Aortic Occlusion with REBOA Reverses Cerebral Ischaemia Induced by Haemorrhagic Shock

Aortic Occlusion with REBOA Reverses Cerebral Ischaemia Induced by Haemorrhagic Shock | 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 Aortic Occlusion with REBOA Reverses Cerebral Ischaemia Induced by Haemorrhagic Shock Sam Er Bader, Anders Magnuson, Camilla Brorsson, Göran Wallin, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8541637/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background In recent years, the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) as a less invasive procedure compared to aortic cross-clamping via thoracotomy (1) has increased as an adjunct resuscitative method and a bridge to damage control surgery, primarily in trauma settings involving haemodynamically unstable patients (2-4). The main function of REBOA in HS is to preserve the remaining blood to the upper part of the body, i.e. to the brain, the lungs, and the heart. Additionally, REBOA reduces ongoing bleeding distal to the occlusion until definitive haemostasis is achieved (5). REBOA increases blood pressure proximal to the occlusion zone (proximal mean arterial pressure (pMAP)); consequently, it might be lifesaving and mitigates cerebral damage and neurological sequelae following the reduction of cerebral perfusion in patients with HS (6, 7). Resuscitative Endovascular Balloon Occlusion of the Aorta REBOA haemorrhagic shock cerebral microdialysis metabolism LPR ischemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background In recent years, the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) as a less invasive procedure compared to aortic cross-clamping via thoracotomy ( 1 ) has increased as an adjunct resuscitative method and a bridge to damage control surgery, primarily in trauma settings involving haemodynamically unstable patients ( 2 – 4 ). The main function of REBOA in HS is to preserve the remaining blood to the upper part of the body, i.e. to the brain, the lungs, and the heart. Additionally, REBOA reduces ongoing bleeding distal to the occlusion until definitive haemostasis is achieved ( 5 ). REBOA increases blood pressure proximal to the occlusion zone (proximal mean arterial pressure (pMAP)); consequently, it might be lifesaving and mitigates cerebral damage and neurological sequelae following the reduction of cerebral perfusion in patients with HS ( 6 , 7 ). However, aortic occlusion (AO) might raise PBP to supraphysiological levels, and potentially disturb cerebral autoregulation (CA) causing cerebral damage ( 8 – 14 ). The unique CA mechanism maintains a stable cerebral blood flow (CBF) in the intact brain despite fluctuations in blood pressure (BP). This mechanism ensures adequate CBF when the mean arterial pressure (MAP) is within the range of 50–150 mmHg. Any changes in MAP outside this may cause cerebral ischaemia or cerebral oedema ( 15 ). Due to the sudden elevation of PBP after AO, total REBOA (tREBOA) has been regarded by some authors as contraindicated in TBI and elevated ICP, as theoretically, the supraphysiological PBP caused by AO may exacerbate cerebral oedema and increase intracranial haemorrhage ( 6 , 7 , 13 , 16 – 20 ). Several animal studies in aortic and thoracic surgery have investigated the effects of AO on the brain using aortic cross-clamping. However, most of these studies were conducted on normovolemic animals ( 21 , 22 ). A few recent animal studies have focused on the cerebral effects of AO by REBOA in hypovolemic scenarios, primarily in trauma settings. These studies have mainly concentrated on haemodynamic and radiological changes in the brain ( 14 , 23 – 26 ). Cerebral microdialysis (CMD) is a validated method for monitoring chemical events and metabolic changes in cerebral tissue before they manifest in the blood ( 27 ). Different neurochemical markers are used to detect early abnormal metabolic changes such as in the case of ischaemia, mitochondrial dysfunction, and cellular damage. Under normal conditions, glucose is the primary substrate for brain energy metabolism. The lactate/pyruvate ratio (LPR) indicates changes in the cellular redox state, and indicator for ischaemia ( 28 – 32 ). To the best of our knowledge, the impact of thoracic AO in hypovolemic shock by REBOA on CM has not yet been described. However, we found two authors who have studied the metabolic changes in the spinal cord by inserting a MD probe into the lumbar spinal cord during AO in normovoleumic pigs. They reported changes in energy-related metabolites