DOI: https://doi.org/10.61189/398977gdmjky

Received March 10, 2026; Accepted May 12, 2026; Published June 12, 2026

1 CLINICAL CHALLENGES OF SEVERE INFECTIONS

The increasing incidence of severe infections is one of the most formidable challenges for critical care medicine, and it is increasingly common worldwide. The epidemiology shows that millions are admitted annually for sepsis and related morbidities, with age-dependent surges in the incidence of sepsis, and a higher risk among elderly patients or those with comorbid conditions [1]. Severe infections have highly variable clinical follow-up needs. Continuous development of antibiotics and intensive care units, along with early diagnosis and combined targeted treatments, still plays a key role in reducing patient mortality.

Severe infection progresses rapidly and is hard to identify, so early recognition is critical to lowering mortality. Conventional inflammatory markers are slow to respond although they are relatively sensitive to stress. Blood cultures (BC) are sensitive, and BC identification detects 50–80% of mixed infections [2, 3]. However, data from large cohorts indicate that only half of cases are accurately diagnosed, since BC often fails to identify low-virulence organisms [2]. Thus, the simultaneous detection of multi-biomarkers has attracted wide research attention to get a balance between sensitivity and specificity for optimal diagnosis and risk stratification.

This diagnostic challenge is particularly evident in vulnerable populations, such as neonates and preterm infants, in whom severe infections may progress rapidly and lead to high mortality in the neonatal intensive care unit. From a clinical perspective, early diagnosis is crucial with the requirement of simultaneous identification of platelet count and platelet indices to optimize comorbid status [4]. Combined detection of multiple biomarkers is an important means to promote early identification of infection; however, clinical application issues remain unsolved, such as lack of standardization, and the approach is risk-dependent.

2 TYPES AND FUNCTIONS OF BIOMARKERS

2.1 Classification of common biomarkers

Biomarkers of severe infection may be classified based on their origin and functions. Systemic inflammatory response is characterized by so-called pro-inflammatory cytokines, such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin (IL)-6. IL-2 and IL-6 also contribute to improved diagnosis of bacterial infection in laboratory testing. Immune-related biomarkers, such as IL-10 and tumor necrosis factor-α (TNF-α), reflect host immune shifts in sepsis; elevated IL-10 indicates immunosuppression and poor prognosis, whereas increased TNF-α suggests hyperinflammation and worse outcomes [5, 6]. Infection-related organ injury is assessed with lactate and liver/kidney function tests. All of these biomarkers can be affected by confounding factors, so the diagnostic and prognostic effects are complementary, warranting their combined use in clinical practice.

2.2 Roles of various biomarkers in diagnosis

Various infection biomarkers serve distinct diagnostic roles. Pathogen-related markers (such as PCT) identify bacterial infections and assess severity; inflammatory or immune-related markers indicate inflammatory and immune status; organ function-related markers evaluate disease progression and prognosis. Combining markers may enhance sensitivity and support early diagnosis. However, biomarker results should be interpreted alongside clinical conditions and individual characteristics to avoid overreliance on a single marker and ensure accurate diagnosis and treatment.

2.3 Research progress on emerging biomarkers

Emerging multi-omics technologies have revealed new biomarkers for severe infections, including immune checkpoint molecules, extracellular vesicle miRNAs, metabolomics, and host transcriptomics. One candidate marker is histone H3 lysine 18 lactylation, which reflects disease severity and regulates macrophage anti-inflammatory function during sepsis through arginase-1 expression and inflammatory factors [7]. For example, extracellular vesicle-derived miRNA signatures have shown high diagnostic accuracy for septic shock, with a three-miRNA model (miR-100-5p, miR-148a-3p, and miR-451a) achieving an area under the curve of 0.894 in validation cohorts [8]. These functional biomarkers reveal immune dysregulation characterized by concurrent inflammation enhancement and immune evasion, paving the way for early risk stratification, prognostic assessment, and personalized therapy. However, there is a lack of standardization, accompanied by high cost and limited accessibility.

3 ADVANTAGES OF COMBINED DETECTION

3.1 Improved sensitivity and specificity

Systemic combined detection of severe infection markers improves diagnostic sensitivity and specificity. Individually, single biomarkers fail to detect early infections due to biological variation and comorbidities. However, multi-biomarker evaluation offsets these limitations through complementary effects. For example, combined detection of IL-6 and PCT showed a sensitivity of 93.84% and a specificity of 96.72% for severe bacterial infection [9]. Thus, combined detection supports early diagnosis and individualized clinical decision-making.

