Abstract
Traumatic brain injury (TBI) remains one of the most fatal and debilitating conditions in the world. Current clinical management in severe TBI patients is mainly concerned with reducing secondary insults and optimizing the balance between substrate delivery and consumption. Over the past decades, multimodality monitoring has become more widely available, and clinical management protocols have been published that recommend potential interventions to correct pathophysiological derangements. Even while evidence from randomized clinical trials is still lacking for many of the recommended interventions, these protocols and algorithms can be useful to define a clear standard of therapy where novel interventions can be added or be compared to. Over the past decade, more attention has been paid to holistic management, in which hemodynamic, respiratory, inflammatory or coagulation disturbances are detected and treated accordingly. Considerable variability with regards to the trajectories of recovery exists. Even while most of the recovery occurs in the first months after TBI, substantial changes may still occur in a later phase. Neuroprognostication is challenging in these patients, where a risk of self-fulfilling prophecies is a matter of concern. The present article provides a comprehensive and practical review of the current best practice in clinical management and long-term outcomes of moderate to severe TBI in adult patients admitted to the intensive care unit.
This is a preview of subscription content, access via your institution.

(modified from The Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)). In patients with ICP monitoring (with/without additional brain oxygen monitoring) the four represent the starting points for deciding a treatment strategy. Tier 0, i.e. basic strategies (not included in the flowchart), apply to TBI patients who are admitted to an intensive care unit (ICU) for whom the decision to monitor ICP has been made. The goal of tier‐zero is to establish a stable, neuroprotective physiologic baseline regardless of eventual ICP readings. Tier-zero sedatives and analgesics target comfort and ventilator tolerance, temperature management targets the avoidance of fever and CPP > 60 mm Hg. Lower tier treatments are viewed as having a more favorable side effect profile than higher tiers and generally should be employed first. Treatments in any given tier are considered equivalent, with the selection of one treatment over another based on individual patient characteristics and physician discretion and multiple items from a single tier can be trialed individually or in combination with the goal of a rapid response. The provider should consider moving to more aggressive interventions in a higher tier quickly if the patient is not responding. Panel A Patients with ICP below the threshold usually do not need treatment except for conditions in which a high intracranial pressure–time burden is present because this condition is associated with worse outcomes. Refer to [1] for details. Therefore, in this setting, treatment could be considered also below the classical threshold of 22 mmHg. Panel B Consensus-based algorithm for the management of severe traumatic brain injury with brain hypoxia and normal intracranial pressure. Panel C Consensus-based algorithm for the management of severe traumatic brain injury with intracranial hypertension and brain hypoxia. Panel D Consensus-based algorithm for the management of severe traumatic brain injury with intracranial hypertension and normal brain oxygenation. Inter-tier recommendations encourage patient reassessment for remediable causes of treatment resistance. Stepping to a higher tier is a potential indicator of increased disease severity. As higher tiers represent interventions with increased associated risks, we recommend reassessing the patient’s basic intra-and extra-cranial physiologic status and reconsidering the surgical status of intracranial mass lesions not previously considered operative

Change history
20 June 2022
A Correction to this paper has been published: https://doi.org/10.1007/s00134-022-06759-1
References
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):56-87. https://doi.org/10.1016/S1474-4422(18)30415-0. [Erratum in: Lancet Neurol. 2021 Dec;20(12):e7]
Stocchetti N, Taccone FS, Citerio G et al (2015) Neuroprotection in acute brain injury: an up-to-date review. Crit Care 19:186. https://doi.org/10.1186/s13054-015-0887-8
Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, Jane JA, Marmarou A, Foulkes MA (1993) The role of secondary brain injury in determining outcome from severe head injury. J Trauma-Inj Infect Critic Care 34(2):216–222
Spaite DW, Hu C, Bobrow BJ, Chikani V, Sherrill D, Barnhart B et al (2017) Mortality and prehospital blood pressure in patients with major traumatic brain injury: implications for the hypotension threshold. JAMA Surg 152(4):360–368
Spahn DR, Bouillon B, Cerny V et al (2019) The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 23:98. https://doi.org/10.1186/s13054-019-2347-3
Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J (2016) Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. https://doi.org/10.1227/NEU.0000000000001432
Geeraerts T, Velly L, Abdennour L, Asehnoune K, Audibert G, Bouzat P, Bruder N, Carrillon R, Cottenceau V, Cotton F, Courtil-Teyssedre S, Dahyot-Fizelier C, Dailler F, David JS, Engrand N, Fletcher D, Francony G, Gergelé L, Ichai C, Javouhey É, Leblanc PE, Lieutaud T, Meyer P, Mirek S, Orliaguet G, Proust F, Quintard H, Ract C, Srairi M, Tazarourte K, Vigué B, Payen JF, French Society of Anaesthesia; Intensive Care Medicine; in partnership with Association de neuro-anesthésie-réanimation de langue française (Anarlf); French Society of Emergency Medicine (Société Française de Médecine d’urgence (SFMU); Société française de neurochirurgie (SFN); Groupe francophone de réanimation et d’urgences pédiatriques (GFRUP); Association des anesthésistes-réanimateurs pédiatriques d’expression française (Adarpef) (2018) Management of severe traumatic brain injury (first 24hours). Anaesth Crit Care Pain Med 37(2):171–186. https://doi.org/10.1016/j.accpm.2017.12.001
Ract C, Le Moigno S, Bruder N, Vigue B (2007) Transcranial Doppler ultrasound goal-directed therapy for the early management of severe traumatic brain injury. Intensive Care Med 33(4):645–651
Davis DP, Koprowicz KM, Newgard CD, Daya M, Bulger EM, Stiell I et al (2011) The relationship between out-of-hospital airway management and outcome among trauma patients with Glasgow Coma Scale Scores of 8 or less. Prehosp Emerg Care 15(2):184–192
Murray GD, Butcher I, McHugh GS, Lu J, Mushkudiani NA, Maas AI et al (2007) Multivariable prognostic analysis in traumatic brain injury: results from the IMPACT study. J Neurotrauma 24(2):329–337
Chesnut RM, Videtta W (2020) Situational intracranial pressure management: an argument against a fixed treatment threshold. Crit Care Med 48:1214–1216
Lazaridis C, Goldenberg FD (2020) Intracranial pressure in traumatic brain injury: from thresholds to heuristics. Crit Care Med 48:1210–1213
Robba C, Graziano F, Rebora P et al (2021) (2021) Intracranial pressure monitoring in patients with acute brain injury in the intensive care unit (SYNAPSE-ICU): an international, prospective observational cohort study. Lancet Neurol 20(7):548–558
Hawryluk GWJ, Aguilera S, Buki A, Bulger E, Citerio G, Cooper DJ, Arrastia RD, Diringer M, Figaji A, Gao G, Geocadin R, Ghajar J, Harris O, Hoffer A, Hutchinson P, Joseph M, Kitagawa R, Manley G, Mayer S, Menon DK, Meyfroidt G, Michael DB, Oddo M, Okonkwo D, Patel M, Robertson C, Rosenfeld JV, Rubiano AM, Sahuquillo J, Servadei F, Shutter L, Stein D, Stocchetti N, Taccone FS, Timmons S, Tsai E, Ullman JS, Vespa P, Videtta W, Wright DW, Zammit C, Chesnut RM (2019) A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med 45:1783–1794
Chesnut R, Aguilera S, Buki A, Bulger E, Citerio G, Cooper DJ, Arrastia RD, Diringer M, Figaji A, Gao G, Geocadin R, Ghajar J, Harris O, Hoffer A, Hutchinson P, Joseph M, Kitagawa R, Manley G, Mayer S, Menon DK, Meyfroidt G, Michael DB, Oddo M, Okonkwo D, Patel M, Robertson C, Rosenfeld JV, Rubiano AM, Sahuquillo J, Servadei F, Shutter L, Stein D, Stocchetti N, Taccone FS, Timmons S, Tsai E, Ullman JS, Vespa P, Videtta W, Wright DW, Zammit C, Hawryluk GWJ (2020) A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med 46:919–929
Åkerlund CA, Donnelly J, Zeiler FA, Helbok R, Holst A, Cabeleira M et al (2020) 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 15:e0243427
Güiza F, Depreitere B, Piper I et al (2015) Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury. Intensive Care Med 41:1067–1076. https://doi.org/10.1007/s00134-015-3806-1
Launey Y, Fryer TD, Hong YT, Steiner LA, Nortje J, Veenith TV, Hutchinson PJ, Ercole A, Gupta AK, Aigbirhio FI, Pickard JD, Coles JP, Menon DK (2020) Spatial and temporal pattern of ischemia and abnormal vascular function following traumatic brain injury. JAMA Neurol 77(3):339–349
Hermanides J, Hong YT, Trivedi M, Outtrim JG, Aigbirhio FI, Nestor PJ, Guilfoyle M, Winzeck S, Newcombe SFJ, Das T, Correia MM, Carpenter KLH, Hutchinson PJA, Gupta AK, Fryer TD, Pickard JD, Menon DK, Coles JP (2021) Metabolic derangements are associated with impaired glucose delivery following traumatic brain injury. Brain. https://doi.org/10.1093/brain/awab255
Calviello LA, Donnelly J, Zeiler FA, Thelin EP, Smielewski P, Czosnyka M (2017) Cerebral autoregulation monitoring in acute traumatic brain injury: what’s the evidence? Minerva Anestesiol 83(8):844–857. https://doi.org/10.23736/S0375-9393.17.12043-2
Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Joint Section on Neurotrauma Critical Care--AANS CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW (2007) Guidelines for the management of severe traumatic brain injury. J Neurotrauma 24(Suppl 1):S1-106
Sorrentino E, Diedler J, Kasprowicz M, Budohoski KP, Haubrich C, Smielewski P, Outtrim JG, Manktelow A, Hutchinson PJ, Pickard JD, Menon DK, Czosnyka M (2012) Critical thresholds for cerebrovascular reactivity after traumatic brain injury. Neurocrit Care 16(2):258–266. https://doi.org/10.1007/s12028-011-9630-8
