools are particularly attractive because they can standardize triage, trigger reassessment, and support escalation of care (10,15). However, their practical utility depends not only on predictive performance, but also on whether they are feasible at the point of initial evaluation, sufficiently sensitive for early disease, and adaptable to age-related physiological variation. Current scoring approaches can be broadly grouped into early warning systems intended for bedside deterioration screening and organ dysfunction-based systems designed to identify or quantify sepsis severity more specifically.

Among bedside screening tools, the Pediatric Early Warning System (PEWS) and related variants remain widely used because they are simple, rapid, and largely based on observable clinical parameters such as heart rate, respiratory status, behavior, and perfusion (16). The original Bedside PEWS was developed to identify deteriorating hospitalized children rather than sepsis specifically, and its main strength lies in its ease of implementation and compatibility with routine nursing assessment (16). In practice, this makes PEWS attractive for ED screening, especially in settings where laboratory data are not immediately available. Nevertheless, its application to pediatric sepsis has important limitations. Because PEWS was not designed as a sepsis-specific tool, its abnormalities often reflect general physiological stress rather than infection-related organ dysfunction. Consequently, PEWS may facilitate early suspicion and repeated observation, but it cannot reliably distinguish sepsis from other causes of tachycardia, tachypnea, or altered appearance in acutely ill children (10,15). This limitation is especially relevant in overcrowded emergency settings, where nonspecific alerts may contribute to overtriage and alert fatigue.

Organ dysfunction-based scores were developed to address some of these shortcomings by linking sepsis recognition more directly to clinically meaningful physiological derangement. The pSOFA, adapted from the adult Sequential Organ Failure Assessment (SOFA) score, represents one of the most important advances in this area (17). Matics and Sanchez-Pinto demonstrated that pSOFA could quantify organ dysfunction and predict mortality in critically ill children, thereby providing a pediatric analogue to Sepsis-3 concepts (17). Compared with early warning scores, pSOFA offers stronger pathophysiological alignment with contemporary definitions of sepsis because it focuses on dysfunction across respiratory, cardiovascular, neurologic, hematologic, hepatic, and renal systems (17). However, its strengths are also the source of its practical limitations in emergency care. Several of its components require laboratory values or interventions that may not yet be available at triage, and the score may perform better once organ dysfunction has become established than at the earliest stage of clinical presentation (4,17). Thus, pSOFA is often more useful for severity assessment, prognostic stratification, and ongoing evaluation than for first-line screening in children with subtle early sepsis, as shown in Table 2.

This gap between conceptual strength and bedside feasibility is evident in ED validation studies. In a multicenter pediatric ED cohort, Balamuth et al. found that pSOFA had good discriminative ability for in-hospital mortality among patients with suspected infection, supporting its clinical relevance in emergency care (4). At the same time, the study also highlighted an important practical point: the data needed to compute organ dysfunction scores may emerge progressively during the ED stay rather than at the moment of presentation. In other words, pSOFA may function well as a dynamic assessment tool but less well as a pure early-warning screen. This distinction is critical when designing ED pathways, because recognition systems that depend too heavily on later-available variables may fail to accelerate the earliest time-sensitive interventions.

The recent development of the Phoenix criteria and Phoenix Sepsis Score represents a major attempt to modernize pediatric sepsis classification using a large, international, data-driven framework (5). By deriving criteria from organ dysfunction patterns associated with mortality across diverse settings, the Phoenix approach addresses long-standing limitations of prior inflammation-centered definitions and provides a more consistent basis for defining pediatric sepsis and septic shock (5). Its conceptual significance is substantial, particularly for research harmonization and risk stratification. However, it is important to state explicitly that the Phoenix criteria were not derived as an early-warning sepsis recognition tool for use at ED triage. Rather, they were developed as standardized criteria for defining pediatric sepsis and septic shock. As with pSOFA, important questions therefore remain about real-time ED applicability. Commentaries and subsequent validation work have emphasized that criteria optimized for broad classification and prognostic discrimination may not automatically function as ideal frontline screening tools in emergency or low-resource settings, where rapid decisions must often be made before the full organ dysfunction profile is available (18). Recent ED-based validation data are encouraging, but they also suggest that the Phoenix score may currently be more robust as a prognostic and definitional framework than as a stand-alone trigger for the earliest bedside suspicion of sepsis (18,19).

For neonatal populations, scoring challenges are even greater because standard pediatric tools often do not adequately account for the physiology and disease patterns of premature and very low birth weight infants. The neonatal SOFA (nSOFA) was developed to fill this gap and has shown promising prognostic value in late-onset sepsis, particularly for mortality prediction in preterm neonates (20). Its value lies in providing a neonatal organ dysfunction framework that is more biologically appropriate than generic pediatric tools. However, nSOFA is primarily relevant to neonatal and intensive care contexts rather than the broader pediatric ED population, and its specialized nature limits its applicability as a universal recognition instrument across all pediatric age groups (20). This reinforces the broader principle that no single score is likely to perform equally well across all pediatric subpopulations.

Meta-analytic evidence also supports a cautious interpretation of scoring system performance in pediatric sepsis. A meta-analysis comparing SIRS, age-adapted pSOFA, and quick SOFA (qSOFA) found that age-adapted pSOFA generally showed better predictive accuracy for adverse outcomes than the other two approaches, while qSOFA performed poorly in children (21). These findings are consistent with the broader shift away from simple inflammation-based or adult-derived rapid screeners toward pediatric-specific organ dysfunction assessment. Even so, the same evidence base indicates that the available scores are not interchangeable and should not be overinterpreted as definitive diagnostic instruments (21). Rather, they are best understood as probabilistic tools whose performance depends on when they are applied, in whom they are applied, and for what purpose they are used, such as triage, mortality prediction, or protocol activation.

