Nonlinear dose–response relationship between norepinephrine and microcirculatory perfusion: identifying the tipping point in septic shock

Background and objectives

While norepinephrine (NE) is the cornerstone of septic shock resuscitation, “macrocirculation–microcirculation decoupling” at high doses remains a critical clinical challenge. This study aimed to explore the quantitative tipping point where the NE dose shifts from a life-saving vasopressor to a microcirculatory toxin in septic intensive care unit patients.

Methods

In this prospective observational study (January–September 2025), we used handheld vital microscopy to monitor sublingual microcirculation (microvascular flow index [MFI], total vessel density, perfused vessel density, proportion of perfused vessels [PPV], and heterogeneity index [HI]) in adult septic patients within 24 hours of admission and on Day 3. Beyond standard linear analysis, generalized additive models were employed to identify the dose–response thresholds associated with microcirculatory deterioration, adjusted for Acute Physiology and Chronic Health Evaluation II, interleukin-6, and systemic hemodynamics.

Results

Of 144 screened patients, 66 were analyzed. The NE dose showed strong linear correlations with lactate (r = 0.583, P < 0.001) and HI (r = 0.444, P < 0.001), and negative correlations with MFI (r = −0.492, P < 0.001). Crucially, generalized additive models analysis revealed a significant nonlinear “cliff effect”: when the NE dose exceeds the 0.71–0.80 µg/kg/min threshold (PPV: 0.71 µg/kg/min, HI: 0.72 µg/kg/min, MFI: 0.80 µg/kg/min), microcirculatory perfusion parameters deteriorate abruptly (all P < 0.05). Multivariable Cox regression identified an NE dose of 0.80 µg/kg/min as an independent predictor of increased mortality (hazard ratio = 1.32, 95% confidence interval: 1.28–3.10, P = 0.039).

Conclusions

This study showed that higher NE doses were associated with worse microcirculatory dysfunction and poorer prognosis. This indicates that when the NE infusion dose exceeds 0.71–0.80 µg/kg/min (PPV: 0.71 µg/kg/min, HI: 0.72 µg/kg/min, MFI: 0.80 µg/kg/min), microcirculatory dysfunction should be noted. This provides important evidence for the precise regulation of NE doses in sepsis management, emphasizing the significance of integrating microcirculation monitoring to avoid further deterioration caused by excessive NE use and thereby improve patient prognosis.

Full text

https://www.xiahepublishing.com/2590-3438/JTCCM-2026-00004

The study was recently published in the Journal of Translational Critical Care Medicine.

Journal of Translational Critical Care Medicine (JTCCM), an open access publication academically supported by The First Affiliated Hospital of Harbin Medical University, is a peer-reviewed online journal with continuous print on demand compilation of issues published. The journal allows free access (Open Access) to its contents and permits authors to self-archive final accepted version of the articles on any OAI-compliant institutional/subject-based repository.

The journal covers technical and clinical studies related to health, ethical and social issues in field of Critical Care Medicine, Translational Medicine, Respirology, Infection, Tumor, Surgery. Articles with clinical interest and implications will be given preference.

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