Tas J, Beqiri E, van Kaam RCR, Czosnyka M, Donnelly J, Haeren RH, van der Horst ICC, Hutchinson PJAH, van Kuijk SMJ, Liberti AL, Menon DK, Hoedemaekers CWE, Depreitere B, Smielewski P, Meyfroidt G, Ercole A, Aries MJH (2021) Targeting autoregulation-guided cerebral perfusion pressure after traumatic brain injury (COGiTATE): a feasibility randomized controlled clinical trial. J Neurotrauma 38(20):2790–2800
Klein SP, Depreitere B, Meyfroidt G (2019) How I monitor cerebral autoregulation. Crit Care 23(1):160. https://doi.org/10.1186/s13054-019-2454-1
Smith M, Maas AIR (2019) An algorithm for patients with intracranial pressure monitoring: filling the gap between evidence and practice. Intensive Care Med 45:1819–1821
Wiegers EJA, Lingsma HF, Huijben JA, Cooper DJ, Citerio G, Frisvold S, Helbok R, Maas AIR, Menon DK, Moore EM, Stocchetti N, Dippel DW, Steyerberg EW, van der Jagt M, CENTER-TBI; OzENTER-TBI Collaboration Groups (2021) Fluid balance and outcome in critically ill patients with traumatic brain injury (CENTER-TBI and OzENTER-TBI): a prospective, multicentre, comparative effectiveness study. Lancet Neurol 20(8):627–638. https://doi.org/10.1016/S1474-4422(21)00162-9
Huijben JA, Volovici V, Cnossen MC, Haitsma IK, Stocchetti N, Maas AIR, Menon DK, Ercole A, Citerio G, Nelson D, Polinder S, Steyerberg EW, Lingsma HF, van Jagt M, CENTER-TBI investigators and participants (2018) Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Crit Care 22(1):90
Castle-Kirszbaum M, Parkin WG, Goldschlager T, Lewis PM (2021) Cardiac output and cerebral blood flow: a systematic review of cardio-cerebral coupling. J Neurosurg Anesthesiol. https://doi.org/10.1097/ANA.0000000000000768
Thorup L, Koch KU, Upton RN, Østergaard L, Rasmussen M (2020) Effects of vasopressors on cerebral circulation and oxygenation: a narrative review of pharmacodynamics in health and traumatic brain injury. J Neurosurg Anesthesiol 32(1):18–28
Steiner LA, Siegemund M (2019) Vasoactive agents to improve brain perfusion: pathophysiology and clinical utilization. Curr Opin Crit Care 25(2):110–116
Steiner LA, Johnston AJ, Czosnyka M, Chatfield DA, Salvador R, Coles JP, Gupta AK, Pickard JD, Menon DK (2004) Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med 32(4):1049–1054
Bouras M, Roquilly A, Mahé PJ, Cinotti R, Vourc’h M, Perrot B, Bach-Ngohou K, Masson D, Asehnoune K (2019) Cortisol total/CRP ratio for the prediction of hospital-acquired pneumonia and initiation of corticosteroid therapy in traumatic brain-injured patients. Crit Care 23(1):394
Depreitere B, Meyfroidt G, Güiza F (2018) What do we mean by cerebral perfusion pressure? Acta Neurochir Suppl 126:201–203
Le Roux P, Menon DK, Citerio G, Vespa P, Bader MK, Brophy GM, Diringer MN, Stocchetti N, Videtta W, Armonda R, Badjatia N, Böesel J, Chesnut R, Chou S, Claassen J, Czosnyka M, De Georgia M, Figaji A, Fugate J, Helbok R, Horowitz D, Hutchinson P, Kumar M, McNett M, Miller C, Naidech A, Oddo M, Olson D, O’Phelan K, Provencio JJ, Puppo C, Riker R, Robertson C, Schmidt M, Taccone F, Neurocritical Care Society; European Society of Intensive Care Medicine (2014) Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: a statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine. Intensive Care Med 40(9):1189–1209
Stiefel MF, Spiotta A, Gracias VH, Garuffe AM, Guillamondegui O, Maloney-Wilensky E, Bloom S, Grady MS, LeRoux PD (2005) Reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring. J Neurosurg 103(5):805–811
Spiotta AM, Stiefel MF, Gracias VH, Garuffe AM, Kofke WA, Maloney-Wilensky E, Troxel AB, Levine JM, Le Roux PD (2010) Brain tissue oxygen-directed management and outcome in patients with severe traumatic brain injury. J Neurosurg 113(3):571–580. https://doi.org/10.3171/2010.1.JNS09506
Okonkwo DO, Shutter LA, Moore C, Temkin NR, Puccio AM, Madden CJ, Andaluz N, Chesnut RM, Bullock MR, Grant GA, McGregor J, Weaver M, Jallo J, LeRoux PD, Moberg D, Barber J, Lazaridis C, Diaz-Arrastia RR (2017) Brain oxygen optimization in severe traumatic brain injury phase-II: A PHASE II RANDOMIZED TRIAL. Crit Care Med 45(11):1907–1914
BOOST-3 | SIREN [Internet] (2021). https://siren.network/clinical-trials/boost-3. Accessed 10 Dec 2021
BONANZA-ANZICS [Internet] (2021). https://www.anzics.com.au/current-active-endorsed-research/bonanza/. Accessed 10 Dec 2021
Payen J-F, Richard M, Francony G et al (2020) Comparison of strategies for monitoring and treating patients at the early phase of severe traumatic brain injury: the multicentre randomised controlled OXY-TC trial study protocol. BMJ Open 10:e040550
Timofeev I, Carpenter KL, Nortje J, Al-Rawi PG, O’Connell MT, Czosnyka M, Smielewski P, Pickard JD, Menon DK, Kirkpatrick PJ, Gupta AK, Hutchinson PJ (2011) Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain 134(Pt 2):484–494. https://doi.org/10.1093/brain/awq353