From a practical ED perspective, the most important issue may therefore be not which score is theoretically superior, but how scoring systems are embedded within an overall sepsis recognition strategy (15). Early warning scores such as PEWS can support broad surveillance and repeated bedside reassessment. Organ dysfunction scores such as pSOFA and Phoenix are more useful for refining severity classification and prognosis once sufficient data are available. Neonatal tools such as nSOFA serve specialized populations. Taken together, these systems are complementary rather than mutually exclusive. Their highest value is likely realized when they are combined with clinician judgment, serial examination, laboratory markers, and workflow-integrated digital prompts rather than used in isolation. However, direct head-to-head comparisons remain limited, external validation in general EDs is incomplete, and most studies evaluate screening performance more often than downstream patient benefit. This integrated approach is therefore clinically sensible, but the current evidence base still leaves uncertainty about which combinations are most reliable across different emergency settings.

Biomarkers for early diagnosis and risk stratification

Biomarkers have become an essential adjunct to clinical assessment in pediatric sepsis because bedside signs alone are often insufficient to distinguish early sepsis from other inflammatory or infectious presentations in the emergency department (7,22). In principle, an ideal biomarker for pediatric sepsis should rise early in the disease course, discriminate infectious from noninfectious inflammation, reflect severity, support prognostic stratification, and be rapidly available in routine practice. However, current evidence suggests that no single biomarker fulfills all of these requirements consistently across pediatric age groups and clinical settings (7,22). As a result, biomarkers are best viewed as part of a layered diagnostic strategy rather than as stand-alone diagnostic standards.

Among conventional biomarkers, C-reactive protein (CRP) and procalcitonin (PCT) remain the most commonly used in pediatric practice. CRP is widely available, inexpensive, and familiar to clinicians, but its main limitation is biological timing and specificity. Because CRP rises relatively slowly after inflammatory stimulation and may be elevated in many non-septic conditions, it is often more useful for serial trend assessment than for early diagnostic discrimination at first presentation (7). PCT has generally shown greater specificity for bacterial infection and more favorable kinetics than CRP, which explains why it is often considered the more clinically informative of the two markers in suspected pediatric sepsis (7,23). At the same time, PCT is not a definitive diagnostic solution. Downes has emphasized that the value of PCT in pediatric sepsis depends heavily on clinical context, sampling time, and the decision it is intended to support, such as antibiotic initiation, escalation of concern, or diagnostic refinement (23). In other words, PCT may strengthen diagnostic confidence, but its greatest utility emerges when interpreted together with the patient’s trajectory rather than as an isolated threshold result, as shown in Table 3.

The limitations of CRP and PCT have prompted interest in newer biomarkers with potentially better early diagnostic performance. Presepsin, a soluble CD14 subtype released during monocyte-macrophage activation, has attracted particular attention because it may increase earlier than some traditional inflammatory markers and may better reflect pathogen-related innate immune activation (24,25). In a pediatric meta-analysis, presepsin showed promising overall diagnostic accuracy and compared favorably with CRP and PCT in some cohorts, although the evidence base remained limited and heterogeneous (25). More recent pediatric studies have reinforced both the promise and the uncertainty surrounding presepsin. For example, Khera et al. reported that elevated presepsin levels were associated with septic shock severity, particularly at 72 hours, but also concluded that its early diagnostic utility and prognostic value remained insufficient for independent clinical use (24). Likewise, an emergency department pilot study by Gatto et al. suggested that presepsin may help differentiate bacterial from viral febrile illness in children with suspected sepsis, but the study design and cohort size support cautious interpretation rather than immediate broad implementation (26). Taken together, these findings suggest that presepsin is a promising adjunctive biomarker, especially for dynamic assessment, but still requires larger ED-based validation before routine adoption.

Another emerging biomarker is pancreatic stone protein (PSP), which has generated increasing interest because of its potential to support both diagnosis and severity assessment in pediatric sepsis (27,28). Earlier pediatric work suggested that PSP might correlate with multiorgan dysfunction and mortality, raising the possibility that it reflects more than simple inflammatory activation (27). More recent studies have been more clinically focused. Saleh et al. found that PSP had promising diagnostic value in critically ill children with sepsis, although its performance for mortality prediction was more modest (28). Similarly, Bottari et al. evaluated PSP in children with suspected sepsis admitted through high-dependency and emergency pathways and reported that PSP outperformed CRP and PCT for sepsis discrimination in that cohort, with an area under the receiver operating characteristic curve (AUROC) of 0.82 (29). These findings are encouraging because they suggest that PSP may be particularly useful in diagnostically equivocal cases. Nevertheless, the same study also showed that a positive PSP result did not fully resolve clinical uncertainty, indicating that even high-performing novel biomarkers are unlikely to replace integrated clinical assessment (29).

In addition to protein biomarkers, readily obtainable hematologic indices have been explored because of their low cost and broad availability. Among these, the neutrophil-to-lymphocyte ratio (NLR) has attracted interest as a practical marker of systemic inflammatory imbalance. Zhong et al. reported that initial NLR was associated with severe pediatric sepsis and that its predictive performance improved when combined with PCT and PRISM III (30). Such findings are appealing for resource-limited settings because NLR can be calculated from routine blood counts without additional assay costs. However, its specificity remains limited, and it should be considered primarily as a supportive severity indicator rather than a sepsis-defining biomarker (30). Similarly, lactate has long been used in sepsis evaluation, not because it is specific for infection, but because it reflects tissue hypoperfusion, metabolic stress, and severity of illness. In pediatric cohorts, lactate has shown prognostic value, particularly when interpreted alongside ferritin, CRP, and illness severity scores, but it is better understood as a marker of physiological consequence than as a diagnostic marker of sepsis itself (3,31).

A major conceptual shift in the biomarker field is the move from single-marker testing toward multibiomarker models and enrichment strategies. Wong has argued that the most clinically meaningful future application of pediatric sepsis biomarkers may not be the binary diagnosis of sepsis, but rather prognostic and predictive enrichment, that is, identifying subgroups of children with distinct risk profiles or biological phenotypes who may benefit from more targeted treatment strategies (32). This concept is supported by the development of multibiomarker models such as PERSEVERE, which aim to improve mortality estimation and biological subclassification in pediatric septic shock (33). Although such models are not yet routine ED tools, they represent an important translational direction because they align biomarker science with precision medicine rather than with the unrealistic expectation that one laboratory value can independently diagnose all pediatric sepsis.