3.2 Promoting the practice of individualized medicine

Multiplex detection of severe infection biomarkers reflects the inflammatory and immune status to guide individualized medicine. IL-1β, IL-6, and TNF-α are significantly elevated in sepsis-induced cardiomyopathy, and their combined detection improves diagnostic and prognostic evaluation [10]. These inflammatory factors and related parameters could be incorporated to dynamically assess infection severity and progression, thereby guiding antimicrobial therapy, identifying high-risk patients, and tailoring interventions, serving as a quantitative prognostic reference.

3.3 Improving clinical decision-making and patient prognosis

Multiplex detection improves the early diagnosis of deep infections, aiding risk stratification and therapy. Tracking IL-6, PCT, and CRP identifies high-risk patients for timely treatment and monitoring adjustments. No single biomarker is diagnostic by itself and must align with clinical data. Simultaneous detection enhances diagnostic accuracy and enables individualized management of severe infections, as shown in Figure 1.

4 RISKS OF OVER-RELIANCE ON COMBINED DETECTION

4.1 Potential risks of misdiagnosis and missed diagnosis

These biomarkers indicate immune dysregulation involving both inflammatory amplification and suppression, supporting early stratification, prognostic assessment, and individualized therapy. However, lack of standardization, high cost, limited availability and insufficient validation restrict clinical use. Pro- and anti-inflammatory cytokines in hypothermic sepsis are generally low, and combined detection may fail to detect these cytokines, increasing false negatives [11]. Ignoring history, signs and imaging leads to misdiagnosis and mistreatment. Thus, combination assays must be applied within the clinical context and interpreted cautiously.

4.2 Increased healthcare costs and resource waste

Multiplex biomarker detection may improve the diagnostic sensitivity for severe infections, but at a high cost. Repeated testing increases expenses, prolongs hospitalization and treatment, and consumes resources. Without specific indications, no evidence shows combined detection improves outcomes; instead, it burdens laboratories and adds cost. Hence, evaluating the economic value and clinical necessity of multiplex biomarker testing is necessary for rational and sustainable clinical management.

4.3 Risk of deviating from clinical judgment

Simultaneous evaluation of PCT, CRP, and IL-6 may improve diagnostic and prognostic assessment in severe infection and support clinical decision-making before pathogen identification [12]. As shown in Figure 2, IL-6 increases earlier than PCT, a bacterial infection marker. PCT and lactate require serial monitoring with the Sequential Organ Failure Assessment score to predict shock risk. However, biomarker levels vary with age and comorbidities, and overreliance may obscure accurate assessment and cause overtreatment. Thus, biomarker detection should be integrated with symptoms, signs, and imaging to guide individualized management.

5 FUTURE DIRECTIONS AND PRACTICAL RECOMMENDATIONS

Advances in molecular diagnostics and high-throughput technologies enable precise multidimensional detection of severe infection biomarkers. Liquid biopsy, single-cell analysis, and multiplex immunoassays jointly assess multiple biomarkers, improving sensitivity and specificity. Artificial intelligence and machine learning (e.g., Light Gradient Boosting Machine, Extreme Gradient Boosting Machine, Random Forest) show strong predictive ability in sepsis-associated liver injury. Stacked ensembles enhance prediction robustness for early intervention and personalized therapy [13]. These research findings indicate that the future application of biomarkers should not be limited to the interpretation of a single biomarker, but rather should combine molecular indicators with clinical variables. Nonetheless, these emerging techniques are in need of multi-center validation and guideline development for clinical application in order to tackle issues concerning standardization, cost, and practicability.

Clinically, it is often difficult to distinguish infection-related complications solely based on traditional biomarkers. Therefore, comprehensive analysis is particularly important. Pneumonia, severe sepsis and septic shock are common complications in patients following an out-of-hospital cardiac arrest and are associated with high mortality. PCT and CRP provide limited diagnostic value for infectious complications, and hence lead to incorrect diagnoses derived from electronic medical records if used as the sole biomarkers [14]. Integrating clinical data with biomarker results leads to improved diagnoses and therapy. Biomarkers should be interpreted dynamically against the background of disease progression, comorbidities, infection risk, imaging, microbiology and vital signs to enable comprehensive decision-making. Unifying interpretations may help standardize use, reduce unnecessary interventions and facilitate early identification and targeted treatment of severe infections.

