The Effect of Different Doses of Norepinephrine on Microcirculation in ICU Septic Patients: A Prospective Observational Study

doi:10.21203/rs.3.rs-8376468/v1

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The Effect of Different Doses of Norepinephrine on Microcirculation in ICU Septic Patients: A Prospective Observational Study

https://doi.org/10.21203/rs.3.rs-8376468/v1

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Background

Norepinephrine (NE) is the first-line vasopressor for septic shock, but high doses may exacerbate microcirculatory impairment and organ dysfunction. This study aimed to investigate the relationship between NE dose and microcirculation, as well as its impact on prognosis, in ICU septic patients.

Methods

A prospective observational study was conducted on adult septic patients admitted to the ICU of Zhongnan Hospital of Wuhan University between January and September 2025. Sublingual microcirculatory parameters (microvascular flow index (MFI), total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), heterogeneity index (HI)) were monitored using a handheld imaging system within 24 hours of admission and on Day 3. Clinical data were simultaneously collected. Multiple regression models were used to analyze associations between NE dose, microcirculation and clinical outcomes (28-day/90-day mortality), with preliminary exploration of their dose-response relationships.

Result

Of 144 screened adult septic patients, 66 were enrolled. NE dose was significantly correlated with multiple microcirculatory parameters: positive correlations were observed with Lac, mottling score, and HI (Lac: r = 0.583, p < 0.001; mottling score: r = 0.364, p = 0.003; HI: r = 0.444, p < 0.001); negative correlations with MFI and PPV (MFI: r = -0.492, p < 0.001; PPV: r = -0.420, p < 0.001). After adjusting for covariates including APACHE II scores, heart rate, and IL-6 levels, the generalized additive model (GAM) analysis revealed significant nonlinear relationships between NE dose and microcirculatory parameters (all p < 0.05). When NE dose exceeds the threshold range of 0.71–0.80 \(\:\mu\:\)g/kg/min, microcirculation in septic patients deteriorates significantly. Multivariable Cox regression showed high NE dose (cut-off value = 0.80 \(\:\mu\:\)g/kg/min) was associated with increased mortality (HR = 1.14, 95% CI: 0.48 to 2.68, p = 0.035).

Conclusions

This study demonstrates that excessive NE use is independently associated with worsening microcirculatory perfusion and increased mortality in ICU septic patients. When NE dose pumping over 0.71–0.80 \(\:\mu\:\)g/kg/min, microcirculatory dysfunction should be noted. This provides important evidence for the precise regulation of NE dose in sepsis management, emphasizing the significance of integrating microcirculation monitoring to avoid further deterioration and improve patient prognosis.

Sepsis

Norepinephrine

Microcirculation

Mortality

Intensive Care Units

Sepsis is a growing global burden, with accumulating evidence indicating increased long-term morbidity and mortality in both developed and developing countries[1, 2]. Sepsis is characterized by dysregulated host response to infection, leading to life-threatening organ dysfunction. This dysregulated host response induced by systemic inflammation induces vasodilation, leading to a relative insufficiency of effective circulating blood volume. This results in microcirculatory disruption and inadequate organ perfusion[3, 4]. Thus, microcirculatory dysfunction may play a pivotal role in the development of multiple organ failure in critically ill patients[5]. Therefore, the primary goal of hemodynamic resuscitation in such patients is to restore microcirculatory perfusion and tissue oxygenation, preventing organ hypoxia and maintaining organ function.

NE, an endogenous catecholamine produced by postganglionic sympathetic nerves and the adrenal gland, is considered the first-line vasopressor for septic shock[6–8]. NE effectively increases vascular tone and contractility to enhance tissue perfusion[9], and protects cardiac function in the early stage by improving myocardial contractility and diastolic arterial pressure to restore coronary perfusion[10]. Studies have shown that NE administration helps ameliorate microcirculatory dysfunction[11, 12]. However, this effect is dose-dependent [11]. With increasing doses, NE may exacerbate microcirculatory impairment, reduce tissue perfusion, and induce organ dysfunction [13, 14]. High-dose NE may even exert multiple adverse prognostic effects on macro- and microcirculation through immune, metabolic, and coagulation pathways[15, 16]. This suggests that only an appropriate NE dose is associated with improved tissue perfusion and organ function.

