Cerebral Glucose Dynamics During Haemorrhagic Shock Resuscitation with Total Aortic Occlusion by REBOA

Cerebral Glucose Dynamics During Haemorrhagic Shock Resuscitation with Total Aortic Occlusion by REBOA | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebral Glucose Dynamics During Haemorrhagic Shock Resuscitation with Total Aortic Occlusion by REBOA Sam Er Bader, A Magnuson, C Brorsson, G Wallin, N Löfgren, F Löfgren, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9413974/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Adequate cerebral glucose (CGlu) availability is essential for maintaining neuronal function and cerebral energy homeostasis. During haemorrhagic shock (HS), impaired systemic perfusion and metabolic stress may compromise cerebral substrate delivery, even in the absence of direct brain injury. Resuscitative endovascular balloon occlusion of the aorta (REBOA) effectively restores proximal arterial pressure; however, its effects on cerebral glucose dynamics, particularly in the presence of elevated intracranial pressure, remain incompletely understood. Objective To investigate CGlu dynamics during HS and subsequent resuscitation with total REBOA (tREBOA), and to assess the influence of intracranial pressure (ICP) on cerebral metabolic responses. Methods In an established experimental porcine model, eighteen animals were subjected to controlled HS followed by resuscitation with tREBOA. Animals were assigned to either a normal intracranial pressure group (NICPG) or an elevated intracranial pressure group (EICPG). CGlu concentrations were measured using cerebral microdialysis throughout baseline, HS, and aortic occlusion (AO). Proximal mean arterial pressure (pMAP), ICP, and cerebral perfusion pressure (CPP) were continuously monitored. Data were analysed using linear mixed-effects models. Results HS was associated with a reduction in CGlu concentrations in both groups, indicating early cerebral metabolic stress. Following initiation of tREBOA, CPP increased markedly; however, CGlu concentrations did not immediately normalise, particularly in EICPG. Instead, CGlu availability demonstrated time-dependent changes during prolonged AO. No consistent differences in CGlu concentrations between groups were observed once perfusion pressure was restored. Conclusions In this experimental model of HS, tREBOA restored CPP and supported recovery of CGlu availability, even in the presence of elevated ICP. However, haemodynamic restoration was not accompanied by immediate metabolic normalization, demonstrating a dissociation between perfusion and CGlu regulation. These findings provide important physiological insights into the cerebral effects of tREBOA and support its cautious, time-limited use in complex trauma scenarios. Future studies incorporating systemic metabolic markers, hormonal profiling, and microcirculatory assessment may further clarify mechanisms underlying cerebral metabolic alterations during REBOA and help define metabolically guided resuscitation strategies. Resuscitative Endovascular Balloon Occlusion of the Aorta REBOA haemorrhagic shock cerebral microdialysis cerebral glucose Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Severe haemorrhagic shock (HS) remains a leading cause of early mortality following trauma and is frequently accompanied by traumatic brain injury (TBI) and intracranial hypertension. In this context, preservation of cerebral perfusion and prevention of secondary brain injury are critical determinants of neurological outcome ( 1 , 2 ). Even brief periods of inadequate cerebral substrate delivery may result in irreversible neuronal injury due to the brain’s limited intrinsic energy reserves ( 3 ). Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as an effective adjunct for temporary haemorrhage control and restoration of proximal arterial pressure during life-threatening non-compressible haemorrhage ( 4 , 5 ). By mechanically redistributing cardiac output toward the heart and brain, total REBOA (tREBOA) rapidly augments proximal mean arterial pressure (pMAP) and cerebral perfusion pressure (CPP). However, this intervention simultaneously excludes the splanchnic circulation, including the liver and pancreas, which play a central role in systemic glucose regulation through glycogenolysis, gluconeogenesis, and hormonal control ( 6 , 7 ). Cerebral glucose (CGlu) is the primary substrate for neuronal energy metabolism and is essential for maintaining membrane stability, synaptic transmission, and cellular homeostasis ( 8 , 9 ). Under physiological conditions, CGlu availability is tightly regulated to match metabolic demand. During systemic stress, however, impaired substrate delivery and increased energy requirements may precipitate cerebral metabolic crisis even in the absence of overt cerebral ischaemia ( 10 ). In polytrauma patients, HS frequently coexists with elevated intracranial pressure (ICP), a condition traditionally viewed as a relative or absolute contraindication to aortic occlusion (AO) due to concerns that supraphysiological pMAP may exacerbate intracranial haemorrhage, cerebral oedema, or blood brain barrier (BBB) disruption ( 11 – 13 ). Experimental studies have suggested that excessive pMAP during AO may impair cerebral autoregulation (CA) and alter cerebrovascular permeability, particularly in the injured brain ( 14 – 16 ). Cerebral microdialysis (CMD) provides a unique opportunity to assess cerebral energy metabolism at the tissue level by measuring extracellular glucose concentrations, which reflect the balance between systemic substrate availability, transport across the BBB, and cellular utilisation ( 17 , 18 ). Decreased CGlu measured by CMD is a sensitive marker of cerebral metabolic stress and has been associated with adverse neurological outcomes, even when conventional haemodynamic parameters appear adequate ( 19 , 20 ). Despite growing clinical use of REBOA, its effects on CGlu availability during HS particularly in the presence of elevated ICP remain poorly characterised. It is unclear whether restoration of CPP during tREBOA is accompanied by normalization of cerebral substrate availability, or whether metabolic disturbances persist despite haemodynamic recovery. Using an established experimental porcine model of HS resuscitated with tREBOA ( 21 ), the present study aimed to investigate CGlu dynamics during HS and subsequent AO using CMD. The primary objective was to characterise temporal changes in CGlu concentration during HS and tREBOA. A secondary objective was to compare CGlu dynamics between animals with normal and elevated ICP. Materials and Methods This study represents an analysis from an established experimental porcine model of HS resuscitated with tREBOA, as previously described in detail by Bader et al. (21). The present analysis specifically focused on CGlu dynamics assessed by CMD during HS and subsequent AO. Ethical Approval All experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments. Anaesthesia and Surgical Preparation For a detailed description of the protocol please see Bader et al. 2024 (21). General anaesthesia was induced and maintained according to the established protocol. Animals were intubated and mechanically ventilated to maintain normocapnia. Arterial and venous catheters were placed for haemodynamic monitoring, blood sampling, and controlled haemorrhage. A REBOA catheter was inserted via femoral arterial access using a cut-down technique and positioned in aortic Zone I. Correct positioning was confirmed prior to balloon inflation. An intraparenchymal catheter measuring ICP and temperature (PSO-PTT, Sophysa, Orsay, France) was calibrated according to the manufacturer’s instructions, introduced through the bolt to a depth of 25 mm into the brain, and connected to an ICP monitor (PSO-4000 Pressio 2, Sophysa, Orsay, France). A microdialysis catheter (70 Brain Catheter, M dialysis AB, Stockholm, Sweden) was introduced through the bolt into the brain, aiming at an insertion depth of approximately 25 mm. The microdialysis probe was perfused with Perfusion Fluid CNS (M dialysis Stockholm, Sweden) using a microdialysis pump (CMA 107; CMA/ Microdialysis Stockholm, Sweden at the flow rate of 2 µl/min. After at least one hour of stabilisation, microdialysis samples were taken at 5-minute intervals until the end of the experiment. The microdialysis samples