Hutchinson PJ, Jalloh I, Helmy A, Carpenter KL, Rostami E, Bellander BM, Boutelle MG, Chen JW, Claassen J, Dahyot-Fizelier C, Enblad P, Gallagher CN, Helbok R, Hillered L, Le Roux PD, Magnoni S, Mangat HS, Menon DK, Nordström CH, O’Phelan KH, Oddo M, Perez Barcena J, Robertson C, Ronne-Engström E, Sahuquillo J, Smith M, Stocchetti N, Belli A, Carpenter TA, Coles JP, Czosnyka M, Dizdar N, Goodman JC, Gupta AK, Nielsen TH, Marklund N, Montcriol A, O’Connell MT, Poca MA, Sarrafzadeh A, Shannon RJ, Skjøth-Rasmussen J, Smielewski P, Stover JF, Timofeev I, Vespa P, Zavala E, Ungerstedt U (2015) Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med 41(9):1517–1528. https://doi.org/10.1007/s00134-015-3930-y.PMID:26194024;PMCID:PMC4550654
Graham NSN, Zimmerman KA, Moro F, Heslegrave A, Maillard SA, Bernini A, Miroz JP, Donat CK, Lopez MY, Bourke N, Jolly AE, Mallas EJ, Soreq E, Wilson MH, Fatania G, Roi D, Patel MC, Garbero E, Nattino G, Baciu C, Fainardi E, Chieregato A, Gradisek P, Magnoni S, Oddo M, Zetterberg H, Bertolini G, Sharp DJ (2021) Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury. Sci Transl Med 13(613):eabg9922. https://doi.org/10.1126/scitranslmed.abg9922
Morelli P, Oddo M, Ben-Hamouda N (2019) Role of automated pupillometry in critically ill patients. Minerva Anestesiol 85:995–1002
Martínez-Ricarte F, Castro A, Poca MA, Sahuquillo J, Expósito L, Arribas M et al (2013) Infrared pupillometry. Basic principles and their application in the non-invasive monitoring of neurocritical patients. Neurologia 28:41–51
Kerr RG, Bacon AM, Baker LL, Gehrke JS, Hahn KD, Lillegraven CL et al (2016) Underestimation of pupil size by critical care and neurosurgical nurses. Am J Crit Care 25:213–219
Meeker M, Du R, Bacchetti P, Privitera CM, Larson MD, Holland MC et al (2005) Pupil examination: validity and clinical utility of an automated pupillometer. J Neurosci Nurs 37:34–40
Robba C, Pozzebon S, Moro B, Vincent JL, Creteur J, Taccone FS (2020) Multimodal non-invasive assessment of intracranial hypertension: an observational study. Crit Care 24:379
Oddo M, Taccone F, Galimberti S, Rebora P, Citerio G (2021) Outcome Prognostication of Acute Brain Injury using the Neurological Pupil Index (ORANGE) study: protocol for a prospective, observational, multicentre, international cohort study. BMJ Open. https://doi.org/10.1136/bmjopen-2020-046948]
Oddo M, Sandroni C, Citerio G, Miroz JP, Horn J, Rundgren M, Cariou A, Payen JF, Storm C, Stammet P, Taccone FS (2018) Quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicenter double-blinded study. Intensive Care Med 44(12):2102–2111
Robba C, Goffi A, Geeraerts T, Cardim D, Via G, Czosnyka M, Park S, Sarwal A, Padayachy L, Rasulo F, Citerio G (2019) Brain ultrasonography: methodology, basic and advanced principles and clinical applications. A narrative review. Intensive Care Med 45(7):913–927
Robba C, Santori G, Czosnyka M, Corradi F, Bragazzi N, Padayachy L et al (2018) Optic nerve sheath diameter measured sonographically as non-invasive estimator of intracranial pressure: a systematic review and meta-analysis. Intensive Care Med 44:1284–1294
Rasulo FA, Bertuetti R, Robba C, Lusenti F, Cantoni A, Bernini M et al (2017) The accuracy of transcranial Doppler in excluding intracranial hypertension following acute brain injury: a multicenter prospective pilot study. Crit Care 21:44
Vespa PM, Nuwer MR, Nenov V et al (1999) Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J Neurosurg 91:750–760
Dreier JP, Fabricius M, Ayata C, Sakowitz OW, Shuttleworth CW, Dohmen C et al (2017) Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the cosbid research group. J Cereb Blood Flow Metab 37:1595–1625
Robba C, Rebora P, Banzato E, Wiegers EJA, Stocchetti N, Menon DK, Citerio G, Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Participants and Investigators (2020) Incidence, risk factors, and effects on outcome of ventilator-associated pneumonia in patients with traumatic brain injury: analysis of a large, multicenter, prospective, observational longitudinal study. Chest 158(6):2292–2303. https://doi.org/10.1016/j.chest.2020.06.064
Robba C, Poole D, McNett M, Asehnoune K, Bösel J, Bruder N et al (2020) Mechanical ventilation in patients with acute brain injury: recommendations of the European Society of Intensive Care Medicine consensus. Intensive Care Med 46:2397–2410
Dauwe DF, Gunst J, Vlasselaers D, Meyfroidt G (2021) Propofol-infusion syndrome in traumatic brain injury: consider the ECMO option. Intensive Care Med 47(1):127–129. https://doi.org/10.1007/s00134-020-06280-3
Citerio G, Robba C, Rebora P et al (2021) Management of arterial partial pressure of carbon dioxide in the first week after traumatic brain injury: results from the CENTER-TBI study. Intensive Care Med 47:961–973. https://doi.org/10.1007/s00134-021-06470-7
Oddo M, Poole D, Helbok R, Meyfroidt G, Stocchetti N, Bouzat P, Cecconi M, Geeraerts T, Martin-Loeches I, Quintard H, Taccone FS, Geocadin RG, Hemphill C, Ichai C, Menon D, Payen JF, Perner A, Smith M, Suarez J, Videtta W, Zanier ER, Citerio G (2018) Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med 44(4):449–463