Although macrocirculation serves as the cornerstone of microcirculatory resuscitation, focusing solely on macrocirculatory resuscitation targets while ignoring microcirculatory responses may lead to therapeutic deviations[17]. Effective resuscitation relies on the coherence between macrocirculation and microcirculation[18–20], i.e., restoring "macrocirculation-microcirculation coupling (MMC)". The proportion of perfused vessel (PPV) of microcirculatory perfusion can serve as an early independent predictor of outcomes in patients with sepsis[21]. Monitoring microcirculation to verify MMC provides crucial evidence for guiding NE use during hemodynamic resuscitation[22]. Based on the principle of sidestream dark filed (SDF) imaging[23], handheld non-invasive sublingual microscopes can be used to analyze microcirculatory changes in septic patients by assessing red blood cell velocity and perfused capillary density[24–28].

Based on this, this study aimed to investigate the relationship between different NE doses and microcirculation, as well as their impact on prognosis in ICU septic patients. Furthermore, we explored the dose-response relationship between NE and microcirculation, providing a rational reference for the treatment of septic patients and future research.

2.1 Study Design

This was a prospective observational study conducted in a 58-bed closed ICU of a tertiary hospital with 3300 beds. The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2025096K). Patients diagnosed with sepsis in the ICU between January 1, 2025, and September 1, 2025, were enrolled. All procedures adhered to the Declaration of Helsinki. All enrolled patients provided written informed consent to participate in the study.

2.2 Study Population

2.2.1 Sample Size Calculation

Based on preliminary experiments, the correlation between NE dose and Heterogeneity Index (HI) was selected as the primary analytical variable. Sample size was estimated using G*Power 3.1 software for F-test. With an effect size f² = 0.15, α = 0.05, and power (1-β) = 0.80, the minimum sample size was calculated as 55. Considering a 20% attrition rate, a total of 66 patients were planned for enrollment.

2.2.2 Inclusion Criteria

Patients meeting the Sepsis 2.0 diagnostic criteria;

Received initial resuscitation within 24 hours of ICU admission;

Aged ≥ 18 years;

Underwent tracheal intubation and mechanical ventilation.

2.2.3 Exclusion Criteria

Pregnant patients or those with peripheral vascular disease;

Patients unable to undergo microcirculation assessment or obtain high-quality SDF images;

Patients who died within 24 hours of admission;

Aged < 18 years or > 80 years.

2.3 Study Methods and Data Collection

2.3.1 Microcirculation Monitoring

After professional training on microcirculation assessment, researchers used an SDF imaging device ("Microsee V100 Sublingual Microcirculation Imaging System") to visualize sublingual microcirculation. Following gentle wiping of oral secretions with gauze, the sublingual microcirculation probe was placed lightly under the tongue. Stable, clear microvascular images were acquired from 3–5 sites adjacent to the lingual frenulum for at least 20 seconds by adjusting light intensity and focal length. Image quality was evaluated according to the method described by Massey et al.[29], and poor-quality images were excluded. Qualified images were analyzed using computer-aided software (AVA 3.0; MicroVision Medical; Amsterdam, the Netherlands) to assess microcirculatory parameters[24], including microvascular flow index (MFI), total vessel density (TVD), perfused vessel density (PVD), the proportion of perfused vessel (PPV), and heterogeneity index (HI). All parameters were analyzed for small vessels[30] (diameter < 20 \(\:\mu\:\)m), as they are the primary sites of oxygen exchange.

2.3.2 Data Collection

All microcirculation assessments were performed after 2 hours of hemodynamic stability and by at least two researchers simultaneously within 24 hours of ICU admission and on the third day. During microcirculation assessment, the following data were collected: demographic variables, hemodynamic parameters, laboratory values, vasopressor dose, sedative and analgesic medications, Capillary Refill Time (CRT), and scoring systems including Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE) II score, as well as mottling score. At ICU discharge, renal replacement therapy, length of ICU stay, and in-hospital mortality were also recorded.