were analysed for glucose using a CMA 600 Analyser (CMA Microdialysis AB, Stockholm, Sweden). Experimental Design and Timeline (Figure 1) Figure 1 Experimental design and timeline Eighteen pigs were randomly assigned to one of two experimental groups with eight animals in each: Normal ICP Group (NICPG) and elevated ICP group (EICPG). After 60 minutes of stabilisation, all animals subjected to controlled HS for 30 minutes by controlled withdrawal of blood to achieve a target pMAP of approximately 40 mmHg. ICP elevation was induced by the end of HS in the EICPG using an established epidural balloon inflation technique previously described (Bader et al., 2024). After completion of the haemorrhage phase, the tREBOA balloon was inflated to achieve complete AO, which was maintained for 90 minutes. pMAP and ICP were monitored continuously. CPP was calculated continuously and was defined as MAP- ICP. CMD samples for CGlu concentration collected with 5 minutes interval. Statistical Analysis Data were analysed using linear mixed-effects models to account for repeated measurements within individual animals. Time and experimental groups were included as fixed effects, and individual animals were included as random effects. All the measured time points on the timeline were compared to time 0 within each group and between the two groups. A p-value < 0.01 was considered statistically significant. Statistical analyses were performed with STATA release 17 (Stata Corp, College Station, TX). Results Eighteen animals were included in the analysis, with nine assigned to the normal intracranial pressure group (NICPG) and nine to the elevated intracranial pressure group (EICPG). All animals completed the experimental protocol. Figures 2–5 show cerebral haemodynamic variables (pMAP, ICP, CPP) and CGlu concentrations over time in the NICPG and EICPG during the bleeding phase (−30 to 0 min) and the AO period up to 90 minutes. Time 0 on the timeline represents the baseline. Cerebral glucose (CGlu) Figure 2 Figure 2 Cerebral Glucose vs time In the NICPG, CGlu slightly decreased during the bleeding phase from 0.19 mmol/L (95% CI: 0.55–5.62) to 0.17 mmol/L (95% CI: 0.48–2.29; p < 0.01). Following initiation of AO, CGlu increased and reached a peak value of 0.23 mmol/L at 25 minutes post-occlusion (p < 0.01). At 45 minutes, CGlu declined to levels comparable to those observed before bleeding and continued to decrease thereafter, reaching low levels at 90 minutes post-occlusion. However, no statistically significant differences were observed between any time point and baseline (T0). In the EICPG, CGlu decreased during the bleeding phase from 0.13 mmol/L (95% CI: 1.30–6.15) to 0.09 mmol/L (95% CI: 0.98–4.23; p < 0.01). CGlu remained markedly low during the first 30 minutes of AO before increasing to statistically significant levels, peaking at 0.18 mmol/L at 50 minutes (p < 0.01). Elevated CGlu concentrations persisted until approximately 80 minutes post-occlusion. Baseline CGlu concentrations were comparable between groups, with mean values of 0.19 mmol/L (95% CI: 0.55–2.62) in the NICPG and 0.13 mmol/L (95% CI: 1.30–6.15) in the EICPG, with no statistically significant difference between groups (p > 0.01). Direct comparisons between groups at corresponding time points revealed no statistically significant differences at the 0.01 level. Although numerically higher CGlu values were observed in the EICPG at several time points, confidence intervals overlapped throughout the observation period. Proximal mean arterial pressure (pMAP) Figure 3 Fig 3 Proximal Mean Arterial Pressure (pMAP) vs time At baseline, pMAP was comparable between groups and within the normal physiological range. During haemorrhage, pMAP decreased significantly in both groups. In the NICPG, pMAP declined from 95 mmHg to 49 mmHg at the onset of AO (p < 0.01). Similarly, in the EICPG, pMAP decreased from 91 mmHg to 46 mmHg prior to occlusion (p < 0.01). Following AO, pMAP increased rapidly in both groups. In the NICPG, pMAP peaked at approximately 129 mmHg 20 minutes post-occlusion and remained significantly elevated throughout the occlusion period. In contrast, the EICPG exhibited a more pronounced hypertensive response, with pMAP peaking at 168 mmHg at 15 minutes post-occlusion (p < 0.01). From 15 minutes onward, pMAP was significantly higher in the EICPG compared with the NICPG at multiple time points. Intracranial Pressure (ICP) Figure 4 Fig 4 Intracranial pressure (ICP) vs time In the NICPG, ICP remained stable throughout the experiment, with mean values ranging between 13 and 16 mmHg and no statistically significant deviations from baseline. In the EICPG, epidural balloon inflation resulted in a statistically significant increase in ICP prior to AO, rising to 29 mmHg at time zero (p < 0.01) and peaking at 38 mmHg at 5 minutes. Although ICP gradually decreased thereafter, it remained significantly higher than in the NICPG throughout the entire occlusion period. Cerebral Perfusion Pressure (CPP) Figure 5 Fig 5 Cerebral Perfusion Pressure (CPP) vs time During the haemorrhage phase, CPP declined markedly in both groups. In the NICPG, CPP decreased from approximately 78 mmHg at baseline to 32 mmHg at the onset of AO (p < 0.01). In the EICPG, CPP decreased to 16 mmHg prior to occlusion (p < 0.01). Following REBOA inflation, CPP increased rapidly in both groups. In the NICPG, CPP peaked at approximately 115 mmHg within 15–20 minutes post-occlusion and remained significantly elevated compared with baseline throughout the occlusion period. In the EICPG, CPP increased to a maximum of approximately 124 mmHg at 15 minutes post-occlusion and remained elevated thereafter. Apart from a transient early difference, no statistically significant between-group differences in CPP were observed during the occlusion phase. Discussion The results of this experimental study provide insight into CGlu dynamics during HS and subsequent resuscitation with tREBOA, particularly under different ICP conditions. By examining CGlu alongside key haemodynamic parameters pMAP, ICP, and CPP these findings highlight the complex relationship between systemic circulatory restoration and cerebral metabolic homeostasis (3, 10, 22). We demonstrate that tREBOA restores cerebral perfusion and supports partial cerebral metabolic recovery by increasing CGlu during HS, even in the presence of elevated ICP. Using CMD, we provide detailed temporal insight into the interplay between CGlu availability, haemodynamics, and ICP during HS and AO (17, 18). Glucose is the principal substrate for cerebral energy metabolism and is required for ATP-dependent processes such as Na+/K+ ATPase activity, which is essential for membrane stability and prevention of cellular injury (23). Because the brain has negligible intrinsic glucose stores, CGlu supply depends on systemic availability and transport across the BBB via specific glucose transporters, primarily GLUT1 and GLUT3 (24, 25). Cerebral extracellular glucose reflects the balance between systemic substrate availability, BBB transport, and cellular utilisation. Under physiological conditions, glucose homeostasis is tightly regulated through hepatic glucose production and pancreatic insulin secretion, maintaining relatively stable cerebral substrate delivery despite systemic fluctuations (3, 22, 26). During systemic stress, however, CGlu functions primarily as a marker of metabolic strain rather than a direct surrogate of cerebral perfusion. In the present study, CGlu decreased during HS, consistent with impaired substrate delivery during systemic hypovolaemia. This decline occurred before AO, indicating early cerebral metabolic stress even in brains with normal ICP (10, 19). Although compensatory mechanisms during HS aim to preserve cerebral blood flow through sympathetic activation and circulatory centralisation, preserved arterial pressure does not ensure adequate microcirculatory flow or substrate delivery (27). Cerebral metabolic disturbances may occur despite apparently adequate CPP (10). The more pronounced CGlu reduction observed in animals with elevated ICP suggests that intracranial hypertension further compromises effective substrate delivery, likely by reducing capillary perfusion gradients and impairing autoregulatory reserve (20). CGlu should therefore not be interpreted as an isolated cerebral variable but as the downstream