Restricted accessResearch articleFirst published online 2026-3
Visualizations of Autoregulatory Insults in Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research-Traumatic Brain Injury Cohort Study
Cerebral blood flow disturbances, including ischemia and hyperemia, due to impaired cerebral autoregulation (CA), are common and unfavorable in traumatic brain injury (TBI). The pressure reactivity index (PRx) reflects CA status and is associated with patient outcomes. Yet, the impact of the combined intensity and duration of CA insults and the temporal evolution of CA impairment in relation to outcome remains unclear. Moreover, how PRx modulates safe and dangerous thresholds for intracranial pressure (ICP), cerebral perfusion pressure (CPP), and CPP deviation from optimal CPP (ΔCPPopt) is not well defined. This study aimed to clarify these relationships using granular outcome heatmaps. In this prospective, observational, cohort within the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI), 166 patients with TBI, admitted between 2014 and 2017 from 21 recruiting centers, were included. Demography, admission status, and clinical outcome were evaluated. A favorable outcome was defined as Extended Glasgow Outcome Scale (GOSE) 5–8 at 6 months post-injury. High-frequency data of ICP, CPP, PRx, and ΔCPPopt during the first 7 days of neurocritical care were analyzed and visualized in color-coded heatmaps. PRx >0.30 and negative ΔCPPopt were strongly associated with unfavorable outcomes, particularly when sustained for longer durations. The physiological ranges associated with a favorable outcome for PRx and ΔCPPopt remained stable over the first 7 days post-injury. PRx modulated the safe and dangerous intervals of the other cerebral physiological variable, as the combination of high PRx together with high ICP, low CPP, and negative ΔCPPopt, respectively, was particularly associated with worse outcomes. Moreover, the unfavorable effect of negative ΔCPPopt primarily occurred when combined with PRx >0.00 rather than for negative ΔCPPopt (mmHg) in general. PRx may be used to fine-tune safe ICP, CPP, and ΔCPPopt targets, particularly in defining the lower limit of CA. Future studies should focus on evaluating the PRx/CPP curve location and steepness rather than mainly focusing on mmHg-deviation from CPPopt or any specific target.
Svedung WettervikT, HowellsT, HilleredL, et al.Autoregulatory or fixed cerebral perfusion pressure targets in traumatic brain injury: Determining which is better in an energy metabolic perspective. J Neurotrauma, 2021; 38(14):1969–1978; doi: 10.1089/neu.2020.7290
2.
DiringerMN, ZazuliaAR, PowersWJ. Does ischemia contribute to energy failure in severe TBI? Transl Stroke Res, 2011; 2(4):517–523; doi: 10.1007/s12975-011-0119-8
3.
GrahamDI, AdamsJH. Ischaemic brain damage in fatal head injuries. Lancet, 1971; 1(7693):265–266; doi: 10.1016/s0140-6736(71)91003-8
4.
RosenthalG, Sanchez-MejiaRO, PhanN, et al.Incorporating a parenchymal thermal diffusion cerebral blood flow probe in bedside assessment of cerebral autoregulation and vasoreactivity in patients with severe traumatic brain injury. J Neurosurg, 2011; 114(1):62–70; doi: 10.3171/2010.6.JNS091360
5.
CarneyN, TottenAM, O’ReillyC, et al.Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery, 2017; 80(1):6–15; doi: 10.1227/NEU.0000000000001432
6.
LangEW, ChesnutRM. A bedside method for investigating the integrity and critical thresholds of cerebral pressure autoregulation in severe traumatic brain injury patients. Br J Neurosurg, 2000; 14(2):117–126; doi: 10.1080/02688690050004534
7.
Svedung WettervikT, HowellsT, EnbladP, et al.Temporal neurophysiological dynamics in traumatic brain injury: Role of pressure reactivity and optimal cerebral perfusion pressure for predicting outcome. J Neurotrauma, 2019; 36(11):1818–1827; doi: 10.1089/neu.2018.6157
8.