2.4 Statistical Analysis

The Shapiro-Wilk test was used to assess the normality of variables. Normally distributed variables were expressed as mean ± standard deviation (SD), non-normally distributed variables as median (interquartile range, IQR), and categorical variables as counts (percentages, %). Intergroup comparisons were performed using independent samples t-test, Wilcoxon rank-sum test, chi-square test, or Fisher's exact test based on data distribution characteristics. Pearson and Spearman correlation analyses were used to evaluate associations between variables, with Benjamini-Hochberg method for False Discovery Rate (FDR) correction. Univariate and multiple linear regression analyses were used to assess the independent association between NE dose and microcirculatory parameters. Nonlinear relationships were tested by adding a quadratic term of NE dose, and the significance of the quadratic term was evaluated using ANOVA for model comparison. Kaplan-Meier curves were plotted to illustrate survival, with Log-rank test for intergroup differences. Cox proportional hazards regression model was used to assess the relationship between NE dose and mortality risk. Statistical analyses and figure preparation were performed using SPSS software (version 22.0), GraphPad Prism software (version 8.0), and R software (version 4.3.2). A two-tailed p < 0.05 was considered statistically significant.

3.1 Cohort Characteristics

A total of 144 adult ICU septic patients were consecutively enrolled after ICU admission. 78 patients were excluded (Fig. 1) from further analysis. Therefore, 66 adult septic patients receiving NE treatment in the ICU were finally enrolled. Microcirculatory parameters, NE dose, and relevant laboratory values were collected on Day 1 and Day 3 of ICU admission. Baseline characteristics were compared between two groups stratified by the median NE dose on Day 1 (0.46 \(\:\mu\:\)g/kg/min) (Table 1). Compared to the low NE dose group(\(\:\le\:\) 0.46 \(\:\mu\:\)g/kg/min, n = 34), patients in the high dose group (> 0.46 \(\:\mu\:\)g/kg/min, n = 32) had higher APACHE II scores (29.12 ± 6.68 vs. 24.76 ± 5.50, p = 0.005), serum lactate (Lac) levels (3.20 (1.90 to 7.50) vs. 1.30 (1.10 to 1.80) mmol/L, p < 0.001), and heart rate (112.88 ± 15.73 vs. 85.85 ± 17.21 bpm, p < 0.001) compared to the low dose group. Notably, microcirculatory parameters were more deteriorated in the high dose group: significant differences were observed in mottling score (0 (0 to 1) vs. 0 (0 to 0), p = 0.005), HI (0.25 (0.12 to 0.49) vs. 0.18 (0.11 to 0.34), p = 0.033), MFI (2.83 (2.77 to 2.96) vs. 2.92 (2.88 to 2.98), p = 0.031), PPV (100.00 (97.30 to 100.00) vs. 100.00 (100.00 to 100.00), p = 0.025), and PVD (14.91 ± 3.79 vs. 17.34 ± 4.80 mm/mm², p = 0.026). Finally, there was a significant difference in 28-day mortality between the high and low dose groups (60.6% vs. 30.3%, p = 0.026).