expression of an integrated systemic cerebral metabolic axis (22, 26). Haemorrhagic shock (HS) CGlu availability is a key determinant of cerebral energy metabolism, particularly in states of systemic hypoperfusion such as HS (3). The reduction in CGlu concentration associated with low CPP during HS reflecting a critically reduced cerebral perfusion in both groups, however, most severe with critically low values in EICPG where hypotension is associated with intracranial hypertension (20). This pattern is consistent with reduced cerebral substrate delivery, microvascular dysfunction, and increased metabolic demand (10, 19). Reduced CGlu availability during HS is a recognised indicator of cerebral metabolic stress and may signal evolving metabolic crisis or ischaemia, particularly when CA is impaired. Cerebral ischaemia is typically associated with low brain tissue oxygen tension and glucose together with increased lactate/pyruvate ratio, reflecting a shift toward anaerobic metabolism (28-30). Under conditions of limited glucose availability, the brain can partially utilise alternative substrates such as lactate, pyruvate, and ketone bodies, although these pathways are less efficient and require additional metabolic processing (23, 24). Aortic occlusion (AO) After AO, pMAP increased rapidly and remained elevated, restoring CPP to supraphysiological levels and confirming effective proximal perfusion augmentation (5, 21, 31). The hypertensive response was greater in EICPG, likely reflecting both pMAP augmentation and Cushing-type reflex mechanisms (32). CGlu increased in both groups, but with different temporal profiles. In EICPG, CGlu rose modestly after AO, peaked approximately 25 minutes post-occlusion, and gradually declined thereafter. These changes did not differ significantly from pre-occlusion values, suggesting relatively preserved metabolic coupling between cerebral blood flow (CBF) and glucose utilisation. In contrast, the EICPG demonstrated a delayed but statistically significant CGlu increase, with persistently higher levels during early occlusion. This response likely reflects the combined effects of supraphysiological pMAP, elevated ICP and eventually altered CA (21, 32, 33). When blood pressure exceeds the autoregulatory range, CBF becomes pressure-passive, potentially increasing substrate delivery but also stressing the BBB (15, 34, 35). Between group comparisons did not show statistically significant CGlu differences at corresponding time points despite numerical separation at several intervals. This suggests that systemic metabolic consequences of tREBOA may outweigh the isolated effect of ICP when CPP is forcibly maintained. CMD measures extracellular concentration rather than metabolic flux; similar CGlu levels may therefore represent different metabolic states (17, 36). A central observation is the dissociation between haemodynamic recovery and cerebral metabolic response, particularly in the EICPG during early AO. Although pMAP and CPP were rapidly restored, CGlu did not normalise in parallel. Similar dissociations between perfusion metrics and metabolic status have been described in TBI and other critical illness states (10, 19). Pressure based metrics alone are therefore insufficient indicators of cerebral metabolic recovery, particularly when major metabolic organs are excluded from the circulation during AO (17, 22). The observed time dependent fluctuations in cerebral glucose during prolonged AO likely represent evolving metabolic responses to sustained circulatory redistribution and non-physiological conditions. tREBOA excludes the splanchnic circulation, including the liver and pancreas, thereby disrupting hepatic glucose output and insulin regulation. Consequently, CGlu during AO does not reflect normal metabolic regulation but rather the balance between restricted systemic metabolic control and ongoing cerebral demand (6, 7, 37). This mechanism provides a plausible physiologically explanation for delayed CGlu normalisation despite restored CPP, particularly in EICPG and highlighting the importance of occlusion duration. ICP remained stable in animals with normal baseline ICP, indicating that supraphysiological arterial pressures during AO did not independently destabilise intracranial dynamics. In contrast, ICP increased further after AO in the elevated ICP group and remained persistently higher, although this did not prevent CPP or CGlu recovery. Experimental and clinical data indicate that brain injury is associated with metabolic and perfusion heterogeneity extending beyond the primary lesion (10, 38). Despite sustained differences in ICP, CGlu concentrations were not consistently lower in the EICPG once cerebral perfusion pressure was restored. This suggests that intracranial pressure alone does not determine CGlu availability when perfusion pressure is forcibly maintained (19, 20). Importantly, similar CGlu concentrations should not be interpreted as evidence of similar metabolic states, as CMD reflects concentration rather than metabolic flux (17, 36). Limitations This study has several limitations. First, the controlled porcine model limits direct extrapolation to human trauma. Second, systemic glucose and insulin concentrations were not measured, restricting interpretation of systemic metabolic regulation. Third, CMD provides local rather than global metabolic information. Fourth, the model reflects an acute physiological scenario and does not address long-term neurological outcomes. Sixth, anaesthesia may have reduced absolute metabolic rates, although relative dynamic patterns were preserved. Seventh, fluid therapy, glucose administration, and vasoactive agents may have influenced haemodynamics and metabolism. Eighth, histological correlates were not assessed. And finally, the elevated ICP model represents only TBI with acute intracranial hypertension rather than traumatic brain injury in general. Conclusion In this experimental model of HS, tREBOA restored CPP and supported recovery of CGlu availability, even in the presence of elevated ICP. However, haemodynamic restoration was not accompanied by immediate metabolic normalization, demonstrating a dissociation between perfusion and cerebral glucose regulation. These findings provide important physiological insights into the cerebral effects of tREBOA and support its cautious, time-limited use in complex trauma scenarios. Future studies incorporating systemic metabolic markers, hormonal profiling, and microcirculatory assessment may further clarify mechanisms underlying cerebral metabolic alterations during tREBOA and help define metabolically guided resuscitation strategies. Abbreviations AO: Aortic Occlusion CA: Cerebral Autoregulation CBF: Cerebral Blood Flow CGlu: Cerebral Glucose CPP: Cerebral Perfusion pressure EICPG : Elevated Intracranial Pressure Group HS: Haemorrhagic shock ICP: Intracranial Pressure MAP: Mean Arterial Pressure NICPG : Normal Intracranial Pressure Group pMAP: Proximal Mean Arterial Pressure REBOA: Resuscitative Endovascular Balloon Occlusion of the Aorta TBI: Traumatic Brain Injury tREBOA: Total Resuscitative Endovascular Balloon Occlusion of the Aorta Declarations Ethical Approval All experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments. Funding Declaration This study was supported by grants from the County Council of Örebro Country OLL-961358 (2021-01-26), OLL-935974 (2020-03-17), OLL-934649), OLL-933525 (2019-10-31), OLL-942131 (2020-11-01 and OLL-836061 (2018-08-17), and from the County Council of Västerbotten Country RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07). Author Contribution - Authors' contributionsA: S Bader; B: Anders Magnuson; C: C Brorsson; D: N Löfgren; E: F Löfgren; F: P-J Blind; G: M Öman; H: M Olivecrona; I: G WallinA: Developed the theoretical formalism, conceived and planned the experiments, carried out the experiments, processed the experimental data and performed the analytic calculations, designed the figures, analysis and interpretation of the results, formulating the discussion, Wrote the manuscript with support from M Olivecrona and M Öman. B: Processed the experimental data and performed the analytic calculations, designed the figures. CDEF: Contributed in planning and performing the experiments.G: Developed the theoretical formalism, contributed in planning and performing the experiments, provided critical feedback and helped shape the research, discussed the results, supported S Bader in manuscript writing.H: Supervised the project, developed the theoretical formalism, conceived and planned the experiments, supervised the carrying out the experiments, contributed to the interpretation of the results and formulation of the discussion Supervised S Bader in the writing of the manuscript. I: Supervised S Bader in the writing of the manuscript. Acknowledgement - Clinical Trial Number:Not applicable.