Roquilly A, Moyer JD, Huet O, Lasocki S, Cohen B, Dahyot-Fizelier C, Chalard K, Seguin P, Jeantrelle C, Vermeersch V, Gaillard T, Cinotti R, Demeure Dit Latte D, Mahe PJ, Vourc’h M, Martin FP, Chopin A, Lerebourg C, Flet L, Chiffoleau A, Feuillet F, Asehnoune K (2021) Effect of continuous infusion of hypertonic saline vs standard care on 6-month neurological outcomes in patients with traumatic brain injury: the COBI randomized clinical trial. JAMA 325(20):2056–2066. https://doi.org/10.1001/jama.2021.5561
Poole D, Citerio G, Helbok R, Ichai C, Meyfroidt G, Oddo M, Payen J-F, Stocchetti N (2020) Evidence for mannitol as an effective agent against intracranial hypertension: an individual patient data meta-analysis. Neurocrit Care 32(1):252–261
Rowland MJ, Veenith T, Scomparin C et al (2019) Sugar or Salt (“SOS”): a protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension. medRxiv. https://doi.org/10.1101/19008276
Huijben JA, van der Jagt M, Cnossen MC, Kruip MJHA, Haitsma IK, Stocchetti N, Maas AIR, Menon DK, Ercole A, Maegele M, Stanworth SJ, Citerio G, Polinder S, Steyerberg EW, Lingsma HF, CENTER-TBI Investigators and Participants (2018) Variation in blood transfusion and coagulation management in traumatic brain injury at the intensive care unit: a survey in 66 neurotrauma centers participating in the Collaborative European Neuro Trauma Effectiveness Research in Traumatic Brain Injury Study. J Neurotrauma 35(2):323–332. https://doi.org/10.1089/neu.2017.5194
Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, Epo Severe TBI Trial Investigators, Baldwin A, Rivera-Lara L, Saucedo-Crespo H, Ahmed O, Sadasivan S, Ponce L, Cruz-Navarro J, Shahin H, Aisiku IP, Doshi P, Valadka A, Neipert L, Waguspack JM, Rubin ML, Benoit JS, Swank P (2014) Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312(1):36–47
Gobatto ALN, Link MA, Solla DJ, Bassi E, Tierno PF, Paiva W, Taccone FS, Malbouisson LM (2019) Transfusion requirements after head trauma: a randomized feasibility controlled trial. Crit Care 23(1):89
Robba C, Banzato E, Rebora P, Iaquaniello C, Huang CY, Wiegers EJA, Meyfroidt G, Citerio G, Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) ICU Participants and Investigators (2021) Acute kidney injury in traumatic brain injury patients: results from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study. Crit Care Med 49(1):112–126
Luu D, Komisarow J, Mills BM, Vavilala MS, Laskowitz DT, Mathew J, James ML, Hernandez A, Sampson J, Fuller M, Ohnuma T, Raghunathan K, Privratsky J, Bartz R, Krishnamoorthy V (2021) Association of severe acute kidney injury with mortality and healthcare utilization following isolated traumatic brain injury. Neurocrit Care. https://doi.org/10.1007/s12028-020-01183-z
Skrifvars MB, Bailey M, Moore E, Mårtensson J, French C, Presneill J, Nichol A, Little L, Duranteau J, Huet O, Haddad S, Arabi YM, McArthur C, Cooper DJ, Bendel S, Bellomo R, Erythropoietin in Traumatic Brain Injury (EPO-TBI) Investigators and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group (2021) A post hoc analysis of osmotherapy use in the erythropoietin in traumatic brain injury study-associations with acute kidney injury and mortality. Crit Care Med 49(4):e394–e403
Yamane DP, Maghami S, Graham A, Vaziri K, Davison D (2020) Association of hyperchloremia and acute kidney injury in patients with traumatic brain injury. J Intensive Care Med 7:885066620978735. https://doi.org/10.1177/0885066620978735
Hefny F, Stuart A, Kung JY, Mahmoud SH (2022) Prevalence and risk factors of augmented renal clearance: a systematic review and meta-analysis. Pharmaceutics 14(2):445. https://doi.org/10.3390/pharmaceutics14020445
McGeown JP, Hume PA, Theadom A, Quarrie KL, Borotkanics R (2021) Nutritional interventions to improve neurophysiological impairments following traumatic brain injury: a systematic review. J Neurosci Res 99(2):573–603
Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, Hiesmayr M, Mayer K, Montejo JC, Pichard C et al (2018) ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. https://doi.org/10.1016/j.clnu.2018.08.037
Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H (2020) Early enteral nutrition in patients with severe traumatic brain injury: a propensity score-matched analysis using a nationwide inpatient database in Japan. Am J Clin Nutr 111(2):378–384
Reintam BA, Starkopf J, Alhazzani W, Berger MM, Casaer MP, Deane AM, Fruhwald S, Hiesmayr M, Ichai C, Jakob SM et al (2017) Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med 43(3):380–398
Ridley EJ, Davies AR, Bernard S, McArthur C, Murray L, Paul E, Trapani A, Cooper DJ, Group ACT (2021) Measured energy expenditure in mildly hypothermic critically ill patients with traumatic brain injury: a sub-study of a randomized controlled trial. Clin Nutr 40(6):3875–3882
Casaer MP, Bellomo R (2019) Micronutrient deficiency in critical illness: an invisible foe? Intensive Care Med 45(8):1136–1139
Vankrunkelsven W, Gunst J, Amrein K, Bear DE, Berger MM, Christopher KB, Fuhrmann V, Hiesmayr M, Ichai C, Jakob SM et al (2020) Monitoring and parenteral administration of micronutrients, phosphate, and magnesium in critically ill patients: the VITA-TRACE survey. Clin Nutr***
Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ (2005) Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64(8):1348–1353