reflecting considerable ischaemia in the spinal cord tissue ( 33 , 34 ). The purpose of this paper is to fill the knowledge gap regarding the impact of total AO by tREBOA on CM, in animals with HS. The first aim is to describe the changes in CM during total AO during HS in animals with normal and elevated ICP, and the second aim is to study whether there is a difference between CM in the two groups. The null hypothesis is that there are more pronounced cerebral metabolic changes in the group with elevated ICP, indicating that REBOA should not be used in individuals with suspected raised ICP or severe head injury. Material and methods Ethics The study was approved by the Animal Experimental Ethics Committee at Umeå University, Sweden (A 32–19). And conducted in accordance with Directive 2010/63/EU on the protection of animals used for scientific purposes, and the Guide for the Care and Use of Laboratory Animals , National Research Council, Washington, DC, USA, 1996. Study overview We studied two groups of animals with nine pigs in each, both males and females: The normal ICP group (NICPG), and the elevated ICP group (EICPG). The experiment comprised five phases illustrated in Fig. 1: the preparation phase, stabilisation phase, bleeding phase, occlusion phase, and lastly the termination phase (Fig. 1). Animal preparation For detailed information about the general experimental setup and protocol, see Bader et al. ( 14 ). Anaesthesia The animals were sedated with ketamine and atropine sulphate, whereafter anaesthesia was started using sodium pentobarbital. Anaesthesia was maintained using fentanyl, midazolam, and sodium pentobarbital. After sedation, the animals were tracheostomised and mechanically ventilated. Ringer’s acetate was given as fluid maintaining a central venous pressure of 5–10 mmHg. General monitoring and surgical preparation Oxygen saturation was measured by pulse oximetry and heart rate was monitored by ECG. The CVP, PBP and the distal blood pressure in the femoral artery were monitored with the zero reference at heart level. A REBOA was inserted via the right femoral artery. Confirmation of the balloon’s adequate placement in the aortic zone 1 was obtained under tactile guidance. Saturation and ABP were documented every five minutes until the end of the experiment. Cerebral monitoring After anaesthesia and overall monitoring were established, the animal was placed in a prone position. The head was shaved, cleaned, and disinfected. The cranial bone was exposed with a paramedian incision 6 cm long on the left side. A 3 mm burr hole was drilled frontally. Next, the dura was opened sharply, and haemostasis secured by diathermy. A four-lumen bolt (H QFlow 500 Titanium, Hemedex, Waltham, MA, USA) was placed in the burr hole. 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 10 mm into the brain, and connected to an ICP monitor (PSO-4000 Pressio 2, Sophysa, Orsay, France). ICP was continuously measured and manually recorded every five minutes. CPP was calculated according to the formula CPP = MAP − ICP. To simulate an acute epidural haematoma in EICPG, an extra 6 mm burr hole was drilled on the right side of the skull, where a Foley catheter (Ch12) was inserted into the epidural space. The balloon was inflated with saline to mimic an epidural haematoma. Microdialysis A microdialysis catheter (70Brain Catheter, mdialysis 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 (mdialysis Stockholm etc) using a microdialysis pump (CMA 107; CMA/ Microdialysis etc) 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. Samples were first stored at – 6°C and transferred to a – 20°C freezer. The microdialysis samples were analysed for glucose, lactate, and pyruvate using a CMA 600 Analyser (CMA Microdialysis AB, Stockholm, Sweden). Study design and experimental protocol Stabilisation phase (60 minutes) In a supine position with 15° table inclination, the animal was immobilised, keeping the head and heart on the same level; hence, the zero level of the PBP equals that of the ICP. Antibiotic prophylaxis with Cefuroxime 750 mg (MIP Pharma GmbH, Blieskastel, Germany) was given, and the 60-minutes stabilisation phase initiated. Bleeding phase (30 minutes) Blood volume for each animal was estimated at 8% of the animal’s body weight. Over 30 minutes 40% of the animal’s estimated blood volume was drained from the left femoral artery. The bleeding was calculated in ml/min according to the equation: Bleeding speed = Estimated blood volume / 30. Intravenous infusion of 5000 IE Heparin (Heparin LEO Pharma AB; Malmö, Sweden) was administered before the bleeding started, and Adrenaline (Mylan, Canonsburg, Pennsylvania, USA) was given if needed to keep the MAP around 40 mmHg and to simulate the physiological stress response. During this phase, the epidural Foley balloon in the EICPG was injected slowly with saline, aiming at an ICP of 25–30 mmHg. Occlusion phase (90 minutes) Once hypovolemia was achieved with MAP around 40 mmHg, the REBOA was inflated with saline (tREBOA) until ABP in the femoral artery disappeared (T = 0 minutes) and the tREBOA was kept inflated for 90 minutes. After AO we administered intravenously 500 ml of 6% hydroxyethyl starch in sodium chloride (Voluven Fresenius Kabi, Homburg, Germany) to mimic prehospital treatment of haemorrhagic shock. Termination After 90 minutes of total AO, at a rate of 1 ml/min, the balloon was deflated, whereafter the animal was euthanized with a lethal intravenous injection of potassium chloride 40 mmol (Kaliumklorid; B. Braun Medical AB, Danderyd, Sweden) and sodium pentobarbital 400 mg. Statistics The outcomes pMAP, ICP, CPP, CL, CP and LPR were compared within and between study groups (EICPG, NICPG) at every 5- minute time point from − 30 until 90 minutes after AO with a random intercept linear mixed model. Study groups and time points and the interaction (group x time points) were used as fixed factors. All outcomes except pMAP and CPP were evaluated on the natural log scale, which showed better normal distribution assumptions for the standardised residuals. Sensitivity analyses were performed by excluding outliers if the standardised residual was greater than 3 (in absolute value). Association measures were mean differences with 95% confidence intervals (CI), and on the log scale, mean ratios (95% CI). A mean ratio of 1.20 interprets as the mean being 20% higher for exposed vs. unexposed. To reduce the risk of false-positive findings due to multiple testing because of many time points, a P-value below 0.01 was considered statistically significant. All analyses were performed with STATA release 17 (StataCorp, College Station, TX). Results Eighteen pigs (thirteen female and five male) with a mean weight of 48.6 kg with (SD = 6.9) were included in statistical analysis. Proximal Mean Arterial Pressure (pMAP) : During the bleeding phase in NICPG, pMAP showed a statistically significant decrease from initial mean 95 mmHg to baseline mean 49 mmHg before AO, mean difference 46 (95% CI 29–63; P < 0.01), then increased rapidly after AO, peaking 20 minutes later up to 159 mmHg and remaining elevated throughout the experiment. A similar pattern was observed in the EICPG; however, pMAP reached its peak of 168 mmHg 15 minutes post-AO. No statistically significant difference in pMAP was observed between groups during the bleeding phase. However, the pMAP in the EICPG was statistically significantly higher than in the NICPG from 15 minutes post-AO onward at multiple time points (Fig. 2). Intracranial Pressure (ICP): In the NICPG, ICP remained stable with a mean of around 15 mmHg throughout the experiment. In the EICPG, inflation of the epidural balloon led to a significant rise in ICP from 17 mmHg to 29 mmHg prior to AO (P 0.01). ICP was statistically significantly higher in EICPG than in NICPG from 5 minutes before AO until the end of the experiment (Fig. 3). Cerebral Perfusion Pressure (CPP): In the NICPG, CPP declined from 78 mmHg to 32 mmHg during the bleeding phase (P < 0.01), then rose rapidly after AO, peaking at 115 mmHg after 20 minutes. It remained statistically significantly elevated compared to pre-AO baseline for the rest of the experiment. In the EICPG, CPP dropped to 16 mmHg pre-AO and rose to a peak of 124 mmHg 15 minutes post-AO, staying statistically significantly above baseline thereafter. There was no statistically significant difference in CPP between the groups, except at one time point (5 minutes post-AO), where EICPG had significantly lower CPP than NICPG (P < 0.01) (Fig. 4). Cerebral Lactate (CL): In the NICPG, CL gradually increased during the bleeding phase from 0.71 mmol/L to 1.13 mmol/L pre-AO (P < 0.01), and continued to rise slowly during the occlusion phase, though not statistically significant on any time point. In the EICPG, CL started to increase earlier than in NICPG and reached statistically significant elevated levels from 55 minutes into the timeline. No statistically significant differences in CL were observed between the groups throughout the experiment (Fig. 5). Cerebral