Advances in the diagnostic and treatment of neonatal septic shock: a narrative review

Introduction

Sepsis is a severe condition characterized by a dysregulated response to infection leading to immunologic dysregulation, systemic inflammation and circulatory failure (i.e., septic shock). Neonates, especially preterm infants, are particularly vulnerable to sepsis and rapid progression to shock due to their underdeveloped immune responses and higher susceptibility to infections (1). Although neonatal sepsis early recognition is crucial for timely intervention, its clinical presentation may be subtle, it may overlap with normal physiological changes at birth, or it may resemble other events such as apnea of prematurity. This can make prompt diagnosis challenging, increasing the likelihood of progression to septic shock (2-5). In fact, septic shock is one of the leading causes of neonatal mortality worldwide, with an estimate of over 550,000 deaths every year (6).

Significant progress has been made in neonatal intensive care. As will be discussed throughout this review, these advances include the widespread adoption of bedside ultrasonography, the application of personalized medicine supported by machine learning, larger studies comparing different vasoactive agents and novel therapeutic alternatives for septic shock. In the database search, it was observed that these novel approaches have been evaluated individually in previous reviews (7-15). However, no comprehensive review has been identified that examines these themes collectively. Therefore, we present a narrative review of the most recent evidence on the diagnosis and management of septic shock in the neonatal period. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-91/rc).

Methods

A literature search was conducted using the PubMed, Embase and Cochrane Library databases. Key terms included “neonatal”, “premature”, “preterm” and “septic shock”, with related derived words (Table 1 and Table S1). Peer-review studies in English published from inception to 2024 were included. We prioritized randomized controlled trials, systematic reviews, and meta-analyses. The selection process involved screening abstracts for inclusion, followed by a full-text review of articles that met the criteria, in addition to citation chaining (searching the references of selected articles to identify other relevant publications). This process was performed by two authors (E.A.S.O. and L.K.O.J.) independently, with consensus agreement of eventual discordances. Relevant data were extracted and summarized in eight domains, presented below. PRISMA statements and SANRA scale were used for quality reporting (16,17).

Guidelines and data-driven neonatal care

Guidelines, such as Advanced Cardiovascular Life Support, Pediatric Advanced Life Support, and the Surviving Sepsis Campaign, have increasingly emphasized the importance of healthcare services maintaining clear protocols and a well-trained team to ensure the early identification of critical conditions such as septic shock, as well as to reduce the time required for interventions and the variability in treatment (18).

Recent publications have also highlighted the importance of efficient data management (7,19-21). A neonatal intensive care unit constantly generates a wide range of data (e.g., vital signs, fluid balance, laboratory test results, ultrasound data, electroencephalography patterns), challenging the healthcare team to transform this data into meaningful information. Automation in data collection and analysis, aided by recent artificial intelligence models, can enable faster and more systematic patient analysis while reducing reliance on manual labor (8). Current challenges include ensuring compatibility between equipment for integrated monitoring, continuous improvement of artificial intelligence models for better diagnostic accuracy, and training staff to understand the adopted models in order to reduce possible mistrust or low adherence, as well as to identify situations that require clinical interpretation to confirm the validity of the data.

Early identification and diagnosis

The classic definition of an “evidence of pathogen in the bloodstream” is impractical due to its low sensitivity and due to delay in test positivity (1,22-25). The latest International Consensus Criteria for Pediatric Sepsis and Septic Shock have established definitions for sepsis and septic shock but excluded the neonatal population (2). The definition offered by Sepsis-3 as “a life-threatening organ dysfunction caused by a dysregulated host response to infection” is commonly adapted for neonates, but the defining “organ dysfunction” can be difficult in neonates (3). Common laboratory tests have reference values that vary or are not well-defined according to gestational age, and abnormalities can occur in conditions other than infection, such as maternal diseases, respiratory distress or corticosteroid use. Defining shock in neonates is a major challenge, as preterm infants possess limited capacity to increase cardiac output other than tachycardia, and reference values for hypotension are not well-established (4).

New methods have been explored. In one study, presepsin was found to effectively discriminate between infection, sepsis and septic shock, outperforming C-reactive protein and procalcitonin with an area under the curve of 0.90 for sepsis and 0.94 for septic shock (9). Another study investigated electrical cardiometry for monitoring cardiac output and systemic vascular resistance in neonates and found that it can be helpful in assessing hemodynamic status and differentiating between warm and cold shock (10). In addition, studies of plasma vasopressin in neonates less than 34 weeks gestation found that lower vasopressin levels were associated with progression to septic shock with an adjusted odds ratio of 0.97, emphasizing its potential as an early marker (26). Proteomics, transcriptomics and metabolomics have been applied to identify early sepsis and septic shock biomarkers (27); for instance, a recent study applied machine learning to identify metabolic biomarkers associated with an early sepsis diagnosis, with positive results (11).