Table 1

Baseline characteristics stratified by median NE dose
Characteristic	Overall n = 66	Low NE dose (≤ 0.46\(\:\:\mu\:\)g/kg/min) n = 34	High NE dose (> 0.46\(\:\:\mu\:\)g/kg/min) n = 32	p-value²
Age (years)	61.65(13.70)	62.82(12.42)	60.48(14.97)	0.49
Body max index (kg/m²)	23.43 (3.27)	23.99 (3.02)	22.87 (3.47)	0.17
SOFA (points)	9.36 (3.11)	9.06 (3.20)	9.67 (3.04)	0.43
APACHE II (points)	26.94 (6.46)	24.76 (5.50)	29.12 (6.68)	0.005
ICU stay(days)	10.00 (5.00,19.00)	10.00 (8.00, 19.00)	9.00 (4.00, 14.00)	0.12
28-day mortality, n (%)	30.0 (45.5)	10.0 (30.3)	20.0 (60.6)	0.026
90-day mortality, n (%)	34.0 (51.5)	13.0 (39.4)	21.0 (63.6)	0.085
CRRT, n (%)	49.0 (74.2)	22.0 (66.7)	27.0 (81.8)	0.26
ECMO, n (%)	14.0 (21.2)	9.0 (27.3)	5.0 (15.2)	0.37
Vasopressors use³, n (%)	13.0 (19.7)	3.0 (9.1)	10.0 (30.3)	0.063
CRT(s)	3.00 (2.00, 7.50)	2.00 (2.00, 4.00)	3.00 (2.00, 7.50)	0.28
Peripheral perfusion index	0.64 (0.18, 2.20)	1.20 (0.33, 2.50)	0.35 (0.11, 2.10)	0.080
Mottling score(points)	0 (0, 0)	0 (0, 0)	0.00 (0, 1)	0.005
Lactate(mmol/L)	1.90 (1.30, 4.10)	1.30 (1.10, 1.80)	3.20 (1.90, 7.50)	< 0.001
Microvascular flow index(points)	2.92 (2.81, 2.98)	2.92 (2.88, 2.98)	2.83 (2.77, 2.96)	0.031
Proportion of perfused vessel (%)	100.00(99.80,100.00)	100.00(100.00,100.00)	100.00 (97.30,100.00)	0.025
Heterogeneity index	0.23 (0.11, 0.36)	0.18 (0.11, 0.34)	0.25 (0.12, 0.49)	0.033
Total vessel density(mm/mm²)	16.01 (13.42, 18.44)	16.61 (14.44, 19.66)	15.02 (13.10, 16.57)	0.047
Perfused vessel density(mm/mm²)	16.12 (4.46)	17.34 (4.80)	14.91 (3.79)	0.026
Heart rate(bpm)	99.36 (21.29)	85.85 (17.21)	112.88 (15.73)	< 0.001
Mean arterial pressure(mmHg)	81.50 (13.10)	82.45 (10.74)	80.55 (15.21)	0.56
CVP (cmH2O)	13.13 (3.99)	12.96 (4.33)	13.29 (3.68)	0.73
Procalcitonin (ng/ml)	30.28 (3.14, 140.14)	20.47 (1.43, 68.48)	34.39 (15.36, 140.14)	0.17
IL-6(pg/ml)	533.00 (64.30,3,081.00)	234.00 (37.20, 654.00)	1,096.00(381.00,7,500.00)	0.001
Serum creatinine(mmol/L)	169.85 (113.20, 245.00)	138.70 (77.00, 207.10)	215.00 (142.00, 282.40)	0.015
Urea nitrogen(mmol/L)	14.40 (11.06, 21.48)	14.20 (10.20, 19.80)	14.84 (11.80, 23.30)	0.42
¹Variables are displayed in mean (standard deviation), median (Q1, Q3) or n (%).
²Pearson's Chi-squared test; Welch Two Sample t-test; Wilcoxon rank sum test; Wilcoxon rank sum exact test ³Whether patients under vasopressor support excluding NE on the first day of ICU admission. ⁴SOFA = sequential organ failure assessment; APACHE II = acute physiology and chronic health evaluation II; CRRT = continuous renal replacement therapy; ECMO = extracorporeal membrane oxygenation; CRT = capillary refill time; CVP = Central venous pressure; NE = norepinephrine.

3.2 Correlation between NE Dose and Microcirculatory Parameters

In the total cohort (n = 66), NE dose was significantly correlated with multiple microcirculatory parameters: negative correlations with MFI and PPV (MFI: r = -0.492, p < 0.001; PPV: r = -0.420, p < 0.001) ; positive correlations were observed with HI, mottling score and Lac (HI: r = 0.444, p < 0.001; mottling score: r = 0.364, p = 0.003; Lac: r = 0.583, p < 0.001); (Fig. 2, Supplement Table 1). These associations remained statistically significant after FDR correction (p < 0.05). No significant correlations were found between NE dose and CRT, PI, TVD, or PVD (p > 0.05).

3.3 Multivariate Regression Analysis of NE Dose and Microcirculatory Parameters

Univariate linear regression analysis showed that NE dose was significantly positively correlated with mottling score, HI and Lac (mottling score: p = 0.003, 95% CI: 0.161 to 0.730; HI: p < 0.001, 95% CI: 0.078 to 0.237; Lac: p < 0.001, 95% CI: 2.294 to 4.742), and significantly negatively correlated with MFI and PPV (MFI: p < 0.001, 95% CI: -0.149 to -0.058; PPV: p < 0.001, 95% CI: -3.289 to -0.983). After adjusting for APACHE II scores, heart rate, and IL-6 levels, most of these associations remained statistically significant (p \(\:<\) 0.05), except for mottling score which was no longer significant after adjustment (p = 0.115). (Table 2). The GAM analysis was employed to analyze the nonlinear relationship between NE dose and microcirculatory parameters, while also identifying inflection points in the dose-response curve. After adjusting for covariates including APACHE II scores, heart rate, and IL-6 levels, the GAM analysis revealed significant nonlinear relationships between NE dose and microcirculatory parameters (all p < 0.05). Significant inflection points of the NE dose (Fig. 3) were identified within these nonlinear relationships (MFI: 0.80 \(\:\mu\:\)g/kg/min, p < 0.001, R² = 0.532; PPV: 0.71 \(\:\mu\:\)g/kg/min, p = 0.031, R² = 0.301; HI: 0.72 \(\:\mu\:\)g/kg/min, p = 0.014, R² = 0.460; mottling score: 0.25 \(\:\mu\:\)g/kg/min, p = 0.029, R² = 0.123; Lac: 1.65 \(\:\mu\:\)g/kg/min, p < 0.001, R² = 0.455).

