The lower limit margin: a determinant of autoregulatory sensitivity to changes in cerebral perfusion pressure

Bögli et al. Critical Care (2025) 29:455 https://doi.org/10.1186/s13054-025-05686-z Critical Care Open Access RESEARCH The lower limit margin: a determinant of autoregulatory sensitivity to changes in cerebral perfusion pressure Stefan Yu Bögli1,4* , Ihsane Olakorede1, Erta Beqiri1, Xuhang Chen1, Andrea Lavinio3, Peter Hutchinson2 and Peter Smielewski1 Abstract Introduction The Lower Limit Margin, defined as the difference between the autoregulation-informed optimal cerebral perfusion (CPP) target (CPPopt) and the lower limit of autoregulation (LLA), was recently introduced as a potential dynamic prognostic marker after traumatic brain injury (TBI). Conceptually, CPPopt marks the CPP associated with “optimal” autoregulatory function, while LLA represents the CPP at which cerebrovascular autoregulation is already impaired and deteriorates with further decreases in CPP. Based on the hypothesis that the effect of the Lower Limit Margin on outcome is critically mediated by the level of short-term CPP variability and the associated increase in time spent below the LLA, we aimed to explore the prognostic value of this novel marker. Materials and methods In a prospective cohort of 234 severe TBI patients receiving invasive multimodality monitoring, we evaluated the prognostic and physiological relevance of the Lower Limit Margin. Minute-by-minute CPP, CPPopt, and LLA were derived using automated, validated methods. The association between the Lower Limit Margin with 6-month Glasgow Outcome Scale, short-term CPP variability, and autoregulatory burden (time spent below LLA) was assessed using logistic regression, ordinal analyses, mixed-effects models, causal mediation analysis, and generalized additive modeling. Results Patients with wider Lower Limit Margins experienced significantly less time with CPP below the LLA (β = − 2.1, CI − 2.2 to − 1.9) and had decreased odds of unfavorable outcome (OR 0.59, CI 0.41–0.83, p = 0.003). Causal mediation analysis indicated that 58.9% effect of the Lower Limit Margin on outcome was mediated by time spent below the LLA. A significant interaction between Lower Limit Margin and short-term CPP variability was observed: a narrow Lower Limit Margin combined with high short-term CPP variability were associated with the worst outcomes and higher amount of time spent with CPP below LLA. Nearly 50% of hourly short-term CPP variability exceeded ± 5 mmHg. Conclusion Our findings demonstrate that a narrow Lower Limit Margin is a marker of increased physiological vulnerability, associated with more frequent and severe CPP insults and worse neurological outcomes after TBI. These *Correspondence: Stefan Yu Bögli Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Bögli et al. Critical Care (2025) 29:455 Page 2 of 10 results support a shift away from single-threshold strategies (e.g., CPPopt or LLA alone) toward a resilience-informed approach that integrates the dynamic interplay between autoregulatory reserve and short-term CPP variability. Keywords Traumatic brain injury, Multimodality monitoring, Cerebral perfusion pressure, Cerebrovascular autoregulation Introduction Cerebral perfusion pressure (CPP) management is one of the key aspects of intensive care management after traumatic brain Injury (TBI) [1]. While current guidelines still propose fixed targets ranging between 60 and 70 mmHg [1], personalized CPP targets, which account for the state of cerebrovascular autoregulation, have largely outperformed these when assessed against outcome [2–5]. Cerebrovascular autoregulation describes an innate mechanism that aims at stabilizing cerebral blood flow [6]. Specifically, it counteracts slow changes in systemic driving pressure by adjusting arteriolar diameter [6]. In intensive care, different personalized targets have been proposed for the management of TBI patients, namely CPPopt (i.e., optimal CPP) [3] and the LLA (i.e., the lower limit of autoregulation) [4, 5]. Both are based on the pressure reactivity index (PRx), a proxy measure of cerebrovascular autoregulation which quantifies the change in intracranial pressure (ICP – herein used to quantify the magnitude of change in diameter of the arterioles) to slow changes in arterial blood pressure (ABP) [7]. First described in 2002 [3], CPP and PRx often display a distinct U-shaped relationship, from which both CPPopt and LLA are derived. Specifically, CPPopt is defined as the CPP value associated with the lowest PRx across this relationship, while LLA is the CPP value at which cerebrovascular autoregulation is already impaired and further deteriorates with decreasing CPP [2–5]. Particularly, below LLA, cerebral blood flow cannot be stabilized sufficiently, leading to the risk of hypoxia and hypoperfusion [8, 9]. Of note, PRx and PRx derived metrics reflect cerebrovascular reactivity [7], which in itself is just one aspect affected by the cerebrovascular autoregulation mechanism [5]. However, given that PRx remains the most widely used continuous proxy for the patients autoregulatory status, the term LLA and autoregulation (rather than lower limit of reactivity and cerebrovascular reactivity) will be used throughout for simplicity. Both CPPopt and LLA can be estimated at the bedside using automated methods [2, 10, 11]. From a conceptual standpoint [12], when CPP is maintained at CPPopt, the cerebrovascular autoregulation mechanism “optimally” supports the stabilization of cerebral blood flow. Conversely, LLA is more frequently seen as a critical “safety” threshold, since a higher frequency of CPP below the LLA is strongly associated with worse outcomes due to the association to decreased cerebral blood flow [5]. Most recently, we introduced the Lower Limit Margin, which describes the difference in CPP between CPPopt and LLA [13]. The Lower Limit Margin was distinctly dynamic throughout the TBI course, with patients with narrow Lower Limit Margins displaying distinctly worse outcomes. Of note, in some patients, the Lower Limit Margin was as narrow as 5–6 mmHg. This raises the question of whether the pragmatically us (...truncated)