- Ethical Approval and Consent to participate:In this animal study , all experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments. Consent to participate is not applicable.- Consent for publication:No applicable- Availability of supporting data: All the experiments digital data is available in tables and can be provided when its needed.- Competing interests:No, I declare that the authors have no competing interests that might be perceived to influence the results and/or discussion reported in this paper.- Funding Declaration: This study was supported by grants from the County Council of Örebro Country OLL-961358 (2021-01-26), OLL-935974 (2020-03-17), OLL-934649), OLL-933525 (2019-10-31), OLL-942131 (2020-11-01 and OLL-836061 (2018-08-17), and from the County Council of Västerbotten Country RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07).- Authors' contributions:A: S Bader; B: Anders Magnuson; C: C Brorsson; D: N Löfgren; E: F Löfgren; F: P-J Blind; G: M Öman; H: M Olivecrona; I: G WallinA: Developed the theoretical formalism, conceived and planned the experiments, carried out the experiments, processed the experimental data and performed the analytic calculations, designed the figures, analysis and interpretation of the results, formulating the discussion, Wrote the manuscript with support from M Olivecrona and M Öman. B: Processed the experimental data and performed the analytic calculations, designed the figures. CDEF: Contributed in planning and performing the experiments.G: Developed the theoretical formalism, contributed in planning and performing the experiments, provided critical feedback and helped shape the research, discussed the results, supported S Bader in manuscript writing.H: Supervised the project, developed the theoretical formalism, conceived and planned the experiments, supervised the carrying out the experiments, contributed to the interpretation of the results and formulation of the discussion Supervised S Bader in the writing of the manuscript. I: Supervised S Bader in the writing of the manuscript.-Acknowledgements: Not Applicable.- Language editing:During the preparation of this work , the authors used AI tools in order to improve the language and readability of the manuscript. 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Coles JP, Fryer TD, Coleman MR, Smielewski P, Gupta AK, Minhas PS, et al. Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism. Crit Care Med. 2007;35(2):568–78. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 11 May, 2026 Reviewers agreed at journal 24 Apr, 2026 Reviewers invited by journal 22 Apr, 2026 Editor assigned by journal 15 Apr, 2026 Submission checks completed at journal 15 Apr, 2026 First submitted to journal 14 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9413974","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630867017,"identity":"39bf4c64-178f-43fd-b74a-18e9dd3aa007","order_by":0,"name":"Sam Er 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10:10:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9413974/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9413974/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108242225,"identity":"79d5caef-c68e-4bfd-b5ce-a8de6970604a","added_by":"auto","created_at":"2026-04-30 21:22:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34528,"visible":true,"origin":"","legend":"\u003cp\u003eExperimental design and timeline\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/6d49212ee16ee43397e343fb.png"},{"id":108491990,"identity":"8307b182-0c68-42e1-ab66-e7750432d745","added_by":"auto","created_at":"2026-05-05 09:56:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85739,"visible":true,"origin":"","legend":"\u003cp\u003eCerebral Glucose vs time\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/a47bf547952f1ccfa11f1ab0.png"},{"id":108242227,"identity":"59b3c36a-4d06-45bf-86a3-2d9b594d1ac1","added_by":"auto","created_at":"2026-04-30 21:22:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84081,"visible":true,"origin":"","legend":"\u003cp\u003eProximal\u003cstrong\u003e \u003c/strong\u003eMean Arterial Pressure (pMAP) vs time\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/271e654c8702ef093d7f836d.png"},{"id":108491508,"identity":"d9f4416f-ae80-4de1-87da-3f737665c6c7","added_by":"auto","created_at":"2026-05-05 09:54:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":90233,"visible":true,"origin":"","legend":"\u003cp\u003eIntracranial pressure (ICP) vs time\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/24b163dcbc3d70923b6d8dff.png"},{"id":108242229,"identity":"eba4faa7-6150-484e-9c9c-1a01bd9ed69a","added_by":"auto","created_at":"2026-04-30 21:22:41","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":83906,"visible":true,"origin":"","legend":"\u003cp\u003eCerebral Perfusion Pressure (CPP) vs time\u003c/p\u003e","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/f05ec73d142f75177da31e55.png"},{"id":108804371,"identity":"feb076cf-90d0-4044-934a-3c5fc1796f80","added_by":"auto","created_at":"2026-05-08 15:19:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":833813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9413974/v1/63c4040e-15ac-4d52-bde0-c15a94bbfbc0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebral Glucose Dynamics During Haemorrhagic Shock Resuscitation with Total Aortic Occlusion by REBOA","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSevere haemorrhagic shock (HS) remains a leading cause of early mortality following trauma and is frequently accompanied by traumatic brain injury (TBI) and intracranial hypertension. In this context, preservation of cerebral perfusion and prevention of secondary brain injury are critical determinants of neurological outcome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Even brief periods of inadequate cerebral substrate delivery may result in irreversible neuronal injury due to the brain\u0026rsquo;s limited intrinsic energy reserves (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eResuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as an effective adjunct for temporary haemorrhage control and restoration of proximal arterial pressure during life-threatening non-compressible haemorrhage (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). By mechanically redistributing cardiac output toward the heart and brain, total REBOA (tREBOA) rapidly augments proximal mean arterial pressure (pMAP) and cerebral perfusion pressure (CPP). However, this intervention simultaneously excludes the splanchnic circulation, including the liver and pancreas, which play a central role in systemic glucose regulation through glycogenolysis, gluconeogenesis, and hormonal control (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCerebral glucose (CGlu) is the primary substrate for neuronal energy metabolism and is essential for maintaining membrane stability, synaptic transmission, and cellular homeostasis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Under physiological conditions, CGlu availability is tightly regulated to match metabolic demand. During systemic stress, however, impaired substrate delivery and increased energy requirements may precipitate cerebral metabolic crisis even in the absence of overt cerebral ischaemia (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn polytrauma patients, HS frequently coexists with elevated intracranial pressure (ICP), a condition traditionally viewed as a relative or absolute contraindication to aortic occlusion (AO) due to concerns that supraphysiological pMAP may exacerbate intracranial haemorrhage, cerebral oedema, or blood brain barrier (BBB) disruption (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Experimental studies have suggested that excessive pMAP during AO may impair cerebral autoregulation (CA) and alter cerebrovascular permeability, particularly in the injured brain (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCerebral microdialysis (CMD) provides a unique opportunity to assess cerebral energy metabolism at the tissue level by measuring extracellular glucose concentrations, which reflect the balance between systemic substrate availability, transport across the BBB, and cellular utilisation (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Decreased CGlu measured by CMD is a sensitive marker of cerebral metabolic stress and has been associated with adverse neurological outcomes, even when conventional haemodynamic parameters appear adequate (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite growing clinical use of REBOA, its effects on CGlu availability during HS particularly in the presence of elevated ICP remain poorly characterised. It is unclear whether restoration of CPP during tREBOA is accompanied by normalization of cerebral substrate availability, or whether metabolic disturbances persist despite haemodynamic recovery.