Table 2

Univariate and Multivariate Analysis Between NE and Microcirculatory Parameters
	Univariate Analysis		Multivariate Analysis (model-1^a)
parameters	Regression coefficient(95% CI)	p value	Regression coefficient(95% CI)	p value
Mottling Score	0.445(0.161, 0.730)	0.003	0.342(-0.086, 0.770)	0.115
MFI	-0.103(-0.149, -0.058)	< 0.001	-0.099(-0.163, -0.034)	0.003
PPV	-2.136(-3.289, -0.983)	< 0.001	-1.698(-3.391, -0.004)	0.049
HI	0.157(0.078, 0.237)	< 0.001	0.146(0.031, 0.260)	0.013
Lac	3.518(2.294, 4.742)	< 0.001	2.502(0.700, 4.305)	0.007
^amodel-1: APACHE II scores, heart rate and IL-6 levels were adjusted
NE = norepinephrine, MFI = microvascular flow index, TVD = total vessel density, PVD = perfused vessel density, PPV = proportion of perfused vessel, HI = heterogeneity index

Table 2

Univariate and Multivariate linear Regression Analysis Between NE and Microcirculatory Parameters
	Univariate Analysis		Multivariate Analysis (Model-1^a)
parameters	Regression coefficient(95% CI)	P-value	Regression coefficient(95% CI)	P-value
Mottling Score	0.445(0.161, 0.730)	0.003	0.342(-0.086, 0.770)	0.115
MFI	-0.103(-0.149, -0.058)	< 0.001	-0.099(-0.163, -0.034)	0.003
PPV	-2.136(-3.289, -0.983)	< 0.001	-1.698(-3.391, -0.004)	0.049
HI	0.157(0.078, 0.237)	< 0.001	0.146(0.031, 0.260)	0.013
Lac	3.518(2.294, 4.742)	< 0.001	2.502(0.700, 4.305)	0.007
^aModel-1: APACHE II score, heart rate and IL-6 were adjusted

3.5 Relationship between Dynamic Changes in NE Dose and Microcirculatory Function

Longitudinal analysis was performed using data from Day 1 and Day 3 to evaluate the dynamic relationship between changes in NE dose (ΔNE dose = NE dose _D3 – NE dose _D1) and changes in microcirculatory parameters (Δ microcirculatory parameters = microcirculatory parameters _D3- microcirculatory parameters _D1). Correlation analysis showed that changes in NE dose were significantly positively correlated with changes in Lac and mottling score (Δ Lac: r = 0.653, p < 0.001; Δ mottling score: r = 0.483, p < 0.001), and significantly negatively correlated with changes in MFI (r = -0.565, p < 0.001). These correlations remained significant after FDR correction (all the parameters’ p < 0.001) (Fig. 4). After adjusting for APACHE II scores, heart rate, and IL-6 levels, multivariate regression analysis further revealed significant correlations between changes in NE dose and changes in Lac, MFI, and mottling scores (Δ Lac: 95% CI: p < 0.001, -0.159 to -0.080; ΔMFI: p < 0.001, 95% CI: 0.003 to 0.006; Δ mottling score: p = 0.003, 95% CI: -0.047 to -0.013). No statistically significant association was observed between NE dose changes and alterations in PPV, PI, HI, TVD, PVD, or CRT (all p > 0.05 for correlation and regression after adjustment) (Fig. 5).