CzosnykaM, SmielewskiP, KirkpatrickP, et al.Continuous assessment of the cerebral vasomotor reactivity in head injury. Neurosurgery, 1997; 41(1):11–17; discussion 17–19; doi: 10.1097/00006123-199707000-00005
9.
TsigarasZA, WeedenM, McNamaraR, et al.; PRECISION-TBI Investigators. The pressure reactivity index as a measure of cerebral autoregulation and its application in traumatic brain injury management. Crit Care Resusc, 2023; 25(4):229–236; doi: 10.1016/j.ccrj.2023.10.009
10.
JohnsonU, LewénA, Ronne-EngströmE, et al.Should the neurointensive care management of traumatic brain injury patients be individualized according to autoregulation status and injury subtype? Neurocrit Care, 2014; 21(2):259–265; doi: 10.1007/s12028-014-9954-2
11.
SteinerLA, CzosnykaM, PiechnikSK, et al.Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med, 2002; 30(4):733–738; doi: 10.1097/00003246-200204000-00002
12.
AriesMJH, CzosnykaM, BudohoskiKP, et al.Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury. Crit Care Med, 2012; 40(8):2456–2463; doi: 10.1097/CCM.0b013e3182514eb6
13.
DonnellyJ, CzosnykaM, AdamsH, et al.Individualizing thresholds of cerebral perfusion pressure using estimated limits of autoregulation. Crit Care Med, 2017; 45(9):1464–1471; doi: 10.1097/CCM.0000000000002575
14.
BeqiriE, ZeilerFA, ErcoleA, et al.; CENTER-TBI HR ICU participants and investigators. The lower limit of reactivity as a potential individualised cerebral perfusion pressure target in traumatic brain injury: A CENTER-TBI high-resolution sub-study analysis. Crit Care, 2023; 27(1):194; doi: 10.1186/s13054-023-04485-8
15.
ZeilerFA, AriesM, CzosnykaM, et al.Cerebral autoregulation monitoring in traumatic brain injury: An overview of recent advances in personalized medicine. J Neurotrauma, 2022; 39(21–22):1477–1494; doi: 10.1089/neu.2022.0217
16.
BögliSY, OlakoredeI, BeqiriE, et al.Cerebral perfusion pressure targets after traumatic brain injury: A reappraisal. Crit Care, 2025; 29(1):207; doi: 10.1186/s13054-025-05458-9
17.
GüizaF, DepreitereB, PiperI, et al.Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury. Intensive Care Med, 2015; 41(6):1067–1076; doi: 10.1007/s00134-015-3806-1
18.
Svedung WettervikT, HånellA, HowellsT, et al.ICP, CPP, and PRx in traumatic brain injury and aneurysmal subarachnoid hemorrhage: Association of insult intensity and duration with clinical outcome. J Neurosurg, 2023; 138(2):446–453; doi: 10.3171/2022.5.JNS22560
19.
ÅkerlundCA, DonnellyJ, ZeilerFA, et al.; CENTER-TBI High Resolution ICU Sub-Study Participants and Investigators. Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study. PLoS One, 2020; 15(12):e0243427; doi: 10.1371/journal.pone.0243427
20.
Svedung WettervikT, HånellA, HowellsT, et al.Autoregulatory management in traumatic brain injury: The role of absolute pressure reactivity index values and optimal cerebral perfusion pressure curve shape. J Neurotrauma, 2023; 40(21–22):2341–2352; doi: 10.1089/neu.2023.0017
21.
LenellS, WettervikTS, HowellsT, et al.Cerebrovascular Reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury. Acta Neurochir (Wien), 2024; 166(1):62; doi: 10.1007/s00701-024-05956-9
22.
Svedung WettervikT, BeqiriE, HånellA, et al.Brain tissue oxygen monitoring in traumatic brain injury-part II: Isolated and combined insults in relation to outcome. Crit Care, 2023; 27(1):370; doi: 10.1186/s13054-023-04659-4
23.
Svedung WettervikT, BeqiriE, HånellA, et al.Visualization of cerebral pressure autoregulatory insults in traumatic brain injury. Crit Care Med, 2024; 52(8):1228–1238; doi: 10.1097/CCM.0000000000006287
24.