In neonatal septic shock, near-infrared spectroscopy may offer early, non-invasive insights into peripheral perfusion by monitoring regional oxygen saturation in critical organs (28). Decreased renal regional saturation could signal early hypoperfusion before changes in cerebral saturation or pulse oximetry occur, and abdominal near-infrared spectroscopy may provide an early warning for splanchnic hypoperfusion, as lower levels have been associated with necrotizing enterocolitis. Although these applications are promising, further studies are needed to confirm the role of near-infrared spectroscopy in septic shock. Renal near-infrared spectroscopy also has the potential to detect circulatory and renal dysfunction at an early stage. It can be used in the prediction of patent ductus arteriosus, the assessment of nephrotoxic drug effects, the detection of sepsis and the monitoring of post-transfusion changes. In addition, renal near-infrared spectroscopy may assist in diagnosing acute kidney injury before conventional markers, particularly in hypoxic ischemic encephalopathy and post-cardiac surgery. Although its impact on improving outcomes is still under investigation, renal near-infrared spectroscopy could serve as a real-time indicator of impaired perfusion, guiding timely interventions to mitigate acute kidney injury severity (29).

Clinical parameters for hemodynamic assessment and vasopressor titration in neonatal septic shock remain limited, highlighting the value of functional echocardiography as a bedside tool for evaluating cardiac function and treatment response. A systematic review of 12 studies involving 438 septic neonates and 232 controls revealed frequent findings of pulmonary hypertension, left ventricular diastolic dysfunction, and a warm shock physiology characterized by elevated cardiac output in septic neonates. However, heterogeneity in sepsis definitions, severity scores, and echocardiographic methodologies restricted the review’s conclusions (30). Despite these limitations, the findings highlight the potential of neonatologist-performed echocardiography to identify hemodynamic changes, advocating for its broader integration into hemodynamic management protocols for septic neonates.

A recent study utilized functional echocardiography in a neonatal intensive care unit setting to assess hemodynamic parameters in 36 neonates with septic shock compared to age-matched healthy controls. Gram-negative bacilli accounted for 78.9% of isolates. At baseline, ventricular outputs, shortening fraction, ventricular diastolic E/A wave ratio (a marker of the ventricle function), and myocardial performance index were comparable between groups. However, the inferior vena cava distensibility index was significantly higher in shock cases (17% vs. 10%, P<0.01). Following inotropic therapy, right ventricular output and right ventricular myocardial performance index improved, whereas left ventricular output remained largely unchanged, and inferior vena cava distensibility decreased (22% to 14%, P=0.013). Notably, no significant echocardiographic differences were found between survivors and non-survivors, highlighting the need for further research to evaluate echocardiography’s predictive value in neonatal septic shock (12).

Antimicrobial therapy

In sepsis, empirical antimicrobial therapy should be initiated promptly after obtaining appropriate cultures. The choice of antimicrobials, often involving two or more agents, and their duration are traditionally guided by likely pathogens, site of infection, local antibiotic susceptibility patterns and clinical resolution. De-escalation is recommended once cultures and sensitivity of the isolate to specific antibiotic agents become available. However, the imprecision in sepsis diagnosis, limitations in pathogen identification, and challenges associated with culture techniques often lead to unnecessary antimicrobial use. This misuse increases the risk of disrupted gut microbiota, long-term neurological impairments, and mortality, while also causing renal and hepatic injuries that compromise physiological functions and exacerbate shock (31,32).

Studies applying machine learning to analyze clinical and laboratorial data may not only allow earlier identification of sepsis, but also improve diagnostic accuracy, enabling a more objective decision on the initiation of antimicrobials and reducing their unnecessary use (33). In addition, molecular techniques, such as polymerase chain reaction and mass spectrometry, have been applied to detect pathogens and determine antimicrobial resistance profiles, and research has explored immunological substances that can be administered or enhanced to improve treatment efficacy or reduce the need for antimicrobials, or the use of real-time antimicrobial concentration monitoring to enable precise dose adjustments (27).

Fluid resuscitation

The rationale for fluid bolus administration is to restore cardiac output and blood pressure by increasing preload. However, in euvolemic or hypervolemic patients, it may cause harm, including reopening a previously closed arterial ductus, exacerbating left-to-right shunting through the ductus, leading to pulmonary edema, or triggering intraventricular hemorrhage. In neonates, particularly preterm infants, the optimal type of fluid, volume, and infusion rate remains uncertain. Recent studies have emphasized the lack of high-quality evidence to support fluid bolus use in neonates with hemodynamic compromise, suggesting a potential for harm (34).