3.6 Relationship between NE Dose and Prognosis

Based on the NE cut-off dose (0.8 \(\:\mu\:\)g/kg/min), survival analysis, stratified by GAM analysis, showed significant differences in survival rates between groups. Kaplan-Meier curves and Log-rank test indicated that the overall survival rate was significantly lower in the high dose group compared to the low dose group (28-day survival: Log-rank p = 0.001; 90-day survival: Log-rank p = 0.006) (Fig. 6). Univariate Cox regression model showed that the risk of death in the high NE dose group was 2.52 times that of the low dose group (HR = 2.52, 95% CI: 1.28 to 4.99, p = 0.007). Importantly, even after adjusting with confounding factors including APACHE II scores, heart rate, and IL-6 levels, the independent effect of high NE dose remained statistically significant (fully adjusted HR = 1.32, 95% CI: 0.86 to 3.10, p = 0.039).

This prospective observational study systematically investigated the relationship between NE dose and microcirculatory perfusion in ICU septic patients through a combination of cross-sectional and longitudinal analysis, and further verified the independent association between NE dose and patient prognosis. The findings not only provide new evidence for understanding the dose-dependent effect of NE on microcirculation but also offer actionable insights for optimizing NE dosage strategies in sepsis management. Correlation and regression analyses consistently showed that NE dose was significantly correlated with microcirculation in ICU septic patients (mottling score, Lac, HI, MFI, PPV), and this association remained stable after adjusting for multiple confounding factors, with the exception of mottling score. This confirms that NE dose exerts an independent effect on microcirculatory perfusion, rather than merely being a surrogate for more severe illness. The most significant finding of this study is the exploration of a nonlinear dose-response relationship between NE and microcirculation. When NE dose exceeds the threshold range of 0.71–0.80 \(\:\mu\:\)g/kg/min, microcirculation in septic patients deteriorates significantly; conversely, it may maintain MMC and improve perfusion. However, this dosage range appears inconsistent in terms of mottling score and lactate levels. In the GAM fitting model, the R² value for NE and mottling score was 0.123, suggesting potential poor model fit, due to factors such as the subjective bias, population characteristics, and sample size. Moreover, when NE dose exceeds 1 \(\:\mu\:\)g/kg/min, which often considered rather high dose NE, it is frequently combined with methylene blue or other vasopressors in clinical practice. This may influence lactate metabolism and NE dosage requirements[31]. Longitudinal data further showed that an increase in NE dose was significantly negatively correlated with improvements in microcirculatory perfusion. Furthermore, this study established an association between NE dose and patient prognosis. Multivariate Cox regression model confirmed that high-dose NE is an independent risk factor of death. This is consistent with the conclusions of AUCHET T et al.[32] and REINIKAINEN M et al.[33], collectively emphasizing a key concept: in the treatment of septic shock, NE should not be regarded as a harmless supportive measure but rather a therapeutic drug that requires careful weighing and precise regulation. De Backer D et al.[34] and KINDERMANS M et al.[35] proposed the concept of "macrocirculation-microcirculation decoupling" in septic shock, noting that normal macrocirculation hemodynamic parameters (e.g. MAP, CVP) do not guarantee adequate microcirculatory perfusion. This is directly supported by our data: although there was no significant difference in MAP between the high and low dose NE groups, the high-dose group exhibited marked microcirculatory deterioration. This highlights the risk of over-reliance on macrohemodynamic targets in NE therapy. Clinicians may mistakenly consider normal MAP as a sign of effective resuscitation, while microcirculatory damage persists. Therefore, KATO R et al.[36] and DE BACKER D et al.[37] have mentioned personalized blood pressure management in septic shock patients, which is consistent with the purpose of this study. A study by MARTIN C et al.[38] further indicated that mortality risk significantly increases when NE doses exceed 0.5–1.0 \(\:\mu\:\)g/kg/min, a range similar to our findings. However, this study represents a breakthrough by linking the underlying microcirculatory mechanisms to this association rather than merely describing prognostic correlations. This mechanistic insight strengthens the rationale for limiting NE doses in clinical practice. Van Genderen et al.[39] previously proposed a resuscitation strategy guided by peripheral perfusion. On the bases, the conclusion of our research suggests that dynamically adjusting NE dose, which is targeting optimal microcirculatory perfusion, is a safer and more individualized management strategy in the treatment of septic patients.

In summary, microcirculatory dysfunction induced by high-dose NE using may be a key mediating link in the increased risk of death in patients. Therefore, in clinical practice, microcirculation monitoring technology should be appropriately utilized to precisely regulate NE dose, thereby enabling refined hemodynamic management of septic patients. This approach prevents further deterioration of microcirculation due to excessive NE administration, ultimately improving patient outcomes.