Overall, current evidence suggests that biomarkers contribute meaningfully to pediatric sepsis recognition and risk stratification, but only when their strengths and limitations are explicitly acknowledged (7,22-33). CRP and PCT remain the most practical conventional markers, with PCT generally offering better infection specificity. Presepsin and PSP are promising newer candidates, especially for diagnostic refinement and severity assessment, but both still require broader validation across ED populations. Hematologic ratios and lactate are useful supportive markers, particularly in rapid or resource-constrained workflows, yet lack sufficient specificity for independent diagnostic use. The emerging consensus is therefore that biomarkers should augment, not replace, structured clinical evaluation and should ideally be incorporated into integrated algorithms that combine bedside assessment, scoring systems, and digital support. At the same time, the literature remains limited by small cohorts, heterogeneity in reference standards, and relatively few head-to-head comparisons that test whether biomarker-informed decisions actually improve ED management or outcomes.

Bundle-based management and nursing in pediatric emergency sepsis care

Conceptual basis and core components of bundle-based management in pediatric emergency sepsis care

Bundle-based management has become a central strategy in pediatric sepsis care because it addresses a key limitation of traditional emergency treatment: recognition alone does not guarantee timely, coordinated intervention (3,9). In pediatric emergency departments, clinicians must make rapid decisions under conditions of diagnostic uncertainty, evolving physiology, and variable access to laboratory confirmation. Under these circumstances, the principal advantage of a sepsis bundle is not simply that it lists recommended therapies, but that it transforms early suspicion into a structured response pathway with predefined priorities, roles, and time targets (3,34). For pediatric sepsis, this is particularly important because deterioration may occur rapidly after an initially nonspecific presentation, and delays in initiating treatment can result in progression to shock and multiple organ dysfunction.

Conceptually, pediatric sepsis bundles are designed to reduce treatment variability and improve the reliability of time-sensitive care. The Surviving Sepsis Campaign pediatric guidelines emphasize that children with suspected septic shock or sepsis-associated organ dysfunction require prompt recognition, rapid antimicrobial therapy, hemodynamic stabilization, and repeated reassessment (3). In practice, bundle-based management operationalizes these recommendations by organizing care into linked steps that can be initiated immediately after sepsis is suspected. This structure is especially valuable in emergency settings, where fragmented decision-making and delays in communication may otherwise hinder the transition from triage concern to full resuscitative response (34). In this sense, a bundle should be understood as a workflow model rather than a static checklist: it coordinates recognition, treatment initiation, and serial evaluation into a unified clinical process.

Although specific bundle designs vary across institutions, several core elements are consistently included in pediatric emergency sepsis pathways (3,9,34,35). These generally involve early identification of suspected sepsis, rapid assessment of perfusion and organ dysfunction, timely vascular access, collection of indicated cultures and laboratory tests, prompt administration of empiric broad-spectrum antibiotics, fluid resuscitation for children with abnormal perfusion or shock, escalation to vasoactive support when hemodynamic instability persists, and serial reassessment of clinical response (3). Among these steps, repeated reassessment is especially important in children because initial compensation may obscure disease severity and therapeutic response can change rapidly over short intervals. For both clinical use and quality measurement, these elements should be translated into discrete operational targets with explicit timing windows rather than described only in general terms. Table 4 has therefore been revised to reflect measurable timing anchors for frontline implementation and bundle-compliance assessment.

From a nursing perspective, bundle-based care is also a surveillance framework. Nurses play a pivotal role in recognizing early deterioration, tracking dynamic physiological changes, initiating escalation, and supporting the execution of time-critical interventions (36). In most emergency settings, nurses are the first clinicians to detect persistent tachycardia, delayed capillary refill, abnormal mental status, increasing work of breathing, or failure to improve after initial treatment. Accordingly, the effectiveness of a sepsis bundle depends heavily on whether nursing staff are empowered to trigger sepsis pathways and whether the pathway itself is integrated into routine triage and monitoring workflows (36,37). This operational reality distinguishes bundle-based sepsis care from general supportive treatment: the bundle is effective not only because of what is done, but because it formalizes how concern is recognized, escalated, and acted upon across the care team.

An important feature of bundle-based management is its balance between standardization and clinical flexibility. On the one hand, bundles seek to minimize avoidable variation by defining key interventions that should occur rapidly once sepsis is suspected (3,9). On the other hand, pediatric sepsis care cannot be reduced to rigid protocol application, because treatment needs vary according to age, comorbidity, source of infection, cardiovascular phenotype, and response to initial therapy. This is particularly evident in fluid resuscitation. While timely isotonic fluid administration remains a cornerstone of early septic shock management, more recent evidence indicates that the relationship between fluid volume and outcome is influenced by illness severity and clinical context, underscoring the need for ongoing reassessment rather than fixed-volume thinking (38). Therefore, the most effective pediatric sepsis bundles are those that standardize early action while preserving space for individualized clinical judgment.

Multidisciplinary coordination is another defining component of successful bundle-based care. Pediatric sepsis management often requires rapid interaction among emergency physicians, nurses, pharmacists, respiratory therapists, intensive care teams, and, in some settings, transport services (34,37). Without a structured pathway, delays may arise from uncertainty regarding team roles, treatment thresholds, or escalation criteria. By contrast, a well-designed bundle clarifies who initiates laboratory workup, who obtains vascular access, who prepares antimicrobials, who reassesses perfusion, and when senior review or intensive care unit (ICU) consultation should occur. Qualitative work from general emergency departments has shown that clinicians value pediatric sepsis guidance that is practical, actionable, and adapted to local workflow, particularly in hospitals with lower pediatric volumes (37). This suggests that the conceptual success of a bundle depends not only on clinical correctness, but also on organizational usability.

Evidence for the clinical effectiveness of bundle-based care

The clinical effectiveness of bundle-based care in pediatric sepsis should be interpreted across two related but distinct domains: improvement in process performance and improvement in patient-centered outcomes. This distinction is important because many sepsis pathway studies consistently demonstrate gains in treatment timeliness and protocol adherence, whereas evidence for hard outcome benefits, such as reduced mortality or shorter length of stay, is more variable (9,35,39). From an implementation science perspective, this pattern is not unexpected. Sepsis bundles are designed first to improve care reliability by reducing delays and omissions in time-sensitive management; whether these process gains translate into measurable outcome benefits depends on illness severity, case mix, institutional readiness, and the extent to which the bundle is delivered consistently across the full clinical pathway.