Pyruvate (CP): In the NICPG, CP increased statistically significantly at 20 minutes post-AO (P < 0.01) and remained elevated (Fig. 6). In the EICPG, CP remained stable during bleeding but increased statistically significantly 15 minutes after AO and stayed elevated. Initial CP levels were statistically significantly lower in the EICPG compared to NICPG (P < 0.01) and 5 and 10 minutes after AO (P < 0.01). However, in the sensitivity analysis, excluding outliers, the differences at 5 and 10 minutes after AO were no longer statistically significant. (Fig. 6). Cerebral Lactate Pyruvate Ratio (LPR): In the NICPG, LPR rose from mean of 26 to 47 during bleeding, (P < 0.01) and gradually decreased after AO, reaching a low mean level of 34 by 25 minutes post-AO but never reached statistically significantly low levels compared to pre-AO until the end of the experiment. In the EICPG, LPR also rose during bleeding and increased further 5 minutes post-AO before gradually declining and remained statistically significantly low compared to pre-AO. Statistically significant differences between groups were found during the first 10 minutes post-AO only (Fig. 7). Discussion Although the human brain accounts for only about 2% of total body weight, it receives nearly 20% of the cardiac output and body energy production. Due to its limited energy reserves, even brief interruptions in CBF can rapidly result in severe neurological impairment ( 35 ). The cerebral cytoplasmic redox state, expressed by the lactate-to-pyruvate ratio (LPR), serves as a sensitive indicator of mitochondrial oxidative metabolism ( 28 – 31 , 36 , 37 ). In this experimental model, we demonstrated at the cellular level that AO using tREBOA is an effective resuscitative strategy in uncontrolled HS. During HS in the normal ICP group (NICPG), LPR increased slightly due to elevated lactate and decreased pyruvate levels but returned to baseline following AO, indicating reversibility of cerebral ischaemia. The same pattern was observed in EICPG, however, LPR reached higher values with about a 20-minute delay before returning to baseline. Changes in LPR align with the changes in cerebral haemodynamic MAP and CPP. In EICPG CPP reached critically low levels by the end of bleeding phase, which might indicate an alteration of CA ( 14 ). The abrupt increase in MAP induced by AO did not significantly affect cerebral metabolism in the NICPG. However, in EICPG, a transient and reversible ischaemic disturbance was observed, evidenced by an LPR peak following the supraphysiological MAP (129 mmHg) induced by AO. To our knowledge, this is the first study to demonstrate enhanced cerebral metabolism and reversible ischaemia following HS resuscitated with tREBOA. Nevertheless, our haemodynamic findings are consistent with previous reports that described comparable effects of AO and tREBOA on MAP, ICP, and CPP in HS ( 14 , 23 – 26 ). In trauma, HS frequently coexists with traumatic brain injury (TBI) and elevated ICP ( 38 – 41 ). Approximately 80% of trauma-related deaths are attributed to uncontrolled haemorrhage and 4% to TBI. (Kelly JF 2008) The coexistence of these two conditions nearly doubles morbidity and mortality compared to HS alone ( 42 , 43 ). Time is a critical factor in trauma management, especially in haemodynamically unstable patients. Fluid resuscitation alone may be insufficient to restore cardiac output and cerebral perfusion. Achieving distal control of bleeding can also be challenging in cases of massive haemorrhage. Inflation of the tREBOA balloon in aortic zone 1 divides the arterial system into two distinct circulatory compartments: a proximal (upper body) circulation and a distal (lower body) circulation. However, minimal collateral flow persists through arterial connections between these two regions ( 44 ). Our animal model replicates two clinical trauma scenarios: NICPG representing uncontrolled HS resuscitated by tREBOA with a target MAP of approximately 40 mmHg, as recommended by the European Society for Intensive Care Medicine ( 45 ). And EICPG a more complex polytrauma model combining uncontrolled HS with acute ICP elevation (25 mmHg) simulating subdural or epidural haematoma, also resuscitated using tREBOA ( 46 ). Normal ICP group (NICPG) Bleeding phase In NICPG, LPR increased significantly between the beginning and end of the bleeding phase (P = 0.0081), indicating cerebral ischaemia. Similar findings were reported by Jakobsen et al., who observed increased LPR in anesthetised pigs during HS (MAP 40 mmHg for 60 