In addition to diagnosis and risk prediction, biomarker-guided strategies also have practical value in treatment monitoring and antimicrobial stewardship. Evidence-based protocols for combined biomarker assessment in severe infections should define each biomarker’s role in diagnosis, monitoring, and treatment evaluation. A PCT-based algorithm guiding antibiotic use in acute pancreatitis reduced unnecessary antimicrobial exposure without compromising safety [15]. Age, comorbidities, and immune status must be considered when setting thresholds and strategies. Overall, future efforts should not only expand biomarker detection but also establish a clinically validated, cost-effective, and dynamically interpretable detection strategy. Through multi-center research, standardized biomarker combinations, thresholds for different disease stages, and clinical decision-making algorithms should be developed. In particular, the detection results of biomarkers should be combined with patients’ clinical signs, imaging, microbiology, and electronic health data. Eventually, the combined detection of biomarkers can not only be used for the early diagnosis of infectious diseases, but also for risk stratification, treatment monitoring, and antibiotic management of severe infections.

DOI: https://doi.org/10.61189/037416axzkek

Received April 16, 2026; Accepted June 1, 2026; Published June 12, 2026

DOI: https://doi.org/10.61189/114823yjtjfu

Received December 21, 2025; Accepted April 20, 2026; Published June 15, 2026

1 INTRODUCTION

Perioperative blood pressure (BP) control is a cornerstone of anesthesiology, as it significantly affects organ recovery and the development of postoperative complications. In pediatric patients undergoing cardiopulmonary bypass, brain injury is associated with impaired cerebral autoregulation. Accurate adjustment of mean arterial pressure (MAP) can preserve cerebral perfusion and thus minimize neurological injury [1]. Hypotension often leads to insufficient perfusion of the brain, heart, and kidneys, resulting in complications such as acute kidney injury (AKI) and cerebral ischemia. 

Recent advancements have shifted perioperative BP management from empirical to goal-directed approaches. For instance, transcranial Doppler monitors cerebral blood flow following vascular occlusion to prevent hyperperfusion. Tools such as esophageal Doppler and the pressure recording analytical method (PRAM) enable more precise titration of circulatory dynamics. Low-dose continuous norepinephrine (NE) infusion combined with goal-directed fluid therapy has been shown to reduce complications in elective pulmonary surgery [2]. The prophylactic use of vasoactive agents and the renal-protective effects of dexmedetomidine (DEX) provide additional strategies for effective perioperative BP control. Defining personalized safety thresholds and integrating multimodal monitoring remain critical challenges. Notably, lower MAP is strongly associated with postoperative AKI, while post-induction hypotension independently increases the odds of adverse events in transcatheter aortic valve replacement [3].

2 MECHANISMS AND IMPACT OF PERIOPERATIVE BP MANAGEMENT

2.1 Effects of BP fluctuations on organ perfusion

Hemodynamic changes during the perioperative period can exert a significant impact on organ perfusion and function. In patients with aneurysmal subarachnoid hemorrhage, the oxygen reactivity index shows superior sensitivity in detecting perfusion derangements associated with delayed cerebral ischemia [4]. While compensatory microcirculatory mechanisms may preserve certain mucosal functions during hypotension, accurate BP control remains vital for critical organs. Personalized BP control based on dynamic hemodynamic variations may attenuate the risk of perfusion mismatch that leads to organ injury. Current clinical consensus suggests that maintaining MAP within 10% of the patient' s baseline or keeping the cerebral oxygenation index below 0.3 serves as a critical threshold for organ protection.

2.2 Correlation between hypotension and postoperative cerebral complications

Perioperative hypotension contributes to cerebral complications through reduced perfusion pressure and disruption of the blood–brain barrier. Orthostatic hypotension is associated with cognitive impairment and microstructural brain damage. However, personalized protocols that maintain cerebral oxygenation within optimal ranges show promise for reducing neurological complications. In addition, acute water intake has been shown to improve orthostatic tolerance in patients with orthostatic hypotension and reduce performance decline associated with insufficient cerebral perfusion, offering a simple perioperative neuroprotective strategy [5]. A critical threshold is typically defined as an absolute MAP below 65 mmHg or a decrease of more than 20% from the pre-induction baseline, both of which significantly elevate the risk of cognitive impairment.