Zhu C, Chen J, Pan J, Qiu Z, Xu T (2018) Therapeutic effect of intensive glycemic control therapy in patients with traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 97(30):e11671
Australian and New Zealand Intensive Care Society Clinical Trials Group and the Canadian Critical Care Trials Group, Finfer S, Chittock D, Li Y, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Hebert P, Henderson W, Heyland D, Higgins A, McArthur C, Mitchell I, Myburgh J, Robinson B, Ronco J (2015) Intensive versus conventional glucose control in critically ill patients with traumatic brain injury: long-term follow-up of a subgroup of patients from the NICE-SUGAR study. Intensive Care Med 41(6):1037–1047. https://doi.org/10.1007/s00134-015-3757-6
Hermanides J, Plummer MP, Finnis M, Deane AM, Coles JP, Menon DK (2018) Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis. Crit Care 22(1):11. https://doi.org/10.1186/s13054-017-1883-y
Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, Spears L, Miller M, Franczyk M, Deprizio D, Schmidt GA, Bowman A, Barr R, McCallister KE, Hall JB, Kress JP (2009) Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 373(9678):1874–1882
Riberholt CG, Wagner V, Lindschou J, Gluud C, Mehlsen J, Møller K (2020) Early head-up mobilisation versus standard care for patients with severe acquired brain injury: a systematic review with meta-analysis and Trial Sequential Analysis. PLoS ONE 15(8):e0237136
Bartolo M, Bargellesi S, Castioni CA, Intiso D, Fontana A, Copetti M, Scarponi F, Bonaiuti D, Intensive Care and Neurorehabilitation Italian Study Group (2017) Mobilization in early rehabilitation in intensive care unit patients with severe acquired brain injury: an observational study. J Rehabil Med 49(9):715–722. https://doi.org/10.2340/16501977-2269
Riberholt CG, Olsen MH, Søndergaard CB, Gluud C, Ovesen C, Jakobsen JC, Mehlsen J, Møller K (2021) Early orthostatic exercise by head-up tilt with stepping vs. standard care after severe traumatic brain injury is feasible. Front Neurol 12:626014
Borgen IMH, Røe C, Brunborg C, Tenovuo O, Azouvi P, Dawes H, Majdan M, Ranta J, Rusnak M, Wiegers EJA, Tverdal C, Jacob L, Cogné M, von Steinbuechel N, Andelic N (2021) Care transitions in the first 6months following traumatic brain injury: lessons from the CENTER-TBI study. Ann Phys Rehabil Med 64(6):101458
Turner-Stokes L, Pick A, Nair A, Disler PB, Wade DT (2015) Multi-disciplinary rehabilitation for acquired brain injury in adults of working age. Cochrane Database Syst Rev 12:CD004170
Kornblith LZ, Moore HB, Cohen MJ (2019) Trauma-induced coagulopathy: the past, present, and future. J Thromb Haemost 17(6):852–862
Moore EE, Moore HB, Kornblith LZ, Neal MD, Hoffman M, Mutch NJ et al (2021) Trauma-induced coagulopathy. Nat Rev Dis Primers 7(1):30
CRASH-3 Trial Collaborators (2019) Effects of tranexamic acid on death, disability, vascular occlusive events, and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 394(10210):1713–1723
Lawati KA, Sharif S, Maqbali SA et al (2021) Efficacy and safety of tranexamic acid in acute traumatic brain injury: a systematic review and meta-analysis of randomized-controlled trials. Intensive Care Med 47:14–27. https://doi.org/10.1007/s00134-020-06279-w
Taccone FS, Citerio G, Stocchetti N (2020) Is tranexamic acid going to CRASH the management of traumatic brain injury? Intensive Care Med 46:1261–1263. https://doi.org/10.1007/s00134-019-05879-5
Spahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ et al (2019) The European guideline on management of major bleeding and coagulopathy following trauma; fifth edition. Crit Care 23(1):98
Maegele M, Schöchl H, Menovsky T, Maréchal H, Marklund N, Buki A et al (2017) Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol 16(8):630–647
Gruen DS, Guyette FX, Brown JB, Okonkwo DO, Puccio AM, Campwala IK et al (2020) Association of prehospital plasma with survival in patients with traumatic brain injury: a secondary analysis of the PAMPer Cluster Randomized Clinical Trial. JAMA Netw Open 3(10):e2016869
Jamjoom AAB, Chari A, Salijevska J, Meacher R, Brennan P, Statham P (2016) A national survey of thromboprophylaxis in traumatic brain injury in the United Kingdom. Br J Neurosurg 30(2):240–245
Robba C, Bonatti G, Pelosi P, Citerio G (2020) Extracranial complications after traumatic brain injury: targeting the brain and the body. Curr Opin Critic Care. https://doi.org/10.1097/MCC.0000000000000707
Needham EJ, Stoevesandt O, Thelin EP, Zetterberg H, Zanier ER, Al Nimer F, Ashton NJ, Outtrim JG, Newcombe VFJ, Mousa HS, Simrén J, Blennow K, Yang Z, Hutchinson PJ, Piehl F, Helmy AE, Taussig MJ, Wang KKW, Jones JL, Menon DK, Coles AJ (2021) Complex autoantibody responses occur following moderate to severe traumatic brain injury. J Immunol 207(1):90–100. https://doi.org/10.4049/jimmunol.2001309
Rass V, Huber L, Ianosi B-A et al (2021) The effect of temperature increases on brain tissue oxygen tension in patients with traumatic brain injury: a Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Substudy. Ther Hypothermia Temp Manag 11:122–131