minutes) resuscitated with autologous blood, although LPR decreased after resuscitation, it remained elevated above baseline ( 47 ). In another experiment for Jakobsen R et al published in 2016 shown that prolonged (90 min) and severe hypotension (MAP 40 mmHg) results in irreversible metabolic perturbation evaluated by CMD ( 32 ). Cerebral ischaemia typically results from reduced CPP or elevated ICP, leading to well-known metabolic disturbances. Oxygen deprivation during ischaemia causes an immediate rise in cytoplasmic and interstitial LPR due to a shift in the lactate dehydrogenase equilibrium ( 28 , 48 ). The observed LPR elevation coincided with MAP falling below 50 mmHg, consistent with transient impairment of CA and reduced CBF ( 14 ). CA maintains constant CBF across a broad CPP range, defined as MAP minus ICP. With normal ICP (5–10 mmHg), CBF remains stable up to MAP values of approximately 120 mmHg. Once CPP decreases below 50 mmHg, autoregulation fails, resulting in progressive cerebral dysfunction ( 49 ). When blood flows decline to 25–30 mL/100 g/min, electroencephalographic changes occur along with alterations in consciousness. With further decreasing below 20 mL/100 g/min, electroencephalogram become isoelectric, and neurons switch to anaerobic metabolism. At 10–12 mL/100 g/min, neurotransmission stops, sodium-potassium pumps fail, and cytotoxic oedema develops. Finaly, at 6–10 mL/100 g/min, cerebral tissue dies ( 35 , 50 ). Occlusion phase After 20 minutes of tREBOA resuscitation, LPR gradually declined and stabilised, simultaneous to increases in CPP and MAP. This decline indicates the recovery of cerebral metabolism and reversal of ischaemia. When cerebral oxygenation is promptly restored, LPR typically returns to near-normal levels. Lactate and pyruvate, being water-soluble, quickly equilibrate across the blood-brain barrier (BBB) and cell membranes ( 48 ). Elevated ICP group (EICPG) Bleeding Phase At the end of the bleeding, ICP was artificially increased to 25–30 mmHg to simulate an acute subdural haematoma, following the method described by Timaru-Kast et al. This model reliably induces reproducible ICP elevation and associated cerebral energy metabolism alterations similar to those observed in TBI ( 51 ). During haemorrhage, LPR rose exponentially, reaching significantly higher levels than in NICPG, indicating more pronounced cerebral ischaemia. The increase in LPR corresponded with critical reductions in CPP (16 mmHg), aggravated by artificially elevated ICP (25 mmHg). According to the Monro–Kellie doctrine, intracranial volume is constant, comprising blood brain tissue, and cerebrospinal fluid. Disruption of this equilibrium through haemorrhage, ischaemia, hydrocephalus, or reperfusion injury raises ICP and can lead to reduced CPP, cerebral ischaemia, or herniation ( 52 – 54 ). In intact autoregulation, hypotension elevates ICP, whereas hypertension may have minimal impact. However, in cases of impaired autoregulation, ICP fluctuates directly with blood pressure ( 55 ). Increased ICP without compensatory hypertension reduces cerebral perfusion and may trigger the Cushing reflex, a physiological triad of hypertension, bradycardia, and irregular respiration in response to ICP > 25 mmHg ( 56 ). Occlusion phase LPR was already increased by the end of bleeding phase. After AO, a further increase occurred after AO, for about 5 minutes, then decreased significantly after 20 minutes, returning to baseline within 30 minutes. This transient rise suggests reversible ischaemic stress. The supraphysiologic arterial pressure up to 168 mmHg in this group can be explained by a double mechanism: The effect of AO itself on cerebral blood volume and alteration of autoregulation, and by Cushing reflex due to ICP increasing over 25 mmHg ( 14 , 56 ). In a study by Bader et al., the authors showed that total AO by tREBOA induces a reversible alteration of CA with positive values of the Modified-Long Pressure Reactivity Index (mL-PRx) ( 14 ). Previous studies demonstrated that acute hypertension caused by descending AO can elevate CBF, cause vasodilation, and disrupt the BBB ( 57 – 64 ). Other experimental studies about the metabolic effects of acute hypertension induced by angiotensin on the brain showed that LPR was not affected but produced multifocal BBB leakage of Evans blue albumin ( 65 , 66 ). Autoregulation remains the brain’s primary protective mechanism against acute hypertension, adjusting cerebrovascular resistance to maintain stable flow ( 67 , 68 ). Yet its capacity