The strongest and most reproducible benefits of bundle-based care have been observed in process measures. In the Pediatric Septic Shock Collaborative, a multicenter quality-improvement initiative involving 19 pediatric emergency departments, implementation of shared screening recommendations, educational resources, and bundle-based care pathways led to improvements in timely vital sign assessment and antibiotic delivery, with particularly meaningful gains in children admitted to the ICU (9). These findings support the view that bundle implementation can improve the reliability of early sepsis management at scale. Similar process-level improvements were reported in the Queensland Pediatric Sepsis Breakthrough Collaborative, where introduction of a statewide pediatric sepsis pathway was associated with improved compliance with key treatment time targets compared with the baseline ICU cohort, although bundle completion within target timeframes remained inconsistent across sites (35). Importantly, this study also showed that performance varied among hospital types, emphasizing that pathway implementation is feasible across diverse emergency settings but that sustained adherence remains challenging (35).

Single-center implementation studies have further reinforced the association between sepsis pathway adoption and improved first-hour care. Rodrigues-Santos et al. reported that after implementation of a pediatric Surviving Sepsis Campaign-based protocol, sepsis recognition increased substantially and compliance with the complete 1-hour bundle improved from 0% to 62%, with large gains in timely blood culture collection, fluid resuscitation, and antibiotic administration (39). These findings are particularly relevant because they illustrate the operational value of a structured protocol in improving early treatment execution rather than merely documenting guideline awareness. Collectively, current studies suggest that one of the clearest advantages of bundle-based pediatric sepsis care is its ability to make critical early interventions more timely and more reproducible.

Whether these improvements in care processes translate into better clinical outcomes is a more nuanced question. In the Pediatric Septic Shock Collaborative, bundle implementation was associated with a reduction in 30-day all-cause in-hospital mortality in the overall sample, providing encouraging multicenter evidence that structured emergency sepsis care may improve meaningful outcomes (9). However, this finding should be interpreted carefully because quality-improvement collaboratives evaluate complex interventions, and mortality changes may reflect multiple simultaneous improvements in recognition, escalation, team coordination, and ICU transition rather than any single bundle component alone. Similarly, other pathway studies have reported improvements in selected outcome measures, including ICU admission patterns, vasopressor exposure, and organ support requirements, but these effects are not uniformly observed across all cohorts (9,35,39). The overall literature therefore supports a cautious but favorable conclusion: bundle-based care appears capable of improving outcomes, yet the magnitude and consistency of benefit remain context dependent.

One reason for this variability is that the relationship between individual bundle components and outcomes is not always linear. Antibiotic timing is a useful example. Early antimicrobial therapy is a foundational component of sepsis bundles and is strongly supported by international guidelines (3). Yet pediatric outcome data are more heterogeneous than is sometimes assumed. Lane et al. found that among children treated for suspected septic shock in a pediatric emergency department, target time-to-antibiotic administration was not independently associated with mortality, although associations with other outcomes were more complex (40). Creedon et al. likewise reported that children who received antibiotics earlier were often sicker and had worse outcomes, illustrating the challenge of confounding by indication in retrospective sepsis timing studies (41). Recent review work has therefore emphasized that time-to-antibiotics recommendations in pediatric sepsis are clinically important but should not be interpreted in isolation from illness severity, diagnostic certainty, and stewardship considerations (42). In other words, the effectiveness of a sepsis bundle cannot be judged solely by whether one element is completed within an arbitrary threshold; the quality of bundle-based care depends on how early interventions are matched to clinical phenotype and reassessed over time.

A similar principle applies to fluid resuscitation. Although isotonic fluid boluses remain a cornerstone of early septic shock care, recent multicenter studies suggest that both the amount and rate of fluid delivery should be interpreted within the broader clinical context (38,43). Eisenberg et al. reported that first-hour intravenous fluid volume was associated with mortality in pediatric septic shock, but the relationship was influenced by severity and likely reflected both therapeutic decisions and underlying shock phenotype (38). Mullan et al. likewise found that fluid bolus rates were associated with outcomes in pediatric sepsis, supporting the concept that fluid resuscitation should be protocolized but not reflexive (43). These data do not undermine bundle-based care; rather, they show that bundle effectiveness depends on integrating rapid treatment with repeated bedside reassessment. A bundle is most clinically effective when it accelerates necessary therapy without suppressing individualized judgment.

Another useful way to interpret the clinical effectiveness of sepsis bundles is to consider that their benefits may emerge through systems performance rather than through any isolated physiological mechanism. Sepsis pathways often improve documentation, escalation triggers, pharmacist involvement, antibiotic access, team communication, and ICU consultation timing, all of which may contribute indirectly to improved outcomes (9,34,35). This broader systems effect likely explains why quality-improvement interventions can succeed even when the independent effect of a single bundle element is difficult to quantify. In pediatric emergency care, where the central challenge is often delayed recognition followed by fragmented response, this systems-level reliability may be one of the most important outcome drivers.

Implementation barriers and practical optimization strategies

Despite the conceptual appeal and growing evidence base for bundle-based pediatric sepsis care, implementation in real-world emergency settings remains inconsistent (34-37,44). This gap between evidence and practice is a recurring theme in the sepsis literature and reflects the fact that a sepsis bundle is not simply a clinical recommendation but a complex behavioral and organizational intervention. Successful implementation requires clinicians to recognize a relatively uncommon but high-risk condition early, initiate multiple time-sensitive actions, communicate effectively across disciplines, and sustain adherence under pressure in environments characterized by crowding, interruptions, and competing priorities (37,44). Consequently, the barriers to bundle adoption are rarely attributable to a single factor; rather, they arise from the interaction of knowledge, staffing, workflow design, local pediatric capability, and institutional support.