2.3 BP-related mechanisms of cardiac and renal dysfunction

Perioperative BP variability profoundly impacts hemodynamic stability and organ perfusion, thereby influencing both cardiac and renal function. Intraoperative hypotension—especially a decrease in MAP—can lead to insufficient myocardial perfusion and ischemic damage; therefore, stable BP is essential for cardiac protection. Higher blood pressure variability (BPV) during cardiopulmonary bypass—particularly when MAP fluctuations exceed 30% of the area under the curve—is significantly associated with cardiac surgery-associated AKI in pediatric patients [6]. For adults, a cumulative duration of MAP below 60 mmHg for more than 20 minutes is identified as a critical threshold for stage 1 AKI.

Perioperative hemodynamic instability—characterized by chronic or repeated episodes of hypotension, hypertension, or increased BPV—leads to microcirculatory deterioration and disruption of autoregulatory responses, ultimately resulting in target organ injury (Figure 1). Notably, patients with chronic hypertension are more prone to these variations due to preexisting arteriolosclerosis and impaired renal autoregulation. This cardiorenal interaction illustrates the complex relationship between hemodynamic instability and organ perfusion in a vulnerable state. Such pathophysiological processes highlight the importance of personalized and dynamic BP management to reduce intraoperative shock and improve early postoperative outcomes.

3 INNOVATIVE MANAGEMENT STRATEGIES AND CLINICAL PRACTICE

Individualized BP management guided by real-time monitoring is essential for preventing complications. Esophageal Doppler-guided therapy decreases pulmonary complications and hospital length of stay, while the PRAM facilitates postoperative triage and reduces healthcare costs. Continuous arterial pressure monitoring and AI-based algorithms enable clinicians to dynamically assess circulatory status. Closed-loop control systems further improve hemodynamic stability. Ac-curate pharmacological regulation effectively protects organ function. Prophylactic NE infusion is superior to bolus epinephrine for reducing post-induction hypotension and complications in major abdominal surgery. Continuous DEX infusion for 24 hours significantly lowers the rate of AKI rates by 29% without hemodynamic risks. Titratable, short-acting α-adrenergic agonists permit stable perfusion and minimize organ injury. Furthermore, closed-loop administration of NE significantly decreases the incidence of postoperative hypotension in ICU patients following cardiac surgery [7].

The integration of continuous BP monitoring with advanced AI algorithms facilitates real-time recognition of hemodynamic changes. Notably, the ClearSight system provides safe, non-invasive arterial pressure measurement via a finger cuff, offering a viable alternative for neurovascular surgery. In the future, these intelligent technologies could be incorporated into a "prediction–prevention–intervention" model to provide more precise control and further reduce perioperative complications [8]. A variety of commonly used perioperative antihypertensive drugs with differentiated administration regimens and corresponding clinical trial outcomes are summarized in Supplementary Table 1.

4 DISCUSSION

4.1 Multidisciplinary collaboration in perioperative BP management

Optimization of perioperative BP is an important factor in preventing postoperative organ dysfunction, and collaboration among various disciplines (anesthesiology, surgery, critical care, and nursing) is crucial for its successful implementation. Real-time monitoring-guided, patient-specific BP management strategies may facilitate optimal intraoperative and postoperative decision-making. For instance, intraoperative transcranial Doppler monitoring allows early detection of cerebral hyperperfusion syndrome after carotid endarterectomy, whereas esophageal Doppler and PRAM improve the reliability of hemodynamic data and contribute to continuity of care [9]. With multidisciplinary support, encephaloduroarteriosynangiosis can be optimally performed with further improvements in surgical techniques, strict hemodynamic control during anesthesia, and versatile methods of medical management [10]. In the future, establishing standardized collaborative workflows, improving information exchange, and enhancing team training will be crucial for transitioning BP intervention from isolated treatment to coordinated, whole-process management.

4.2 Key challenges and emerging research priorities

Despite exciting advances in personalized BP management for preventing postoperative organ injury, major hurdles remain in implementing this approach at the bedside. The use of real-time monitoring systems is restricted by their availability and the lack of standardized operating procedures, which hinders their application in primary hospitals. BPV can influence cerebral perfusion and is associated with the development of ICU delirium; however, its mechanistic involvement in organ injury, diagnostic parameters, and therapeutic targets have yet to be elucidated [11]. Combined pharmacological and technological approaches, such as closed-loop NE infusion systems, appear promising for improving BP control; however, there is a lack of evidence regarding their long-term beneficial impact and cost-effectiveness. Furthermore, the ClearSight system enables non-invasive arterial pressure measurement via a finger cuff and may be a safe alternative for use in neurovascular surgery [8]. Future research should focus on intelligent, non-invasive monitoring technologies, multicenter randomized controlled trials, and integrated models that combine biomarkers with hemodynamic parameters to enable precise risk stratification and targeted interventions.