Although balanced solutions are preferred in adult and pediatric populations with septic shock, evidence for the neonatal population is scarce (35). A multicenter observational study of 163 neonates with hemodynamic instability (due to septic shock and other causes) found that normal saline is the most commonly administered fluid, typically infused over a median of 30 minutes; clinicians reported minimal or no clinical improvement in 40% of cases (34).

Fluid boluses remain a common practice, either to reverse septic shock or as an “easy and quick” measure before initiating vasoactive drugs, and are included in major guidelines despite noted reservations. The American College of Critical Care Medicine recommends, for neonatal population, to initiate fluid boluses of 10 mL/kg, up to 40 mL/kg, with continuous monitoring for signs of hepatomegaly or increased respiratory effort. Crystalloids are advised for patients with hemoglobin levels above 12 g/dL, while packed red blood cells are recommended if hemoglobin levels are below 12 g/dL (4). Similarly, the Surviving Sepsis Campaign International Guidelines, which excluded neonates less than 37 weeks gestation, advocate administering up to 40–60 mL/kg of crystalloid (preferentially balanced) within the first hour, with discontinuation if signs of fluid overload appear (36).

Inotropes and vasopressors

Current guidelines recommend dopamine as the first-line drug in neonatal septic shock, particularly at lower doses to enhance renal output (4,37-39). While dopamine was historically the drug of choice for septic shock in adult and pediatric populations, it has been replaced by adrenaline and noradrenaline due to evidence demonstrating the superiority of these agents. In adults, dopamine has been associated with a higher incidence of tachyarrhythmias and challenges in titration, primarily due to reduced renal clearance in unstable patients (40,41). Additionally, studies in preterm neonates have associated dopamine use to impaired cerebral vascular autoregulation (42).

As alternatives, a cohort study suggested that noradrenaline may be associated with reduced mortality and morbidity compared to dopamine in septic preterm infants (13). A randomized trial demonstrated better outcomes with adrenaline compared to dopamine in neonates born before 30 weeks of gestation (43). Regarding adrenaline versus noradrenaline, another randomized trial involving 42 neonates with septic shock found no significant difference between the two agents (14).

Methylene blue has been studied as a potential adjunctive therapy for septic shock due to its ability to interfere with guanylate cyclase activity and restore vascular tone. However, its use raises concerns about pulmonary hypertension, methemoglobinemia, hemolysis, and neurotoxicity. A randomized trial involving thirty preterm infants with refractory septic shock compared methylene blue to vasopressin. Methylene blue demonstrated significant improvements in systemic vascular resistance and arterial blood pressure, along with a substantial reduction in norepinephrine requirements over a 24-hour period. These effects were accompanied by a slight increase in pulmonary pressure, though cardiac output remained unaffected (44).

In contrast to generalized approaches, individualized hemodynamic assessment has gained prominence in recent years for four key reasons. First, septic shock is increasingly recognized to produce diverse hemodynamic profiles (4,45). Second, specific cardiovascular agents, within defined dose ranges, exhibit distinct hemodynamic effects, including vasoconstriction, vasodilation, inotropism, chronotropism, or lusitropism (46). Third, neonates exhibit variable responses to drugs based on factors such as drug clearance and the maturity of cellular receptors (47-50). Lastly, studies in pediatric and neonatal populations have demonstrated a weak correlation between clinical evaluations—such as pulse, perfusion, and extremity temperature—and findings from advanced methods like functional echocardiography, central venous oxygen saturation, and near-infrared spectroscopy (4). These advancements have driven the increasing adoption of such tools by pediatricians in neonatal and pediatric intensive care units (4,37).

Corticosteroids

Corticosteroids, most commonly hydrocortisone, are used in refractory to fluid resuscitation and first cardiovascular agents shock. While corticosteroids may enhance vascular responsiveness to vasoconstrictors and address relative adrenal insufficiency, their use is associated with risks such as hyperglycemia, hypernatremia, gastrointestinal hemorrhage, and potential adverse effects on immunity and neonatal development.

Studies in neonates have not demonstrated a clear benefit from corticosteroid use. A retrospective study found no significant difference in survival rates but reported decreased survival at 1-year postmenstrual age among neonates treated with hydrocortisone (51). In pediatric septic shock, corticosteroids may not confer benefits and could increase mortality risk in certain high-risk groups (15,52).