One of the most consistently identified barriers is variable clinician confidence and knowledge regarding pediatric sepsis recognition and treatment, particularly outside specialized pediatric centers (36,37,44). In the Queensland statewide pathway study, nurse knowledge scores varied substantially across participating sites, and higher knowledge was associated with stronger beliefs about capability, more favorable perceptions of the care environment, and dedicated funding for sepsis quality-improvement work (36). These findings suggest that even when a formal pathway is available, staff may not use it effectively unless they understand its rationale, trust their own ability to act on it, and perceive that the clinical environment supports timely implementation. Qualitative work in general emergency departments has similarly shown that clinicians often experience pediatric sepsis as a relatively infrequent but high-stakes scenario and therefore prefer pathways that are highly practical, clear, and easy to operationalize at the bedside (37). This is especially relevant in lower-volume hospitals, where pediatric experience may be less consistent and delays may arise not from unwillingness, but from uncertainty.

A second major barrier is workflow complexity. Sepsis bundles typically require the rapid execution of several interdependent actions, including escalation of concern, physician review, vascular access, blood sampling, antibiotic ordering, fluid administration, reassessment, and sometimes ICU consultation (3,34). If any one of these steps is delayed, overall bundle performance deteriorates. In busy emergency departments, these delays may be caused by interruptions, unclear division of responsibilities, slow access to medications, or competing high-acuity cases. Earlier sepsis implementation research in emergency medicine, although largely from mixed or adult-focused settings, identified practical constraints such as insufficient nursing availability, monitoring limitations, and difficulty identifying septic patients early enough to activate protocol-based care (45). These observations remain highly relevant to pediatric emergency practice because they illustrate that pathway adherence is often limited by operational friction rather than by disagreement with the underlying clinical recommendations.

Resource variation across institutions further complicates implementation. Pediatric sepsis pathways developed in tertiary children’s hospitals may assume access to rapid laboratory turnaround, experienced pediatric staff, dedicated pharmacists, and immediate ICU backup, whereas general emergency departments may have more limited pediatric readiness (6,37). This difference is not trivial. The effectiveness of a bundle depends not only on protocol content but also on whether the required infrastructure exists to support it. Harley and colleagues showed that dedicated nurse funding was associated with better knowledge translation during statewide pediatric sepsis pathway implementation, suggesting that organizational investment directly affects frontline uptake (36). Likewise, broader implementation work has emphasized that pathway success depends on institutional commitment to education, audit, and workflow redesign, not merely the distribution of written protocols (34). Therefore, one practical implication for clinical translation is that sepsis bundles should be adapted to local capability rather than copied wholesale from higher-resource systems.

Another barrier is alert fatigue and the burden of low-specificity screening. Because pediatric sepsis is relatively uncommon compared with the far larger population of children with fever or transient physiological abnormalities, screening systems designed for high sensitivity may produce frequent false-positive activations (10,13,15). This can reduce trust in the pathway, increase unnecessary work, and ultimately weaken compliance with escalation protocols. In implementation terms, this is a classic tradeoff: if the threshold for activation is too low, clinicians may disengage; if it is too high, early sepsis may be missed. Recent implementation redesign work on adult and pediatric sepsis pathways has shown that facilitators and barriers span multiple behavioral domains, including knowledge, memory, environmental context, social influence, and beliefs about capability, and that pathway use can be improved through tailored strategies such as electronic medical record (EMR) modification, audit and feedback, staffing support, and redesigned training (44). These findings reinforce that pathway performance should not be judged solely by screening accuracy but also by whether the system is acceptable and sustainable for frontline teams.

Given these barriers, the most effective optimization strategies are those that treat bundle implementation as an ongoing quality-improvement process rather than as a one-time rollout (34,36,44). First, education should be continuous, role-specific, and linked to real clinical workflow. Nurses, physicians, and pharmacists require different but complementary training, and simulation or case-based rehearsal may be particularly helpful in low-frequency, high-risk scenarios (46). Second, pathways should be simplified to emphasize actionable steps and decision points rather than excessive protocol detail. Qualitative data suggest that clinicians are more likely to adopt pathways that are easy to remember and clearly aligned with ED operations (37). Third, audit and feedback systems are essential. Monitoring time to antibiotics, bundle completion, escalation frequency, and missed sepsis cases allows institutions to identify bottlenecks and refine processes over time (34,47). Fourth, digital tools should be deployed selectively to support workflow, for example through order sets, timed prompts, and documentation support, but not in ways that increase unnecessary alarm burden (13,44,47). Finally, local adaptation should be considered a strength rather than a compromise. Standardization of goals is important, but standardization of implementation should remain flexible enough to reflect site-specific staffing, resources, and pediatric volume.

Future directions

Emerging biomarkers and precision diagnostic strategies

Future progress in pediatric sepsis recognition is likely to depend less on the discovery of a single ‘ideal’ marker and more on the development of integrated precision diagnostic strategies that combine biological profiling with clinical context (22,32,48). The limitations of currently used markers such as CRP, PCT, lactate, and NLR are now well recognized: although they can support clinical judgment, none alone can fully resolve the diagnostic uncertainty created by age-dependent physiology, nonspecific early symptoms, and heterogeneous host responses (7,22,23,31). This has prompted increasing interest in emerging biomarkers and multi-omics approaches that may capture sepsis biology more directly and allow more refined risk stratification than conventional inflammation markers.

One major area of development is multi-omics biomarker discovery. Recent review work has highlighted the growing relevance of transcriptomics, proteomics, metabolomics, and lipidomics in pediatric sepsis research, particularly because these approaches can reveal complex host-response patterns that are not apparent from routine laboratory tests (48). Unlike single-marker strategies, multi-omics platforms are designed to characterize coordinated biological networks, including immune activation, complement dysregulation, endothelial injury, mitochondrial dysfunction, and metabolic reprogramming. This systems-level perspective is especially attractive in pediatric sepsis, where marked interpatient heterogeneity likely reflects the coexistence of multiple biological subphenotypes rather than one uniform disease process (32,48). Accordingly, the future value of multi-omics may lie not only in diagnosis, but also in identifying clinically meaningful subclasses of pediatric sepsis that differ in prognosis and therapeutic responsiveness.