4.3 The role of BP management in overall postoperative recovery

Precise perioperative BP management can markedly lower the incidence of complications in vital organs such as the brain, heart, and kidneys and improve microcirculation and postoperative lung function. These factors contribute to reduced hospital length of stay and improved long-term outcomes. In cardiac surgery, intraoperative DEX can preserve renal function and reduce the use of vasopressors [12]. Goal-directed hemodynamic therapy makes pulmonary recovery more efficient and improves overall rehabilitation. Additionally, combined aerobic and resistance training has been shown to be more effective than aerobic training alone in reducing BP and its variability [13]. Integrating BP management into a comprehensive "surgery–monitoring–rehabilitation" pathway, together with early mobilization and nutritional support, enables the establishment of a patient-centered, multidimensional rehabilitation system that substantially improves the overall quality of perioperative care.

5 CONCLUSION AND CLINICAL IMPLICATIONS

Accurate perioperative BP control is essential for avoiding postoperative multiorgan failure. Although current evidence highlights the critical importance of personalized management, several clinical gaps remain. One major limitation is the lack of universal, high-level evidence that specifically defines "critical thresholds" across diverse surgical populations. Most current studies rely on retrospective data, which may not fully account for individual patient baseline variability [14].

Future research should prioritize multicenter randomized controlled trials to validate the long-term cost-effectiveness and clinical outcomes of intelligent closed-loop infusion systems. Furthermore, integrating non-invasive monitoring technologies with machine-learning algorithms will be crucial for transitioning from reactive treatment to proactive, predictive interventions.

Finally, the successful implementation of these strategies requires robust multidisciplinary collaboration and standardized educational protocols. The ultimate goal is to establish a patient-centered, multidimensional "prediction–prevention–rehabilitation" pathway that ensures safer perioperative recovery, even in resource-limited settings.

DOI: https://doi.org/10.61189/775612vwvmhm

Received October 3, 2025; Accepted February 28, 2026; Published March 31, 2026

DOI: https://doi.org/10.61189/898430njufld

Received October 27, 2025; Accepted December 4, 2025; Published March 31, 2026

DOI: https://doi.org/10.61189/056184yqnaiu

Received December 10, 2025; Accepted February 28, 2026; Published March 31, 2026

DOI: https://doi.org/10.61189/891717grkkpo

Received December 21, 2025; Accepted March 13, 2026; Published March 31, 2026 

DOI: https://doi.org/10.61189/319254ilybgm

Received December 21, 2025; Accepted March 12, 2026; Published March 31, 2026 

DOI: https://doi.org/10.61189/873111rbsjxe

Received September 5, 2025; Accepted March 3, 2026; Published March 31, 2026 

Highlights 

● This review presents a comprehensive overview of the pharmacological effects of traditional Chinese medicine (TCM) in sepsisinduced myocardial injury. 

● It systematically summarizes the molecular mechanisms and recent research advancements regarding protective effects of TCM in sepsis. 

● It proposes a novel "temporal treatment" strategy for Perioperative Sepsis, aligning TCM interventions with the dynamic pathophysiological stages of the disease.

DOI: https://doi.org/10.61189/402108pvrojs

Received November 18, 2025; Accepted March 3, 2026; Published March 31, 2026

Highlights 

● Elevated red cell distribution width (RDW) (>14.65%) at intensive care unit admission independently predicts 30-day mortality in young patients with sepsis-associated encephalopathy (SAE) (hazard ratio=2.7, 95% confidence interval [CI]: 1.4-5.3; P=0.003), persisting after rigorous propensity score matching (352 pairs) and multivariable adjustment. 

● RDW achieved an area under the curve of 0.760 (95% CI: 0.720-0.800), outperforming prior reports in elderly sepsis cohorts and underscoring its specificity for young SAE.

● RDW is a low-cost, routinely available biomarker. Its integration into risk stratification could enable early intervention in resourcelimited settings, challenging the paradigm of youth conferring low risk in SAE.

DOI: https://doi.org/10.61189/189238vryaia

Received December 10, 2025; Accepted February 28, 2026; Published March 31, 2026 

DOI: https://doi.org/10.61189/909222ormctb

Received September 2, 2025; Accepted September 10, 2025; Published March 31, 2026 

DOI: https://doi.org/10.61189/372252akozze

Received November 11, 2025; Accepted March 16, 2026; Published March 31, 2026