SmielewskiP, BeqiriE, MataczynskiC, et al.Advanced neuromonitoring powered by ICM+ and its place in the brand new AI world, reflections at the 20th anniversary boundary. Brain Spine, 2024; 4:102835; doi: 10.1016/j.bas.2024.102835
25.
ZeilerFA, ErcoleA, BeqiriE, et al.; CENTER-TBI High Resolution ICU (HR ICU) Sub-Study Participants and Investigators. Association between cerebrovascular reactivity monitoring and mortality is preserved when adjusting for baseline admission characteristics in adult traumatic brain injury: A CENTER-TBI study. J Neurotrauma, 2020; 37(10):1233–1241; doi: 10.1089/neu.2019.6808
26.
MathieuF, ZeilerFA, ErcoleA, et al.; CENTER-TBI High Resolution Sub-Study Participants and Investigators. Relationship between measures of cerebrovascular reactivity and intracranial lesion progression in acute traumatic brain injury patients: A CENTER-TBI study. J Neurotrauma, 2020; 37(13):1556–1565; doi: 10.1089/neu.2019.6814
27.
BeqiriE, ErcoleA, AriesMJH, et al.; CENTER-TBI High Resolution (HR ICU) Sub-Study Participants and Investigators. Towards autoregulation-oriented management after traumatic brain injury: Increasing the reliability and stability of the CPPopt algorithm. J Clin Monit Comput, 2023; 37(4):963–976; doi: 10.1007/s10877-023-01009-1
28.
DepreitereB, GüizaF, Van den BergheG, et al.Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data. J Neurosurg, 2014; 120(6):1451–1457; doi: 10.3171/2014.3.JNS131500
29.
BeqiriE, SmielewskiP, RobbaC, et al.Feasibility of individualised severe traumatic brain injury management using an automated assessment of optimal cerebral perfusion pressure: The COGiTATE phase II study protocol. BMJ Open, 2019; 9(9):e030727; doi: 10.1136/bmjopen-2019-030727
30.
TeasdaleGM, PettigrewLE, WilsonJT, et al.Analyzing outcome of treatment of severe head injury: A review and update on advancing the use of the glasgow outcome scale. J Neurotrauma, 1998; 15(8):587–597; doi: 10.1089/neu.1998.15.587
31.
WilsonJT, PettigrewLE, TeasdaleGM. Structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: Guidelines for their use. J Neurotrauma, 1998; 15(8):573–585; doi: 10.1089/neu.1998.15.573
32.
KunzmannK, WernischL, RichardsonS, et al.Imputation of ordinal outcomes: A comparison of approaches in traumatic brain injury. J Neurotrauma, 2021; 38(4):455–463; doi: 10.1089/neu.2019.6858
33.
Svedung WettervikT, HowellsT, HånellA, et al.The optimal pressure reactivity index range is disease-specific: A comparison between aneurysmal subarachnoid hemorrhage and traumatic brain injury. J Clin Monit Comput, 2024; 38(5):1089–1099; doi: 10.1007/s10877-024-01168-9
34.
FlechetM, MeyfroidtG, PiperI, et al.Visualizing cerebrovascular autoregulation insults and their association with outcome in adult and paediatric traumatic brain injury. Acta Neurochir (Suppl 2018); 126:291–295; doi: 10.1007/978-3-319-65798-1_57
35.
ZeilerFA, AriesM, CabeleiraM, et al.; CENTER-TBI High Resolution ICU (HR ICU) Sub-Study Participants and Investigators. Statistical cerebrovascular reactivity signal properties after secondary decompressive craniectomy in traumatic brain injury: A CENTER-TBI pilot analysis. J Neurotrauma, 2020; 37(11):1306–1314; doi: 10.1089/neu.2019.6726
36.
HowellsT, JohnsonU, McKelveyT, et al.An optimal frequency range for assessing the pressure reactivity index in patients with traumatic brain injury. J Clin Monit Comput, 2015; 29(1):97–105; doi: 10.1007/s10877-014-9573-7
37.