Metabolomics has been one of the most clinically informative early examples of this approach. In an influential study, Awuti et al. demonstrated that metabolomic profiling could distinguish pediatric septic shock from controls and was also associated with mortality risk, suggesting that metabolic signatures may capture disease severity earlier and more comprehensively than traditional biomarkers alone (49). This work remains important because it established proof of principle that metabolic reprogramming in pediatric sepsis is measurable and clinically relevant. More broadly, metabolomics aligns well with the concept of sepsis as a disorder of dysregulated host response and bioenergetic stress, making it particularly suitable for early phenotyping in critically ill children (48,49). However, although metabolomic signatures are biologically promising, routine clinical translation remains limited by assay complexity, turnaround time, platform standardization, and the need for validation in broader emergency care populations.

Proteomics and related plasma profiling strategies also represent an important frontier. Recent pediatric work has identified phase-specific proteomic signatures associated with acute and recovery-stage sepsis, including complement-associated proteins, acute-phase reactants, and inflammatory mediators (50). Such findings are important because they suggest that proteomics may help define disease trajectories and biological states rather than merely indicating the presence of infection. In translational terms, this could support a shift from static diagnosis toward dynamic biomarker-guided monitoring. Nevertheless, the proteomics field is still in an early stage from a bedside application perspective. Most studies remain exploratory, are conducted in relatively small cohorts, and require specialized analytic platforms that are not yet compatible with rapid emergency department decision-making (48,50). Thus, while omics-derived markers are likely to shape future pediatric sepsis classification, they have not yet displaced the practical role of conventional biomarkers in frontline emergency care.

A second major future direction is biomarker-based enrichment rather than simple binary diagnosis. Wong has argued that the most useful role of next-generation biomarkers in pediatric sepsis may be prognostic and predictive enrichment, meaning the identification of children at highest risk of organ dysfunction, persistent inflammation, or specific biological complications who might benefit from more targeted interventions (32). This concept is already reflected in biomarker risk models such as PERSEVERE and in evolving efforts to biologically phenotype pediatric septic shock (33). The importance of this shift should not be underestimated. Traditional diagnostic models ask whether a child does or does not have sepsis; precision models ask what type of sepsis biology is present, how severe it is likely to become, and whether a particular treatment approach is appropriate. This framework is more closely aligned with modern precision medicine and may ultimately prove more useful than the pursuit of a universally accurate single biomarker.

Artificial intelligence (AI) and machine learning are likely to play a key role in enabling these precision strategies. Machine learning models can integrate demographic data, vital signs, laboratory values, and, increasingly, biomarker information to generate risk estimates that may outperform simpler rule-based systems in some settings (8,51). In pediatric sepsis, machine learning has already been used both for early severe sepsis prediction and for the derivation of computable sepsis phenotypes that may facilitate personalized trial enrollment and biologically informed risk stratification (8,51). These developments are important because they show how precision diagnostics may move beyond ‘marker discovery’ toward clinically actionable multimodal prediction. However, the same limitations remain relevant: model generalizability, local calibration, variable data quality, and the risk of overfitting or workflow disruption (8). Therefore, AI-assisted pediatric sepsis diagnosis should be viewed as an enabling framework for biomarker integration rather than as a replacement for clinical reasoning.

From a practical standpoint, the most realistic near-term future is likely to involve layered precision pathways rather than fully omics-driven bedside diagnostics. In such a model, conventional markers would continue to support frontline assessment, while more advanced biomarker panels, molecular phenotyping, and machine learning tools would be used to refine classification, predict deterioration, and guide escalation in selected high-risk patients (22,32,48,51). This staged approach is attractive because it reflects both biological complexity and real-world feasibility. It also fits the broader evolution of pediatric sepsis care from syndrome-based treatment toward phenotype-informed management. Future studies should therefore prioritize multicenter validation, assay simplification, ED-compatible turnaround times, and integration with workflow-based bundle activation. Only through such translational work can emerging biomarkers move from promising research tools to clinically useful components of pediatric sepsis diagnosis, as shown in Figure 2.

Figure 2 Future translational framework for precision and technology-enabled pediatric sepsis care. This figure summarizes a future-oriented translational model for pediatric sepsis management that integrates emerging biomarkers, multi-omics profiling, machine learning prediction, electronic alerts, intelligent monitoring, nursing-led escalation, and standardized sepsis bundles. The framework highlights how precision diagnostics and digital tools may strengthen early recognition and individualized risk stratification while remaining embedded within multidisciplinary, workflow-based emergency care systems. It also illustrates the role of multicenter collaboration and implementation science in validating and scaling these innovations across different care settings. ED, emergency department; EHR, electronic health record.

Intelligent monitoring, digital support, and AI-enabled nursing pathways

Digital innovation is increasingly viewed as a necessary complement to conventional pediatric sepsis care because timely recognition and bundle delivery depend not only on clinical knowledge, but also on the ability to detect deterioration early, support decisions under uncertainty, and coordinate workflow across multiple providers (8,13,52). In pediatric emergency care, these needs are especially pronounced. Children often present with nonspecific physiological abnormalities, may deteriorate rapidly after an initially subtle presentation, and require repeated reassessment rather than a single static decision point. For these reasons, the most promising future direction is not simply the addition of isolated digital tools, but the creation of intelligent, workflow-integrated systems that combine automated surveillance, clinical decision support, and nursing-triggered escalation into a unified care pathway.

Electronic sepsis alerts embedded within the EHR have been among the earliest and most practical digital strategies in pediatric sepsis. Their main value lies in supporting consistent recognition of high-risk physiological patterns that might otherwise be overlooked during triage or busy ED workflow. Balamuth et al. showed that a vital sign-based electronic sepsis alert, when combined with bedside clinician identification, substantially improved recognition sensitivity for pediatric severe sepsis in the emergency department (13). This finding remains highly influential because it demonstrates a principle that continues to shape digital sepsis design: automated alerts perform best when they augment rather than replace clinical judgment. Subsequent analysis of missed cases after alert implementation also reinforced that even effective digital systems do not eliminate diagnostic misses entirely, especially in patients whose presentation falls outside predefined physiological triggers (52). Thus, digital alerts should be understood as risk amplification tools rather than autonomous diagnostic systems.