\u003c/p\u003e \u003cp\u003eUsing an established experimental porcine model of HS resuscitated with tREBOA (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), the present study aimed to investigate CGlu dynamics during HS and subsequent AO using CMD. The primary objective was to characterise temporal changes in CGlu concentration during HS and tREBOA. A secondary objective was to compare CGlu dynamics between animals with normal and elevated ICP.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis study represents an analysis from an established experimental porcine model of HS resuscitated with tREBOA, as previously described in detail by Bader et al. (21). The present analysis specifically focused on CGlu dynamics assessed by CMD during HS and subsequent AO.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical Approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnaesthesia and Surgical Preparation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor a detailed description of the protocol please see Bader et al. 2024 (21).\u003c/p\u003e\n\u003cp\u003eGeneral anaesthesia was induced and maintained according to the established protocol. Animals were intubated and mechanically ventilated to maintain normocapnia. Arterial and venous catheters were placed for haemodynamic monitoring, blood sampling, and controlled haemorrhage.\u003c/p\u003e\n\u003cp\u003eA REBOA catheter was inserted via femoral arterial access using a cut-down technique and positioned in aortic Zone I. Correct positioning was confirmed prior to balloon inflation.\u003c/p\u003e\n\u003cp\u003eAn intraparenchymal catheter measuring ICP and temperature (PSO-PTT, Sophysa, Orsay, France) was calibrated according to the manufacturer\u0026rsquo;s instructions, introduced through the bolt to a depth of 25 mm into the brain, and connected to an ICP monitor (PSO-4000 Pressio 2, Sophysa, Orsay, France).\u003c/p\u003e\n\u003cp\u003eA microdialysis catheter (70 Brain Catheter, M dialysis AB, Stockholm, Sweden) was introduced through the bolt into the brain, aiming at an insertion depth of approximately 25 mm. The microdialysis probe was perfused with Perfusion Fluid CNS (M dialysis Stockholm, Sweden) using a microdialysis pump (CMA 107; CMA/ Microdialysis Stockholm, Sweden at the flow rate of 2 \u0026micro;l/min. After at least one hour of stabilisation, microdialysis samples were taken at 5-minute intervals until the end of the experiment. The microdialysis samples were analysed for glucose using a CMA 600 Analyser (CMA Microdialysis AB, Stockholm, Sweden).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eExperimental Design and\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;Timeline\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;(Figure 1)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u0026nbsp;\u003c/strong\u003eExperimental design and timeline\u003c/p\u003e\n\u003cp\u003eEighteen pigs were randomly assigned to one of two experimental groups with eight animals in each: Normal ICP Group (NICPG) and elevated ICP group (EICPG). After 60 minutes of stabilisation, all animals subjected to controlled HS for 30 minutes by controlled withdrawal of blood to achieve a target pMAP of approximately 40 mmHg. ICP elevation was induced by the end of HS in the EICPG using an established epidural balloon inflation technique previously described (Bader et al., 2024). After completion of the haemorrhage phase, the tREBOA balloon was inflated to achieve complete AO, which was maintained for 90 minutes. pMAP and ICP were monitored continuously. CPP was calculated continuously and was defined as MAP- ICP. \u0026nbsp;CMD samples for CGlu concentration collected with 5 minutes interval.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were analysed using linear mixed-effects models to account for repeated measurements within individual animals. Time and experimental groups were included as fixed effects, and individual animals were included as random effects. All the measured time points on the timeline were compared to time 0 within each group and between the two groups. A p-value \u0026lt; 0.01 was considered statistically significant. Statistical analyses were performed with STATA release 17 (Stata Corp, College Station, TX).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eEighteen animals were included in the analysis, with nine assigned to the normal intracranial pressure group (NICPG) and nine to the elevated intracranial pressure group (EICPG). All animals completed the experimental protocol.\u003c/p\u003e\n\u003cp\u003eFigures 2\u0026ndash;5 show cerebral haemodynamic variables (pMAP, ICP, CPP) and CGlu concentrations over time in the NICPG and EICPG during the bleeding phase (\u0026minus;30 to 0 min) and the AO period up to 90 minutes. Time 0 on the timeline represents the baseline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCerebral glucose (CGlu)\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2 \u003c/strong\u003eCerebral Glucose vs time\u003c/p\u003e\n\u003cp\u003eIn the NICPG, CGlu slightly decreased during the bleeding phase from 0.19 mmol/L (95% CI: 0.55\u0026ndash;5.62) to 0.17 mmol/L (95% CI: 0.48\u0026ndash;2.29; p \u0026lt; 0.01). Following initiation of AO, CGlu increased and reached a peak value of 0.23 mmol/L at 25 minutes post-occlusion (p \u0026lt; 0.01). At 45 minutes, CGlu declined to levels comparable to those observed before bleeding and continued to decrease thereafter, reaching low levels at 90 minutes post-occlusion. However, no statistically significant differences were observed between any time point and baseline (T0).\u003c/p\u003e\n\u003cp\u003eIn the EICPG, CGlu decreased during the bleeding phase from 0.13 mmol/L (95% CI: 1.30\u0026ndash;6.15) to 0.09 mmol/L (95% CI: 0.98\u0026ndash;4.23; p \u0026lt; 0.01). CGlu remained markedly low during the first 30 minutes of AO before increasing to statistically significant levels, peaking at 0.18 mmol/L at 50 minutes (p \u0026lt; 0.01). Elevated CGlu concentrations persisted until approximately 80 minutes post-occlusion.\u003c/p\u003e\n\u003cp\u003eBaseline CGlu concentrations were comparable between groups, with mean values of 0.19 mmol/L (95% CI: 0.55\u0026ndash;2.62) in the NICPG and 0.13 mmol/L (95% CI: 1.30\u0026ndash;6.15) in the EICPG, with no statistically significant difference between groups (p \u0026gt; 0.01). Direct comparisons between groups at corresponding time points revealed no statistically significant differences at the 0.01 level. Although numerically higher CGlu values were observed in the EICPG at several time points, confidence intervals overlapped throughout the observation period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProximal mean arterial pressure (pMAP) Figure 3\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 3 \u003c/strong\u003eProximal Mean Arterial Pressure (pMAP) vs time\u003c/p\u003e\n\u003cp\u003eAt baseline, pMAP was comparable between groups and within the normal physiological range. During haemorrhage, pMAP decreased significantly in both groups. In the NICPG, pMAP declined from 95 mmHg to 49 mmHg at the onset of AO (p \u0026lt; 0.01). Similarly, in the EICPG, pMAP decreased from 91 mmHg to 46 mmHg prior to occlusion (p \u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003eFollowing AO, pMAP increased rapidly in both groups. In the NICPG, pMAP peaked at approximately 129 mmHg 20 minutes post-occlusion and remained significantly elevated throughout the occlusion period. In contrast, the EICPG exhibited a more pronounced hypertensive response, with pMAP peaking at 168 mmHg at 15 minutes post-occlusion (p \u0026lt; 0.01). From 15 minutes onward, pMAP was significantly higher in the EICPG compared with the NICPG at multiple time points.