Nutrition

Neonates in septic shock face increased energy demands, altered metabolism, and impaired nutrient absorption, which necessitate individualized nutritional strategies. While enteral nutrition is preferred whenever feasible, its use is often limited by hemodynamic instability or gastrointestinal dysfunction. For parenteral nutrition, recent guidelines recommend the administration of composite intravenous lipid emulsions, as low concentrations of omega-3 and omega-6 fatty acids have been associated with an increased risk of sepsis (53).

Although micronutrients and vitamins play a critical role in immune response and recovery, no studies were identified that specifically investigate the relationship between septic shock and deficiencies in zinc, selenium, or vitamins.

Other therapies

As sepsis and its progression to septic shock involve complex immunological processes, various interventions have been proposed targeting specific immune pathways, including blood purification methods, immunoglobulins, anti-IL1 agents, ascorbic acid, and adrenomedullin inhibitors (54). However, for neonatal septic shock, only blood purification therapies have been studied. These strategies aim to remove pathogenic agents and restore immune homeostasis and have been increasingly investigated in recent years, particularly due to technological advances. Techniques range from exchange transfusion to targeted molecule purification.

For blood exchange transfusion, a narrative review reported a lack of clinical efficacy in neonates with life-threatening complications, while a meta-analysis found low certainty of evidence for its use (55,56). Plasma exchange has been considered as an alternative; however, our review identified only one cohort study involving three patients, which suggested a potential benefit (57).

Hemofiltration membranes have been developed to remove endotoxins, cytokines, and other inflammatory mediators with reduced organism toxicity. For instance, the polymyxin B-immobilized fiber column was tested in neonatal piglets, showing a reduction in immune mediators, with potential benefits also reported in neonates (58-60). While other hemofiltration membrane therapies have been developed, further evaluation is necessary to establish their efficacy and safety in the neonatal population.

Discussion

This narrative review offers a comprehensive analysis of recent advancements in the diagnosis and management of neonatal septic shock, identifying critical areas for improving clinical practice, informing policy development, and guiding future research.

Clinical practice for health professionals

This review highlights the critical role of early recognition and timely intervention in neonatal septic shock, particularly given its subtle and often overlapping clinical presentation. It underscores the need for individualized treatment strategies tailored to the unique physiological characteristics of neonates, especially preterm infants. Such approaches include personalized fluid resuscitation, targeted vasopressor therapy, and careful use of corticosteroids, ensuring interventions align with the specific hemodynamic profiles and needs of each patient.

A multidisciplinary approach is critical in the management of neonatal septic shock, as the complexity of the condition necessitates expertise from healthcare professionals other than the neonatologists alone. This collaborative effort ensures timely decision-making and the effective integration of advanced diagnostics, individualized treatment protocols, and supportive care measures. By working together, healthcare professionals can address the nuanced needs of this vulnerable population, particularly in high-risk cases where standard interventions may be insufficient. Such collaboration also fosters the adoption of evidence-based innovations, ensuring that emerging therapies are carefully evaluated and appropriately implemented.

Additionally, the review emphasizes the growing value of advanced diagnostic tools such as near-infrared spectroscopy, point-of-care functional echocardiography, and emerging biomarkers. These tools facilitate early detection, real-time monitoring of hemodynamic changes, and more precise management decisions. Integrating these evidence-based technologies into clinical practice enables healthcare professionals to optimize treatment, improve patient outcomes, and reduce reliance on generalized protocols that may inadequately address the complexities of neonatal septic shock.

Policy development and implementation

This review highlights the critical need for standardized protocols and well-defined treatment pathways tailored to neonatal septic shock. While national and international guidelines, such as those from the Surviving Sepsis Campaign, provide valuable frameworks, they must be adapted to address the unique needs of neonates, particularly preterm infants. Current sepsis definitions and protocols primarily stem from adult and pediatric populations, which often fail to reflect the distinct pathophysiology and clinical presentation of neonatal septic shock. Policymakers should prioritize the inclusion of neonates in sepsis-specific definitions, protocols, and research initiatives. Developing guidelines that account for neonatal physiology—such as appropriate thresholds for hemodynamic support, antimicrobial therapy, and fluid management—is essential to ensure optimal outcomes.

In addition, policy initiatives should focus on supporting the integration of innovative diagnostic and monitoring technologies into routine neonatal intensive care unit workflows. Incentivizing the adoption of tools such as machine learning algorithms for predicting sepsis progression, functional echocardiography, and real-time biomarkers can enhance early detection and treatment precision. However, challenges remain in the widespread implementation of these technologies, particularly in resource-limited settings. Policies must address barriers such as cost-effectiveness, clinician training requirements, compatibility with existing systems, and equitable access across varying healthcare environments. Addressing these gaps is crucial to ensuring that advancements in neonatal care are translated into scalable, evidence-based policies that can be implemented across diverse clinical settings.