Yokobori S, Yokota H (2016) Targeted temperature management in traumatic brain injury. J Intensive Care 4:28. https://doi.org/10.1186/s40560-016-0137-4
van Veen E, van der Jagt M, Citerio G, Stocchetti N, Gommers D, Burdorf A, Menon DK, Maas AIR, Kompanje EJO, Lingsma HF, CENTER-TBI investigators and participants (2021) Occurrence and timing of withdrawal of life-sustaining measures in traumatic brain injury patients: a CENTER-TBI study. Intensive Care Med. https://doi.org/10.1007/s00134-021-06484-1
Izzy S, Compton R, Carandang R et al (2013) Self-fulfilling prophecies through withdrawal of care: do they exist in traumatic brain injury, too? Neurocrit Care 19:347–363. https://doi.org/10.1007/s12028-013-9925-z
Dijkland SA, Foks KA, Polinder S, Dippel DWJ, Maas AIR, Lingsma HF, Steyerberg EW (2020) Prognosis in moderate and severe traumatic brain injury: a systematic review of contemporary models and validation studies. J Neurotrauma 37(1):1–13. https://doi.org/10.1089/neu.2019.6401
Lingsma HF, Roozenbeek B, Steyerberg EW, Murray GD, Maas AI (2010) Early prognosis in traumatic brain injury: from prophecies to predictions. Lancet Neurol 9(5):543–554. https://doi.org/10.1016/S1474-4422(10)70065-X
Haghbayan H, Boutin A, Laflamme M, Lauzier F, Shemilt M, Moore L, Zarychanski R, Douville V, Fergusson D, Turgeon AF (2017) The prognostic value of MRI in moderate and severe traumatic brain injury: a systematic review and meta-analysis. Crit Care Med 45(12):e1280–e1288. https://doi.org/10.1097/CCM.0000000000002731
Moe HK, Follestad T, Andelic N, Håberg AK, Flusund AH, Kvistad KA, Saksvoll EH, Olsen Ø, Abel-Grüner S, Sandrød O, Skandsen T, Vik A, Moen KG (2020) Traumatic axonal injury on clinical MRI: association with the Glasgow Coma Scale score at scene of injury or at admission and prolonged posttraumatic amnesia. J Neurosurg. https://doi.org/10.3171/2020.6.JNS20112
Izzy S, Mazwi NL, Martinez S, Spencer CA, Klein JP, Parikh G, Glenn MB, Greenberg SM, Greer DM, Wu O, Edlow BL (2017) Revisiting grade 3 diffuse axonal injury: not all brainstem microbleeds are prognostically equal. Neurocrit Care 27(2):199–207. https://doi.org/10.1007/s12028-017-0399-2
Puybasset L, Perlbarg V, Unrug J, Cassereau D, Galanaud D, Torkomian G, Battisti V, Lefort M, Velly L, Degos V, Citerio G, Bayen É, Pelegrini-Issac M, MRI-COMA Investigators CENTER-TBI MRI Participants and MRI Only Investigators (2022) Prognostic value of global deep white matter DTI metrics for 1-year outcome prediction in ICU traumatic brain injury patients: an MRI-COMA and CENTER-TBI combined study. Intensive Care Med. https://doi.org/10.1007/s00134-021-06583-z
Claassen J, Doyle K, Matory A, Couch C, Burger KM, Velazquez A, Okonkwo JU, King JR, Park S, Agarwal S, Roh D, Megjhani M, Eliseyev A, Connolly ES, Rohaut B (2019) Detection of brain activation in unresponsive patients with acute brain injury. N Engl J Med 380(26):2497–2505
Whitehouse DP, Monteiro M, Czeiter E, Vyvere TV, Valerio F, Ye Z, Amrein K, Kamnitsas K, Xu H, Yang Z, Verheyden J, Das T, Kornaropoulos EN, Steyerberg E, Maas AIR, Wang KKW, Büki A, Glocker B, Menon DK, Newcombe VFJ, CENTER-TBI Participants and Investigators (2022) Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: a CENTER-TBI study. EBioMedicine 75:103777. https://doi.org/10.1016/j.ebiom.2021.103777
Depreitere B, Meyfroidt G, Roosen G, Ceuppens J, Grandas FG (2012) Traumatic brain injury in the elderly: a significant phenomenon. Acta Neurochir Suppl 114:289–294. https://doi.org/10.1007/978-3-7091-0956-4_56
Galimberti S, Graziano F, Maas AIR, Isernia G, Lecky F, Jain S, Sun X, Gardner RC, Taylor SR, Markowitz AJ, Manley GT, Valsecchi MG, Bellelli G, Citerio G (2022) Effect of frailty on 6-month outcome after traumatic brain injury: a multicentre cohort study with external validation. Lancet Neurol 21(2):153–162. https://doi.org/10.1016/S1474-4422(21)00374-4
Güiza F, Depreitere B, Piper I, Van den Berghe G, Meyfroidt G (2013) Novel methods to predict increased intracranial pressure during intensive care and long-term neurologic outcome after traumatic brain injury: development and validation in a multicenter dataset. Crit Care Med 41(2):554–564. https://doi.org/10.1097/CCM.0b013e3182742d0a
Carra G, Güiza F, Depreitere B, Meyfroidt G, CENTER-TBI High-Resolution ICU (HR ICU) Sub-Study Participants and Investigators (2021) Prediction model for intracranial hypertension demonstrates robust performance during external validation on the CENTER-TBI dataset. Intensive Care Med 47(1):124–126. https://doi.org/10.1007/s00134-020-06247-4
Dams-O’Connor K, Pretz C, Billah T, Hammond FM, Harrison-Felix C (2015) Global outcome trajectories after TBI among survivors and non-survivors: a National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems study. J Head Trauma Rehabil 30(4):E1-10
Dijkland SA, Helmrich I, Nieboer D et al (2021) Outcome prediction after moderate and severe traumatic brain injury: external validation of two established prognostic models in 1742 European patients. J Neurotrauma 38(10):1377–1388