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIntracranial Pressure (ICP) Figure 4\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 4 \u003c/strong\u003eIntracranial pressure (ICP) vs time\u003c/p\u003e\n\u003cp\u003eIn the NICPG, ICP remained stable throughout the experiment, with mean values ranging between 13 and 16 mmHg and no statistically significant deviations from baseline.\u003c/p\u003e\n\u003cp\u003eIn the EICPG, epidural balloon inflation resulted in a statistically significant increase in ICP prior to AO, rising to 29 mmHg at time zero (p \u0026lt; 0.01) and peaking at 38 mmHg at 5 minutes. Although ICP gradually decreased thereafter, it remained significantly higher than in the NICPG throughout the entire occlusion period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCerebral Perfusion Pressure (CPP) Figure 5\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig 5 \u003c/strong\u003eCerebral Perfusion Pressure (CPP) vs time\u003c/p\u003e\n\u003cp\u003eDuring the haemorrhage phase, CPP declined markedly in both groups. In the NICPG, CPP decreased from approximately 78 mmHg at baseline to 32 mmHg at the onset of AO (p \u0026lt; 0.01). In the EICPG, CPP decreased to 16 mmHg prior to occlusion (p \u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003eFollowing REBOA inflation, CPP increased rapidly in both groups. In the NICPG, CPP peaked at approximately 115 mmHg within 15\u0026ndash;20 minutes post-occlusion and remained significantly elevated compared with baseline throughout the occlusion period. In the EICPG, CPP increased to a maximum of approximately 124 mmHg at 15 minutes post-occlusion and remained elevated thereafter. Apart from a transient early difference, no statistically significant between-group differences in CPP were observed during the occlusion phase.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of this experimental study provide insight into CGlu dynamics during HS and subsequent resuscitation with tREBOA, particularly under different ICP conditions. By examining CGlu alongside key haemodynamic parameters pMAP, ICP, and CPP these findings highlight the complex relationship between systemic circulatory restoration and cerebral metabolic homeostasis (3, 10, 22).\u003c/p\u003e\n\u003cp\u003eWe demonstrate that tREBOA restores cerebral perfusion and supports partial cerebral metabolic recovery by increasing CGlu during HS, even in the presence of elevated ICP. Using CMD, we provide detailed temporal insight into the interplay between CGlu availability, haemodynamics, and ICP during HS and AO (17, 18).\u003c/p\u003e\n\u003cp\u003eGlucose is the principal substrate for cerebral energy metabolism and is required for ATP-dependent processes such as Na+/K+ ATPase activity, which is essential for membrane stability and prevention of cellular injury (23). Because the brain has negligible intrinsic glucose stores, CGlu supply depends on systemic availability and transport across the BBB via specific glucose transporters, primarily GLUT1 and GLUT3 (24, 25).\u003c/p\u003e\n\u003cp\u003eCerebral extracellular glucose reflects the balance between systemic substrate availability, BBB transport, and cellular utilisation. Under physiological conditions, glucose homeostasis is tightly regulated through hepatic glucose production and pancreatic insulin secretion, maintaining relatively stable cerebral substrate delivery despite systemic fluctuations (3, 22, 26).\u003c/p\u003e\n\u003cp\u003eDuring systemic stress, however, CGlu functions primarily as a marker of metabolic strain rather than a direct surrogate of cerebral perfusion. In the present study, CGlu decreased during HS, consistent with impaired substrate delivery during systemic hypovolaemia. This decline occurred before AO, indicating early cerebral metabolic stress even in brains with normal ICP (10, 19).\u003c/p\u003e\n\u003cp\u003eAlthough compensatory mechanisms during HS aim to preserve cerebral blood flow through sympathetic activation and circulatory centralisation, preserved arterial pressure does not ensure adequate microcirculatory flow or substrate delivery (27). Cerebral metabolic disturbances may occur despite apparently adequate CPP (10). The more pronounced CGlu reduction observed in animals with elevated ICP suggests that intracranial hypertension further compromises effective substrate delivery, likely by reducing capillary perfusion gradients and impairing autoregulatory reserve (20).\u003c/p\u003e\n\u003cp\u003eCGlu should therefore not be interpreted as an isolated cerebral variable but as the downstream expression of an integrated systemic cerebral metabolic axis (22, 26).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHaemorrhagic shock (HS)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCGlu availability is a key determinant of cerebral energy metabolism, particularly in states of systemic hypoperfusion such as HS (3).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The reduction in CGlu concentration associated with low CPP during HS reflecting a critically reduced cerebral perfusion in both groups, however, most severe with critically low values in EICPG where hypotension is associated with intracranial hypertension (20). This pattern is consistent with reduced cerebral substrate delivery, microvascular dysfunction, and increased metabolic demand (10, 19).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eReduced CGlu availability during HS is a recognised indicator of cerebral metabolic stress and may signal evolving metabolic crisis or ischaemia, particularly when CA is impaired. Cerebral ischaemia is typically associated with low brain tissue oxygen tension and glucose together with increased lactate/pyruvate ratio, reflecting a shift toward anaerobic metabolism (28-30). Under conditions of limited glucose availability, the brain can partially utilise alternative substrates such as lactate, pyruvate, and ketone bodies, although these pathways are less efficient and require additional metabolic processing (23, 24).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAortic occlusion (AO)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter AO, pMAP increased rapidly and remained elevated, restoring CPP to supraphysiological levels and confirming effective proximal perfusion augmentation (5, 21, 31). The hypertensive response was greater in EICPG, likely reflecting both pMAP augmentation and Cushing-type reflex mechanisms (32).\u003c/p\u003e\n\u003cp\u003eCGlu increased in both groups, but with different temporal profiles. In EICPG, CGlu rose modestly after AO, peaked approximately 25 minutes post-occlusion, and gradually declined thereafter. These changes did not differ significantly from pre-occlusion values, suggesting relatively preserved metabolic coupling between cerebral blood flow (CBF) and glucose utilisation.\u003c/p\u003e\n\u003cp\u003eIn contrast, the EICPG demonstrated a delayed but statistically significant CGlu increase, with persistently higher levels during early occlusion. This response likely reflects the combined effects of supraphysiological pMAP, elevated ICP and eventually altered CA (21, 32, 33). When blood pressure exceeds the autoregulatory range, CBF becomes pressure-passive, potentially increasing substrate delivery but also stressing the BBB (15, 34, 35).\u003c/p\u003e\n\u003cp\u003eBetween group comparisons did not show statistically significant CGlu differences at corresponding time points despite numerical separation at several intervals. This suggests that systemic metabolic consequences of tREBOA may outweigh the isolated effect of ICP when CPP is forcibly maintained. CMD measures extracellular concentration rather than metabolic flux; similar CGlu levels may therefore represent different metabolic states (17, 36).