The associations of time-varying norepinephrine dose and duration with severe pressure injuries in ICU patients: A dose-response analysis

OBJECTIVES: To investigate the associations of time-varying norepinephrine (NE) dose and infusion duration with pressure injury (PI) development, particularly for Stage II or higher PIs, in ICU patients requiring vasopressor support. DESIGN: Retrospective cohort study. RESEARCH METHODOLOGY: Data were extracted from the Chinese Database in Intensive Care (CDIC, 2021-2024). NE exposure was quantified as a daily time-varying weighted-average dose (μg/kg/min) and the cumulative duration above the dose threshold. Restricted cubic splines (RCS) modeled dose-response relationships with bootstrap internal validation. Cause-specific time-varying Cox regression analyzed NE exposure for overall PIs and Stage II or higher PIs, respectively. RESULTS: Among 3590 eligible patients, 667 (18.6%) developed any PI (247 were Stage II or higher). For overall PIs, neither daily NE dose above the RCS-derived threshold (P = 0.792) nor cumulative duration above threshold (P = 0.381) was independently significant. Conversely, for Stage II or higher PIs, the thresholds were identified as 0.20 μg/kg/min for daily dose and 2 days for cumulative duration, which were relatively stable in internal bootstrap resampling. In mutually adjusted models, cumulative duration ≥2 days remained a constant independent risk factor (HR 2.292). Importantly, the risk associated with a daily dose >0.20 μg/kg/min escalated substantially over time, with the adjusted HR increasing from 1.50 on day 2 to 4.40 on day 7. CONCLUSION: NE exposure is independently associated with severe PIs, driven by both cumulative duration and an escalating risk from acute high-dose exposure over time. The threshold values identified in this study may be used for patient risk stratification. However, given their exploratory nature and potential optimism bias stemming from derivation and evaluation in the same dataset, these findings require cautious interpretation and external validation. IMPLICATIONS FOR CLINICAL PRACTICE: Clinicians should routinely monitor both daily dose status and cumulative high-dose duration. The derived thresholds may serve as an exploratory reference to identify high-risk patients and guide targeted prevention. Prospective external validation is needed before routine adoption.