Recent implementation studies have supported the broader utility of electronic alert systems while also highlighting their limitations. Oddiri et al. reported that automated severe sepsis alerts linked to EHR and paging systems facilitated earlier identification and treatment initiation in pediatric patients, suggesting that digital notification systems can improve response speed when embedded into organizational workflows (53). However, the wider literature on computerized clinical decision support systems indicates that technological promise is often constrained by heterogeneity in trigger criteria, usability, outcome measurement, and implementation context (54). Ackermann et al. found that pediatric sepsis decision-support systems varied widely in design and evaluation metrics, and that usability and cost-effectiveness were infrequently studied despite their importance for real-world adoption (54). This observation is particularly relevant for pediatric emergency departments, where alert fatigue, limited staffing, and competing acute-care priorities may undermine even technically sound systems if they are poorly aligned with frontline workflow.

AI and machine learning offer a more advanced extension of digital sepsis support by enabling multivariable prediction from high-dimensional clinical data (8,51,55). Unlike traditional rule-based alerts, machine learning models can incorporate complex interactions among demographics, vital signs, laboratory values, comorbidities, and temporal trends to estimate sepsis risk in real time. Early pediatric work by Le et al. demonstrated that machine learning could predict severe sepsis using routinely collected clinical data (8), while subsequent ED-based studies have identified underappreciated risk features and shown promising discrimination for pediatric sepsis prediction (55). These developments are important because they suggest that AI may eventually improve early risk stratification beyond what is possible with threshold-based screening alone. However, several translational barriers remain unresolved, including data quality, local model calibration, generalizability across institutions, interpretability, and the risk that predictive outputs may not be acted upon appropriately in practice (8,54,55). In other words, predictive accuracy does not automatically translate into clinical benefit unless the model is embedded in a trusted and actionable care pathway.

An especially important future direction is the integration of digital support with nursing workflow. In pediatric sepsis, nursing staff are often the first to detect abnormal trends in perfusion, behavior, respiratory effort, or response to initial therapy, making them central to any practical monitoring strategy (36). AI-enabled nursing pathways could enhance this role by combining continuous or repeated physiological data capture with context-sensitive escalation prompts. Rather than generating generic alerts, such systems could prioritize clinically meaningful changes, help distinguish persistent deterioration from transient abnormalities, and link those signals directly to sepsis bundle activation steps. This approach is consistent with the broader digital health perspective proposed by Sanchez-Pinto et al., who argued that digital solutions in pediatric sepsis should be designed not only for prediction but also for implementation, equity, and global usability (56). Their review emphasized that digital technologies are most likely to improve care when they are connected to local infrastructure, clinical workflow, and response capability rather than introduced as isolated predictive tools (56).

Beyond EHR alerts, intelligent monitoring technologies may further expand the future scope of pediatric sepsis care. Wearable biosensors, wireless physiologic monitoring systems, and continuous signal analysis platforms have the potential to capture early deterioration that may not be evident from intermittent bedside observation (57). Although pediatric evidence remains limited and most wearable applications are still in early-phase feasibility studies, the underlying concept is highly relevant to sepsis: continuous monitoring may detect subtle trajectory changes earlier than episodic assessment, especially in patients under observation or in resource-constrained environments where continuous direct clinician presence is not feasible (57). However, current limitations are substantial, including motion artifact, age-specific device design, signal quality, regulatory validation, and unclear integration into emergency workflow (57). Thus, while intelligent monitoring is promising, it should currently be considered an emerging support technology rather than an established component of pediatric sepsis management.

A key lesson from both pediatric and broader sepsis informatics literature is that digital support systems must be evaluated not only on prediction performance, but also on implementation outcomes. Alert acceptance, workflow burden, response time, usability, and the ability to improve bundle completion are arguably as important as sensitivity or AUROC in determining whether a digital intervention meaningfully improves care (54,56). This is especially true in pediatric sepsis, where delayed action often reflects operational friction as much as diagnostic uncertainty. Therefore, future AI-enabled nursing pathways should be designed around clinical decisions and team behaviors rather than around prediction alone. Systems that identify high-risk children but fail to produce timely escalation or treatment will have limited practical value.

Multicenter collaboration, pathway standardization, and future research priorities

A central lesson from contemporary pediatric sepsis research is that meaningful progress will depend not only on better biomarkers or more sophisticated digital tools, but also on stronger multicenter collaboration and more consistent pathway standardization (9,35,58-60). Pediatric sepsis is a comparatively low-frequency but high-consequence condition, and single-center studies often lack the sample size, case-mix diversity, and implementation variability needed to generate broadly generalizable conclusions. This challenge is particularly relevant in emergency care, where patient populations, pediatric readiness, staffing models, and workflow structures differ substantially between tertiary children’s hospitals and general emergency departments (6,37). As a result, multicenter collaboration is not simply desirable for statistical reasons; it is essential for developing evidence that is representative of real-world pediatric sepsis care. The strongest current evidence in this area supports improved process reliability, but it is much less certain which pathway components are indispensable or how well high-performing programs transfer to lower-volume EDs.

Collaborative quality-improvement models have already demonstrated their value in this field. The Pediatric Septic Shock Collaborative and the Queensland Pediatric Sepsis Breakthrough Collaborative both showed that shared metrics, common pathway elements, regular feedback, and cross-site learning can improve process reliability and support broader dissemination of pediatric sepsis best practices (9,35). Similarly, the Children’s Hospital Association Improving Pediatric Sepsis Outcomes collaborative was explicitly designed to create a scalable multicenter infrastructure for sepsis improvement across emergency departments, ICUs, general wards, and hematology-oncology units (58). These collaborative efforts are important because they move pediatric sepsis research beyond isolated institutional success stories and toward a learning-health-system model in which protocols, data structures, and outcome measures can be compared and refined across sites. In practical terms, this approach is one of the most promising ways to reduce unwarranted variation in pediatric sepsis recognition and treatment.