\u003c/p\u003e\n\u003cp\u003eA central observation is the dissociation between haemodynamic recovery and cerebral metabolic response, particularly in the EICPG during early AO. Although pMAP and CPP were rapidly restored, CGlu did not normalise in parallel. Similar dissociations between perfusion metrics and metabolic status have been described in TBI and other critical illness states (10, 19).\u003c/p\u003e\n\u003cp\u003ePressure based metrics alone are therefore insufficient indicators of cerebral metabolic recovery, particularly when major metabolic organs are excluded from the circulation during AO (17, 22).\u003c/p\u003e\n\u003cp\u003eThe observed time dependent fluctuations in cerebral glucose during prolonged AO likely represent evolving metabolic responses to sustained circulatory redistribution and non-physiological conditions. tREBOA excludes the splanchnic circulation, including the liver and pancreas, thereby disrupting hepatic glucose output and insulin regulation. Consequently, CGlu during AO does not reflect normal metabolic regulation but rather the balance between restricted systemic metabolic control and ongoing cerebral demand (6, 7, 37). This mechanism provides a plausible physiologically explanation for delayed CGlu normalisation despite restored CPP, particularly in EICPG and highlighting the importance of occlusion duration.\u003c/p\u003e\n\u003cp\u003eICP remained stable in animals with normal baseline ICP, indicating that supraphysiological arterial pressures during AO did not independently destabilise intracranial dynamics. In contrast, ICP increased further after AO in the elevated ICP group and remained persistently higher, although this did not prevent CPP or CGlu recovery. Experimental and clinical data indicate that brain injury is associated with metabolic and perfusion heterogeneity extending beyond the primary lesion (10, 38).\u003c/p\u003e\n\u003cp\u003eDespite sustained differences in ICP, CGlu concentrations were not consistently lower in the EICPG once cerebral perfusion pressure was restored. This suggests that intracranial pressure alone does not determine CGlu availability when perfusion pressure is forcibly maintained (19, 20). Importantly, similar CGlu concentrations should not be interpreted as evidence of similar metabolic states, as CMD reflects concentration rather than metabolic flux (17, 36).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLimitations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the controlled porcine model limits direct extrapolation to human trauma. Second, systemic glucose and insulin concentrations were not measured, restricting interpretation of systemic metabolic regulation. Third, CMD provides local rather than global metabolic information. Fourth, the model reflects an acute physiological scenario and does not address long-term neurological outcomes. Sixth, anaesthesia may have reduced absolute metabolic rates, although relative dynamic patterns were preserved. Seventh, fluid therapy, glucose administration, and vasoactive agents may have influenced haemodynamics and metabolism. Eighth, histological correlates were not assessed. And finally,\u0026nbsp;the elevated ICP model represents only TBI with acute intracranial hypertension rather than traumatic brain injury in general.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this experimental model of HS, tREBOA restored CPP and supported recovery of CGlu availability, even in the presence of elevated ICP. However, haemodynamic restoration was not accompanied by immediate metabolic normalization, demonstrating a dissociation between perfusion and cerebral glucose regulation. These findings provide important physiological insights into the cerebral effects of tREBOA and support its cautious, time-limited use in complex trauma scenarios. Future studies incorporating systemic metabolic markers, hormonal profiling, and microcirculatory assessment may further clarify mechanisms underlying cerebral metabolic alterations during tREBOA and help define metabolically guided resuscitation strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAO:\u003c/strong\u003e Aortic Occlusion\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCA:\u0026nbsp;\u003c/strong\u003eCerebral Autoregulation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCBF:\u003c/strong\u003e Cerebral Blood Flow\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCGlu:\u003c/strong\u003e Cerebral Glucose\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCPP:\u0026nbsp;\u003c/strong\u003eCerebral Perfusion pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEICPG\u003c/strong\u003e: Elevated Intracranial Pressure Group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHS:\u003c/strong\u003e Haemorrhagic shock\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eICP:\u0026nbsp;\u003c/strong\u003eIntracranial Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMAP:\u0026nbsp;\u003c/strong\u003eMean Arterial Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNICPG\u003c/strong\u003e: Normal Intracranial Pressure Group\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003epMAP:\u0026nbsp;\u003c/strong\u003eProximal Mean Arterial Pressure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eREBOA:\u0026nbsp;\u003c/strong\u003eResuscitative Endovascular Balloon Occlusion of the Aorta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTBI:\u003c/strong\u003e Traumatic Brain Injury\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003etREBOA:\u003c/strong\u003e Total Resuscitative Endovascular Balloon Occlusion of the Aorta\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical Approval\u003c/h2\u003e\n\u003cp\u003eAll experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments.\u003c/p\u003e\n\u003ch2\u003eFunding \u003cstrong\u003eDeclaration\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThis study was supported by grants from the County Council of \u0026Ouml;rebro Country OLL-961358 (2021-01-26), OLL-935974 (2020-03-17), OLL-934649), OLL-933525 (2019-10-31), OLL-942131 (2020-11-01 and OLL-836061 (2018-08-17), and from the County Council of V\u0026auml;sterbotten Country RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003e- Authors\u0026apos; contributionsA: S Bader; B: Anders Magnuson; C: C Brorsson; D: N L\u0026ouml;fgren; E: F L\u0026ouml;fgren; F: P-J Blind; G: M \u0026Ouml;man; H: M Olivecrona; I: G WallinA: Developed the theoretical formalism, conceived and planned the experiments, carried out the experiments, processed the experimental data and performed the analytic calculations, designed the figures, analysis and interpretation of the results, formulating the discussion, Wrote the manuscript with support from M Olivecrona and M \u0026Ouml;man. B: Processed the experimental data and performed the analytic calculations, designed the figures. CDEF: Contributed in planning and performing the experiments.G: Developed the theoretical formalism, contributed in planning and performing the experiments, provided critical feedback and helped shape the research, discussed the results, supported S Bader in manuscript writing.H: Supervised the project, developed the theoretical formalism, conceived and planned the experiments, supervised the carrying out the experiments, contributed to the interpretation of the results and formulation of the discussion Supervised S Bader in the writing of the manuscript. I: Supervised S Bader in the writing of the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003e- Clinical Trial Number:Not applicable.- Ethical Approval and Consent to participate:In this animal study , all experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. The study protocol was approved by the local Animal Experimental Ethics Committee prior to initiation of the experiments. Consent to participate is not applicable.- Consent for publication:No applicable- Availability of supporting data: All the experiments digital data is available in tables and can be provided when its needed.- Competing interests:No, I declare that the authors have no competing interests that might be perceived to influence the results and/or discussion reported in this paper.- Funding Declaration: This study was supported by grants from the County Council of \u0026Ouml;rebro Country OLL-961358 (2021-01-26), OLL-935974 (2020-03-17), OLL-934649), OLL-933525 (2019-10-31), OLL-942131 (2020-11-01 and OLL-836061 (2018-08-17), and from the County Council of V\u0026auml;sterbotten Country RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07).