AdamsH, DonnellyJ, CzosnykaM, et al.Temporal profile of intracranial pressure and cerebrovascular reactivity in severe traumatic brain injury and association with fatal outcome: An observational study. PLoS Med, 2017; 14(7):e1002353; doi: 10.1371/journal.pmed.1002353
38.
BradyKM, LeeJK, KiblerKK, et al.Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: Comparison of 3 methods. Stroke, 2008; 39(9):2531–2537; doi: 10.1161/STROKEAHA.108.514877
39.
BhattacharyayS, CarusoPF, ÅkerlundC, et al.; CENTER-TBI investigators and participants. Mining the contribution of intensive care clinical course to outcome after traumatic brain injury. NPJ Digit Med, 2023; 6(1):154; doi: 10.1038/s41746-023-00895-8
40.
MartinNA, PatwardhanRV, AlexanderMJ, et al.Characterization of cerebral hemodynamic phases following severe head trauma: Hypoperfusion, hyperemia, and vasospasm. J Neurosurg, 1997; 87(1):9–19; doi: 10.3171/jns.1997.87.1.0009
41.
JhaRM, KochanekPM, SimardJM. Pathophysiology and treatment of cerebral edema in traumatic brain injury. Neuropharmacology, 2019; 145(Pt B):230–246; doi: 10.1016/j.neuropharm.2018.08.004
42.
Svedung WettervikT, HånellA, HowellsT, et al.Autoregulatory cerebral perfusion pressure insults in traumatic brain injury and aneurysmal subarachnoid hemorrhage: The role of insult intensity and duration on clinical outcome. J Neurosurg Anesthesiol, 2024; 36(3):228–236; doi: 10.1097/ANA.0000000000000922
43.
WijayatungaP, KoskinenL-OD, SundströmN. Probabilistic prediction of increased intracranial pressure in patients with severe traumatic brain injury. Sci Rep, 2022; 12(1):9600; doi: 10.1038/s41598-022-13732-x
44.
CzosnykaM, SteinerL, BalestreriM, et al.Concept of “true ICP” in monitoring and prognostication in head trauma. Acta Neurochir, 2005; 95:341–344; doi: 10.1007/3-211-32318-x_70
45.
SorrentinoE, DiedlerJ, KasprowiczM, et al.Critical thresholds for cerebrovascular reactivity after traumatic brain injury. Neurocrit Care, 2012; 16(2):258–266; doi: 10.1007/s12028-011-9630-8
46.
BeqiriE, TasJ, CzosnykaM, et al.Does targeting CPP at CPPopt actually improve cerebrovascular reactivity? a secondary analysis of the COGiTATE randomized controlled trial. Neurocrit Care, 2025; 42(3):937–944; doi: 10.1007/s12028-024-02168-y
47.
ZeilerFA, ErcoleA, BeqiriE, et al.; CENTER-TBI High Resolution ICU (HR ICU) Sub-Study Participants and Investigators. Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: A CENTER-TBI analysis. Acta Neurochir (Wien), 2019; 161(9):1955–1964; doi: 10.1007/s00701-019-03980-8
48.
ÅkerlundCAI, HolstA, BhattacharyayS, et al.; CENTER-TBI participants and investigators. Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): A multicentre observational cohort study. Lancet Neurol, 2024; 23(1):71–80; doi: 10.1016/S1474-4422(23)00358-7
49.
SteyerbergEW, WiegersE, SewaltC, et al.; CENTER-TBI Participants and Investigators. Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: A European prospective, multicentre, longitudinal, cohort study. Lancet Neurol, 2019; 18(10):923–934; doi: 10.1016/S1474-4422(19)30232-7
50.
HowellsT, JohnsonU, McKelveyT, et al.The effects of ventricular drainage on the intracranial pressure signal and the pressure reactivity index. J Clin Monit Comput, 2017; 31(2):469–478; doi: 10.1007/s10877-016-9863-3
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