Admittedly, this study has several limitations. First, as a single-center observational study, despite controlling for confounding factors through multivariate adjustment and various analytical methods, residual confounding and bias cannot be completely excluded. Second, the sample size is relatively limited. Although it meets the statistical requirements, the sample size limited subgroup analyses and a more appropriate restricted cubic spline analysis could not be performed to refine the depiction of the dose-response curve when exploring the dose-response relationship. Finally, although dynamic changes in microcirculation were monitored, the study mainly focused on short-term microcirculatory changes, and the long-term effects of NE on microcirculatory remodeling and perfusion of different organs require further investigation. Future research should address these gaps through multicenter randomized controlled trials comparing the proposed “microcirculation-guided NE therapy” with conventional MAP guided therapy to validate its impact on 28-day and 90-day mortality rates. A large cohort study employing restricted cubic spline functions aimed to further determine the precise NE dose threshold associated with worsening microcirculation and increased risk of mortality. A longitudinal study to evaluate the impact of NE on microcirculation and organ function following ICU discharge (e.g., 3–6 months post-sepsis) to assess long-term prognosis.

This study demonstrated that excessive, high-dose NE infusion exacerbates microcirculatory dysfunction and worsens prognosis. Which means, when NE dose pumping over 0.71–0.80 \(\:\mu\:\)g/kg/min, microcirculatory dysfunction should be noted. This provides important evidence for the precise regulation of NE dose in sepsis management, emphasizing the significance of integrating microcirculation monitoring to avoid further deterioration caused by excessive NE use and thereby improve patient prognosis.

APACHE II	Acute Physiology and Chronic Health Evaluation II
CI	Confidence Interval
CRT	Capillary Refill Time
CRRT	Continuous Renal Replacement Therapy
CVP	Central Venous Pressure
ECMO	Extracorporeal Membrane Oxygenation
FDR	False Discovery Rate
GAM	Generalized Additive Model
HI	Heterogeneity Index
ICU	Intensive Care Unit
IQR	Interquartile Range
IL-6	Interleukin-6
Lac	Lactate
MFI	Microvascular Flow Index
MMC	Macrocirculation-Microcirculation Coupling
NE	Norepinephrine
PVD	Perfused Vessel Density
PPV	Proportion of Perfused Vessel
PI	Peripheral Perfusion Index
SOFA	Sequential Organ Failure Assessment
SD	Standard Deviation
SDF	Sidestream Dark Field
TVD	Total Vessel Density

7. Acknowledgements

None.

8. Authors’ contributions

YPD and YZ was involved in the drafting the manuscript, creating figures and performing key revisions. YPD, YZ and HC were involved in the data collection and analysis. YML and ZYP took part in the study concept and supervised all aspects of this research. All authors read and approved the final manuscript.

9. Funding

None.

10. Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

11. Declarations

11.1 Human Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2025096K). The study was conducted in accordance with the Declaration of Helsinki. All enrolled patients provided written informed consent to participate in the study.

11.2 Clinical trial number

Not applicable.

11.3 Consent for publication

Not applicable.

11.4 Competing interests

The authors declare no competing interests.

12. Author details

¹ Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China;

² Hubei Clinical Research Center for Critical Care Medicine, Wuhan, Hubei Province, China;

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The Effect of Different Doses of Norepinephrine on Microcirculation in ICU Septic Patients: A Prospective Observational Study

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Abstract

Background

Methods

Result

Conclusions

Figures

1. Introduction

2. Materials and Methods

2.1 Study Design

2.2 Study Population

2.2.1 Sample Size Calculation

2.2.2 Inclusion Criteria

2.2.3 Exclusion Criteria

2.3 Study Methods and Data Collection

2.3.1 Microcirculation Monitoring

2.3.2 Data Collection

2.4 Statistical Analysis

3. Results

3.1 Cohort Characteristics

3.2 Correlation between NE Dose and Microcirculatory Parameters

3.3 Multivariate Regression Analysis of NE Dose and Microcirculatory Parameters

3.5 Relationship between Dynamic Changes in NE Dose and Microcirculatory Function

3.6 Relationship between NE Dose and Prognosis

4. Discussion

5. Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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