- Authors\u0026apos; contributions:A: S Bader; B: Anders Magnuson; C: C Brorsson; D: N L\u0026ouml;fgren; E: F L\u0026ouml;fgren; F: P-J Blind; G: M \u0026Ouml;man; H: M Olivecrona; I: G WallinA: Developed the theoretical formalism, conceived and planned the experiments, carried out the experiments, processed the experimental data and performed the analytic calculations, designed the figures, analysis and interpretation of the results, formulating the discussion, Wrote the manuscript with support from M Olivecrona and M \u0026Ouml;man. B: Processed the experimental data and performed the analytic calculations, designed the figures. CDEF: Contributed in planning and performing the experiments.G: Developed the theoretical formalism, contributed in planning and performing the experiments, provided critical feedback and helped shape the research, discussed the results, supported S Bader in manuscript writing.H: Supervised the project, developed the theoretical formalism, conceived and planned the experiments, supervised the carrying out the experiments, contributed to the interpretation of the results and formulation of the discussion Supervised S Bader in the writing of the manuscript. I: Supervised S Bader in the writing of the manuscript.-Acknowledgements: Not Applicable.- Language editing:During the preparation of this work , the authors used AI tools in order to improve the language and readability of the manuscript. After using AI, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGreve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mt Sinai J Med. 2009;76(2):97\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChesnut RM. Secondary brain insults after head injury: clinical perspectives. New Horiz. 1995;3(3):366\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiesjo BK. Brain energy metabolism and catecholaminergic activity in hypoxia, hypercapnia and ischemia. J Neural Transm Suppl. 1978(14):17\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrenner ML, Moore LJ, DuBose JJ, Tyson GH, McNutt MK, Albarado RP, et al. A clinical series of resuscitative endovascular balloon occlusion of the aorta for hemorrhage control and resuscitation. 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Cerebral autoregulation dynamics in humans. Stroke. 1989;20(1):45\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujishima M, Ibayashi S, Fujii K, Mori S. Cerebral blood flow and brain function in hypertension. Hypertens Res. 1995;18(2):111\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ F. Volume regulation of the central nervous system: Raven Press; 1984 1984.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUngerstedt U, Rostami E. Microdialysis in neurointensive care. Curr Pharm Des. 2004;10(18):2145\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerich JE, Lilly. lecture 1988. Glucose counterregulation and its impact on diabetes mellitus. Diabetes. 1988;37(12):1608-17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColes JP, Fryer TD, Coleman MR, Smielewski P, Gupta AK, Minhas PS, et al. 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Crit Care Med. 2007;35(2):568\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scandinavian-journal-of-trauma-resuscitation-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stre","sideBox":"Learn more about [Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine](http://sjtrem.biomedcentral.com)","snPcode":"13049","submissionUrl":"https://submission.nature.com/new-submission/13049/3","title":"Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine","twitterHandle":"@SJTREM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Resuscitative Endovascular Balloon Occlusion of the Aorta, REBOA, haemorrhagic shock, cerebral microdialysis, cerebral glucose","lastPublishedDoi":"10.21203/rs.3.rs-9413974/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9413974/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAdequate cerebral glucose (CGlu) availability is essential for maintaining neuronal function and cerebral energy homeostasis. During haemorrhagic shock (HS), impaired systemic perfusion and metabolic stress may compromise cerebral substrate delivery, even in the absence of direct brain injury. Resuscitative endovascular balloon occlusion of the aorta (REBOA) effectively restores proximal arterial pressure; however, its effects on cerebral glucose dynamics, particularly in the presence of elevated intracranial pressure, remain incompletely understood.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate CGlu dynamics during HS and subsequent resuscitation with total REBOA (tREBOA), and to assess the influence of intracranial pressure (ICP) on cerebral metabolic responses.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e In an established experimental porcine model, eighteen animals were subjected to controlled HS followed by resuscitation with tREBOA. Animals were assigned to either a normal intracranial pressure group (NICPG) or an elevated intracranial pressure group (EICPG). CGlu concentrations were measured using cerebral microdialysis throughout baseline, HS, and aortic occlusion (AO). Proximal mean arterial pressure (pMAP), ICP, and cerebral perfusion pressure (CPP) were continuously monitored. Data were analysed using linear mixed-effects models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHS was associated with a reduction in CGlu concentrations in both groups, indicating early cerebral metabolic stress. Following initiation of tREBOA, CPP increased markedly; however, CGlu concentrations did not immediately normalise, particularly in EICPG. Instead, CGlu availability demonstrated time-dependent changes during prolonged AO. No consistent differences in CGlu concentrations between groups were observed once perfusion pressure was restored.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn this experimental model of HS, tREBOA restored CPP and supported recovery of CGlu availability, even in the presence of elevated ICP. However, haemodynamic restoration was not accompanied by immediate metabolic normalization, demonstrating a dissociation between perfusion and CGlu regulation. These findings provide important physiological insights into the cerebral effects of tREBOA and support its cautious, time-limited use in complex trauma scenarios. Future studies incorporating systemic metabolic markers, hormonal profiling, and microcirculatory assessment may further clarify mechanisms underlying cerebral metabolic alterations during REBOA and help define metabolically guided resuscitation strategies.\u003c/p\u003e","manuscriptTitle":"Cerebral Glucose Dynamics During Haemorrhagic Shock Resuscitation with Total Aortic Occlusion by REBOA","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-30 21:22:37","doi":"10.21203/rs.3.rs-9413974/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"260085248746698047128095300553965203732","date":"2026-05-11T16:17:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220538657857641513677917241050624704008","date":"2026-04-24T19:50:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-22T19:38:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-15T08:19:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-15T08:18:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine","date":"2026-04-14T09:54:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scandinavian-journal-of-trauma-resuscitation-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stre","sideBox":"Learn more about [Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine](http://sjtrem.biomedcentral.com)","snPcode":"13049","submissionUrl":"https://submission.nature.com/new-submission/13049/3","title":"Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine","twitterHandle":"@SJTREM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2d641a0e-0af3-49f0-b895-f0b066cdcf46","owner":[],"postedDate":"April 30th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"260085248746698047128095300553965203732","date":"2026-05-11T16:17:58+00:00","index":33,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T21:22:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-30 21:22:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9413974","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9413974","identity":"rs-9413974","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}