Moreover, to enhance neonatal septic shock outcomes, policies must support the integration of structured antimicrobial stewardship programs within neonatal intensive care units. This approach not only optimizes antimicrobial therapy but also reduces the overuse of broad-spectrum antibiotics, mitigating the risk of antimicrobial resistance and its long-term consequences for neonatal health. Clear policy mandates for routine antimicrobial de-escalation, combined with robust surveillance systems for resistance trends, will be crucial for implementing these stewardship strategies effectively (61,62).

Furthermore, policymakers should address disparities in access to advanced technologies and therapies for neonatal care, particularly in resource-limited settings. Incentives for the adoption of affordable, scalable innovations—such as portable functional echocardiography devices and simplified hemodynamic monitoring tools—can bridge gaps in care delivery. Collaborations between governments, research institutions, and industry could focus on developing cost-effective alternatives, ensuring that evidence-based practices are accessible across diverse healthcare environments. Policies should also emphasize equitable distribution of essential resources, such as composite lipid emulsions and vasopressors, to ensure standardized care regardless of geographical or economic constraints.

Future research

A protocol is being developed to establish a core outcome for managing neonatal septic shock (63). Along with this effort, a critical area for future research is the development of neonate-specific reference values for clinical parameters such as blood pressure, heart rate, and vasopressor dosages, which are currently extrapolated from pediatric and adult populations. Establishing accurate benchmarks tailored to neonatal physiology, particularly for preterm and full-term infants, is essential for optimizing management strategies. The review also emphasizes the need to explore the distinct pathophysiological mechanisms underlying septic shock in neonates compared to older children and adults, focusing on immune responses and hemodynamic differences.

Further research should validate emerging diagnostic tools, such as near-infrared spectroscopy and preseason, for their utility in routine clinical practice. Clinical trials are necessary to evaluate the efficacy and safety of individualized therapeutic approaches, including the use of corticosteroids, blood purification therapies, and novel agents like methylene blue. Additionally, longitudinal studies should investigate the long-term outcomes of neonatal septic shock survivors, assessing critical areas such as neurodevelopment, growth trajectories, and overall quality of life. Such research would provide vital insights into the potential impact of current treatments and guide the refinement of future therapeutic protocols.

Limited focus on neonatal-specific data

While the review underscores the unique physiology of neonates, particularly preterm infants, much of the clinical guidance remains heavily reliant on data extrapolated from adult and pediatric populations. This limitation raises concerns about the applicability of such evidence to the nuanced pathophysiology of neonatal septic shock. Additionally, many studies reviewed, especially those investigating diagnostic tools or therapeutic strategies like vasopressors and fluid resuscitation, are constrained by small sample sizes and significant heterogeneity in methodologies, definitions, and severity scoring systems. These inconsistencies hinder the synthesis of findings and complicate the formulation of robust, evidence-based recommendations.

Moreover, while the review highlights promising advances in therapeutic and diagnostic approaches, it provides limited exploration of the long-term outcomes for neonates who survive septic shock. Critical aspects such as neurodevelopmental trajectories, growth patterns, and quality of life remain underrepresented, underscoring the need for future research to address these gaps and provide a comprehensive understanding of the lifelong impact of neonatal septic shock.

Conclusions

Key advancements in managing neonatal septic shock include streamlined protocols and training, innovative diagnostic tools such as biomarkers and machine learning, individualized therapeutic strategies for fluids, vasopressors, corticosteroids, emerging immunomodulatory therapies, and extracorporeal techniques. Despite new advancements, prevention remains the easiest and most cost-effective intervention to reduce neonatal mortality due to sepsis.

Since neonates, particularly preterm infants, exhibit distinct physiology compared to adults and older children, including specific inflammatory and hemodynamic mechanisms, it is essential to conduct research specifically targeting this population—not only in septic shock—to avoid relying on even robust adaptations derived from non-neonatal evidence.

As the approach to shock management becomes increasingly individualized, it may be crucial to define specific reference points for clinical presentation—considering factors like euvolemia, cardiac function, and vasomotor response—as well as appropriate drug dosage ranges, gestational age, and renal function. It is important to note that many of the reference values commonly used today are based on studies in adult and pediatric populations. This underscores the urgent need for research focused on identifying accurate reference values for neonates, particularly premature infants, to ensure more precise and safer treatment strategies for this vulnerable population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-91/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-91/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-91/coif). W.A.G.F. participated in the Advisory Board of Chiesi Farmaceutic and received consultant fees and payment or honoraria from Chiesi Farmaceutici. The other 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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