At the same time, the literature makes clear that standardization remains incomplete. One of the most persistent obstacles is inconsistency in definitions, especially regarding sepsis onset, time zero, and eligibility for pathway activation (59,60). Paul highlighted that pediatric sepsis quality improvement has long been limited by the lack of uniform definitions applicable across treatment venues, which complicates benchmarking and cross-site comparison (60). Lessons from earlier collaborative work reached a similar conclusion: institutions often differed in cohort identification strategies, time-zero definitions, and the processes used to classify sepsis severity, making both data collection and interpretation difficult (59). These issues remain highly relevant despite more recent progress in pediatric sepsis definitions, because implementation pathways still require operational definitions that can be applied reliably at the bedside and in quality-improvement databases. Without this level of standardization, even well-designed multicenter studies may struggle to distinguish true performance differences from methodological inconsistency, as shown in Table 5.

The need for broader international collaboration is equally important. Multicenter data from Latin America illustrate how first-hour guideline adherence remains difficult even in tertiary settings, with full achievement of early treatment goals occurring in only a minority of children with pediatric septic shock (61). Such findings are valuable because they highlight that the barriers to timely sepsis care are not confined to one health system and that implementation science must account for diverse resource environments. More generally, epidemiological data from Latin American hospitals have reinforced the ongoing burden of pediatric sepsis and the variability in outcomes across public and private institutions (62). These studies strengthen the case for future multicenter collaborations that include both high-resource and resource-constrained settings, particularly because any global effort to standardize pediatric sepsis pathways must remain adaptable to differing infrastructure, staffing, and diagnostic capacity.

Future research priorities should therefore focus on four intersecting goals. First, pediatric sepsis studies should increasingly adopt harmonized operational definitions, outcome measures, and pathway metrics so that evidence can accumulate coherently across institutions (58-60). This includes clearer specification of recognition thresholds, time-zero definitions, bundle completion metrics, and clinically meaningful outcomes beyond mortality alone, such as escalation delays, organ dysfunction progression, ICU transfer, and treatment-related complications. Second, multicenter validation of emerging tools is urgently needed. Biomarkers, machine learning models, and electronic alert systems may perform well in derivation settings, but their clinical value depends on reproducibility across different patient populations and care environments (48,51,54,56). Third, future studies should evaluate individual bundle elements more explicitly, because current pathway studies often assess the bundle as a whole and therefore cannot easily determine which components drive benefit and which are more context dependent. Fourth, implementation science should be integrated more directly into pediatric sepsis research. It is no longer sufficient to ask whether a tool predicts sepsis; investigators must also examine whether it changes clinician behavior, improves pathway adherence, reduces inequity, and remains sustainable over time (34,44,56).

Another important research direction is the alignment of standardization with personalization. At first glance, protocol standardization and precision medicine may seem to point in opposite directions, but in pediatric sepsis they are increasingly complementary. Standardized pathways are needed to ensure timely recognition and treatment, whereas precision diagnostics and biologic phenotyping may help refine escalation, monitoring, and adjunctive therapies once the pathway has been activated (32,48,51). The future challenge is therefore not choosing between standardization and individualization, but designing clinical systems in which standardized early response can be followed by more tailored risk stratification and management. Multicenter collaboratives are well positioned to support this transition because they can generate the large, diverse datasets needed for both operational benchmarking and phenotype discovery.

Strengths and limitations of this review

This review has several strengths. It focuses specifically on the interface between early recognition and bundle-based management in the emergency department, integrates clinical, biomarker, workflow, and digital-support literature, and gives explicit attention to general ED implementation rather than limiting interpretation to highly resourced pediatric centers. At the same time, important limitations should be acknowledged. As a narrative review, the search was structured for transparency but was not intended to capture every published study in the field. The underlying evidence base is also heterogeneous in definitions, settings, outcomes, and implementation metrics, which limits direct comparison across studies. In addition, much of the available literature remains observational or quality-improvement based, so conclusions about the independent effects of individual recognition tools or bundle elements should be interpreted cautiously.

Conclusions

Pediatric sepsis is a high-stakes, time-sensitive emergency, but early recognition in the ED remains limited by nonspecific presentation, age-related physiology, and uneven pediatric readiness across institutions (1-3,10-14). These constraints explain why isolated bedside signs or single diagnostic tools rarely provide sufficient accuracy for reliable early recognition. Rather, current evidence most strongly supports a layered strategy in which structured clinical assessment, age-appropriate scoring systems, biomarkers, and workflow-integrated digital support are used together to improve diagnostic precision and accelerate escalation (4,5,7,13,15,22).

Bundle-based management remains the most practical framework for converting suspicion into timely action (3,9,34). The literature is most consistent in showing improvement in process reliability, including faster antibiotic administration, clearer escalation, and better bundle adherence. By contrast, evidence for direct improvement in hard clinical outcomes, such as mortality and length of stay, is favorable but less uniform and is often difficult to separate from the broader effects of workflow redesign, staff engagement, and institutional support (9,35,38-43). This means that current bundle evidence is encouraging, but still insufficient to claim that every bundle element is equally evidence based or equally transferable across all emergency settings.

Important uncertainties also remain in the translational space. Biomarkers, molecular phenotyping, machine learning, and digital monitoring systems offer genuine promise, but few have been validated across diverse general ED populations or shown to improve real-world decision making when embedded into routine workflow (32,48-57). Likewise, recognition tools that perform well in derivation studies or specialty settings may not deliver the same clinical value in lower-volume or resource-variable emergency departments. The next phase of pediatric sepsis research therefore needs to move beyond tool development alone and more directly test implementation, usability, and actionability.

The clearest priorities for future work are harmonized definitions, multicenter validation in general ED environments, clearer evaluation of measurable bundle elements, and implementation studies that test how nursing-led escalation and digital decision support influence frontline performance under real-world conditions. In practical terms, the field now needs less descriptive proliferation and more comparative, operationally focused evidence. Progress will depend on building pediatric sepsis systems that are not only biologically informed, but also measurable, usable, and reliable across the full range of emergency care settings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0358/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0358/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0358/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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