Gardner RC, Cheng J, Ferguson AR et al (2019) Divergent six month functional recovery trajectories and predictors after traumatic brain injury: novel insights from the Citicoline Brain Injury Treatment Trial study. J Neurotrauma. https://doi.org/10.1089/neu.2018.6167
Harvey D, Butler J, Groves J et al (2018) Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations. Br J Anaesth 120(1):138–145
Nelson LD, Temkin NR, Dikmen S et al (2019) Recovery after mild traumatic brain injury in patients presenting to US level I trauma centers: a Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. JAMA Neurol 76(9):1049–1059
Steyerberg EW, Wiegers E, Sewalt C et al (2019) Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurol 18(10):923–934
Mikolić A, Polinder S, Steyerberg EW et al (2021) Prediction of global functional outcome and post-concussive symptoms after mild traumatic brain injury: external validation of prognostic models in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. J Neurotrauma 38(2):196–209
Wilson L, Stewart W, Dams-O’Connor K et al (2017) The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurol 16(10):813–825
Fann JR, Ribe AR, Pedersen HS et al (2018) Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study. Lancet Psychiatry 5(5):424–431
Nordström A, Nordström P (2018) Traumatic brain injury and the risk of dementia diagnosis: a nationwide cohort study. PLoS Med 15(1):e1002496
Barnes DE, Kaup A, Kirby KA, Byers AL, Diaz-Arrastia R, Yaffe K (2014) Traumatic brain injury and risk of dementia in older veterans. Neurology 83(4):312–319
Burns TC, Quinones-Hinojosa A (2021) Regenerative medicine for neurological diseases-will regenerative neurosurgery deliver? BMJ 373:n955. https://doi.org/10.1136/bmj.n955
Pischiutta F, Caruso E, Lugo A, Cavaleiro H, Stocchetti N, Citerio G, Salgado A, Gallus S, Zanier ER (2021) Systematic review and meta-analysis of preclinical studies testing mesenchymal stromal cells for traumatic brain injury. NPJ Regen Med 6(1):71. https://doi.org/10.1038/s41536-021-00182-8
Kawabori M, Weintraub AH, Imai H, Zinkevych L, McAllister P, Steinberg GK, Frishberg BM, Yasuhara T, Chen JW, Cramer SC et al (2021) Cell therapy for chronic TBI: interim analysis of the randomized controlled STEMTRA trial. Neurology. https://doi.org/10.1212/WNL.0000000000011450
Latchoumane C-FV, Betancur MI, Simchick GA, Sun MK, Forghani R, Lenear CE, Ahmed A, Mohankumar R, Balaji N, Mason HD et al (2021) Engineered glycomaterial implants orchestrate large-scale functional repair of brain tissue chronically after severe traumatic brain injury. Sci Adv 7:eabe0207. https://doi.org/10.1126/sciadv.abe0207
Xiong Y, Mahmood A, Chopp M (2010) Angiogenesis, neurogenesis, and brain recovery of function following injury. Curr Opin Investig Drugs Lond Engl 2000(11):298–308
Funding
No specific funding was obtained for this manuscript. Geert Meyfroidt is supported Flemish Government (Research Foundation–Flanders (FWO)), as Senior Clinical Researcher (1843118 N) and has project funding from the KU Leuven (C24/17/072).
Author information
Authors and Affiliations
Contributions
All authors have contributed to sections of the text. GM has written the first draft and drafted the final manuscript. First editing was done by GC. All authors have proofread the first draft and made corrections. All authors have read and approved the final draft.
Corresponding author
Ethics declarations
Conflict of interest
MPC receives funding from the Research Foundation Flanders (FWO) (Grant No. 1832817N) and Onderzoeksraad, KU Leuven (Grant No. C24/17/070) and from the Private Charity Organization “Help Brandwonden Kids”. AIRM declares receiving institutional support for CENTER-TBI from the European Union seventh Framework Program (grant 602150), and additional support from the Hannelore Kohl Stiftung (Germany), from OneMind (USA), from Integra LifeSciences Corporation (USA) and from NeuroTrauma Sciences (USA). Personal fees were received from PresuuraNeuro (DSMB) and NeuroTrauma Sciences, outside the scope of this work. DKM reports grants, consultancy fees, or payment for educational activity, from NeuroTrauma Sciences LLC, Lantmannen AB, GlaxoSmithKline Ltd, Calico LLC, Cortirio Ltd, all outside the submitted work. VFJN hold a grant from Roche Pharmaceuticals related to blood biomarkers and TBI. MO is consultant and member of Scientific Advisory Board of Neuroptics. MS is Editor-in-Chief of the Journal of Neurosurgical Anesthesiology. FST received lecture fees from INTEGRA and is Advisory Board Member from Neuroptics, all outside the submitted work. GC reports grants, personal fees as Speakers’ Bureau Member and Advisory Board Member from Integra and Neuroptics, all outside the submitted work. The other authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised: An incorrect version of the color legend of Figure 1 has been published.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Meyfroidt, G., Bouzat, P., Casaer, M.P. et al. Management of moderate to severe traumatic brain injury: an update for the intensivist. Intensive Care Med 48, 649–666 (2022). https://doi.org/10.1007/s00134-022-06702-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-022-06702-4