Early multimodal vasopressor therapy, individualized fluid resuscitation, and artificial intelligence–supported monitoring may improve septic shock management, according to a narrative review of emerging critical care strategies.
Lead researcher Marc Leone, MD, of Aix Marseille Université, and colleagues reviewed evolving hemodynamic approaches aimed at optimizing perfusion while limiting complications from high-dose vasopressors and excessive fluid administration.
The narrative review was published in Anaesthesia Critical Care & Pain Medicine.
Multiple Mechanisms Drive Vasodilatory Shock
The researchers described septic shock as a complex syndrome driven by multiple interacting pathophysiologic mechanisms that lead to systemic vasodilation and impaired vascular responsiveness.
Inflammatory mediators stimulate nitric oxide synthase and cyclooxygenase pathways, increasing nitric oxide and prostaglandin production, contributing to vasodilation. At the same time, autonomic dysfunction and prolonged exposure to catecholamines may lead to reduced adrenergic receptor responsiveness.
The renin–angiotensin–aldosterone system may also become dysregulated, impairing endogenous vasoconstrictive responses. In addition, relative vasopressin deficiency can develop during prolonged septic shock, further contributing to refractory hypotension.
Together, these mechanisms may limit the effectiveness of single-agent vasopressor therapy, the researchers noted.
Fluid Resuscitation Strategies Continue to Evolve
Initial fluid resuscitation remains a cornerstone of septic shock management. Current Surviving Sepsis Campaign guidelines recommend administering at least 30 mL/kg of intravenous crystalloid within the first hours of treatment.
Balanced crystalloids are generally preferred over saline because of their lower chloride content and reduced risk of metabolic complications.
However, recent trials have questioned whether aggressive fluid administration improves outcomes. The CLASSIC trial found that a restrictive fluid strategy resulted in similar mortality compared with standard care. Likewise, the CLOVERS trial reported no statistically significant difference in mortality between restrictive and liberal fluid strategies.
These findings underscore the importance of individualized fluid management guided by dynamic assessments of responsiveness, the researchers wrote.
Vasopressors Remain Central to Hemodynamic Support
Norepinephrine continues to be recommended as the first-line vasopressor for septic shock because of its vasoconstrictive effects and relatively favorable safety profile.
Vasopressin is commonly used as a second-line agent when adequate blood pressure cannot be maintained with norepinephrine alone. Clinical trials such as VASST and VANISH have evaluated vasopressin as an adjunct therapy, although results have shown mixed effects on mortality.
The researchers also discussed angiotensin II, which was evaluated in the ATHOS-3 trial as an additional vasopressor for patients with refractory vasodilatory shock.
Interest Growing in Early Multimodal Vasopressor Therapy
Because septic shock involves multiple disrupted regulatory pathways, the researchers noted growing interest in strategies that combine vasopressors targeting different mechanisms.
The review describes early multimodal vasopressor therapy—combining norepinephrine with agents such as vasopressin or angiotensin II—as a strategy to limit exposure to high-dose catecholamines, although evidence of a mortality benefit remains limited.
Evidence regarding the optimal timing of vasopressor initiation remains mixed. Some analyses suggest that earlier use of vasopressors may improve hemodynamic stability, but randomized and meta-analytic data have not consistently demonstrated a mortality benefit.
One confounder-controlled analysis cited in the review found that delaying vasopressin initiation after norepinephrine use was associated with increased mortality, highlighting the potential importance of timely escalation in selected patients. However, the researchers cautioned that observational findings may be affected by confounding and should not be interpreted as proof of causality.
Biomarkers and Artificial Intelligence May Help Personalize Treatment
The review also highlighted emerging interest in biomarker-guided therapy and artificial intelligence tools that could help clinicians identify optimal treatment strategies for individual patients.
For example, the researchers noted that renin levels may serve as a prognostic biomarker and may help identify patients most likely to benefit from therapies targeting the renin–angiotensin system.
Machine-learning models are also being explored to help clinicians predict hemodynamic deterioration and guide treatment decisions in real time.
Evidence Gaps Remain
Despite these advances, the researchers emphasized that many hemodynamic strategies used in septic shock are supported by weak to moderate evidence, underscoring the need for larger randomized trials to clarify optimal treatment approaches.
The authors suggest future research should focus on integrating physiologic monitoring, biomarker-guided therapy, and multimodal vasopressor strategies to better personalize septic shock management.
Disclosures can be found in the review.