diminishes under sudden or extreme pressure changes ( 69 ). Mild increases in ICP activate astrocyte-mediated sympathetic responses to preserve perfusion whereas larger increases trigger the Cushing reflex ( 70 – 72 ). Thus, elevated ICP during hypertension can further impair cerebral perfusion due to dysfunction of autoregulatory and baroreflex mechanisms ( 73 – 75 ). Moreover, the BBB plays a key role in regulating cerebral volume, as its low permeability to solutes such as sodium and chloride makes it a critical determinant of brain homeostasis ( 76 ). Limitations This study has several limitations. First, CMD provides regional measurements, reflecting metabolism only near the probe tip; localised perfusion differences may influence results. Second, anaesthesia and surgical stress can modify metabolic responses, as anaesthesia generally reduces cerebral metabolic demand. Third, fluid resuscitation, vasopressor use, glucose administration, or antibiotics may have influenced perfusion and metabolism. Fourth, the absence of sham controls. Finally, the short 90-minute observation period may have prevented detection of delayed metabolic disturbances. The limited number of animals, owing to cost and resource constraints, also restricts statistical power. Nevertheless, pigs remain the preferred translational model because of their close physiology to humans. Conclusion tREBOA effectively restores cerebral haemodynamic and reverses cerebral ischaemia induced by HS. Even in the presence of raised ICP, tREBOA did not exacerbate metabolic injury, suggesting that its use may be neuro-protective rather than contraindicated in poly-trauma patients with concomitant head injury. These findings call attention to the potential of tREBOA to extend the “golden hour” in severe HS until definitive surgical control is achieved. Abbreviations AO Aortic Occlusion BBB Blood-Brain Barrier CA Cerebral Autoregulation CBF Cerebral Blood Flow CH Cerebral Hemodynamics CL Cerebral Lactate CMD Cerebral Microdialysis CP Cerebral Pyruvate CPP Cerebral Perfusion Pressure EICPG Elevated Intracranial Pressure Group HS Haemorrhagic Shock ICP Intracranial Pressure LPR Lactate Pyruvate Ratio MAP Mean Arterial Pressure NICPG Normal Intracranial Pressure Group pMAP Proximal Mean Arterial Pressure PRX Pressure Reactivity Index REBOA Resuscitative Endovascular Balloon Occlusion of the Aorta tREBOA Total Resuscitative Endovascular Balloon Occlusion of the Aorta Declarations Funding Declaration This study was supported by grants from the County Council of the County Council of Örebro Län 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 the County Council of Västerbotten RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07). Author Contribution A: S BaderB: Anders MagnusonC: C BrorssonD: N LöfgrenE: F LöfgrenF: P-J BlindG: M ÖmanH: M OlivecronaA: 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. Acknowledgement - This study was supported by grants from the County Council of the County Council of Örebro Län 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 the County Council of Västerbotten RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07). We are also grateful for the help given by PO Medica AB (Sparsör, Sweden) for providing the Sophysa ICP monitoring equipment.- AI-assisted writing disclosure:An AI-based language tool was used to improve grammar and clarity. All scientific content, data analysis, interpretation, and conclusions are the sole responsibility of the authors. References White JM, Cannon JW, Stannard A, Markov NP, Spencer JR, Rasmussen TE. Endovascular balloon occlusion of the aorta is superior to resuscitative thoracotomy with aortic clamping in a porcine model of hemorrhagic shock. Surgery. 2011;150(3):400–9. Hughes CW. 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2","display":"","copyAsset":false,"role":"figure","size":70893,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/863378e22d3da14a82dd6771.jpg"},{"id":100561523,"identity":"f2eed308-47dc-4f3e-9c57-ef4a4e74626a","added_by":"auto","created_at":"2026-01-19 08:44:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":75982,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/49eb69a3c672133a938e5b64.jpg"},{"id":100561557,"identity":"2cfc5ac3-4018-49fd-b930-427e7112c8d7","added_by":"auto","created_at":"2026-01-19 08:44:08","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":66444,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/14f54d436e75ac9dcaab1ac9.jpg"},{"id":100594916,"identity":"a7eb16d1-de43-41d4-be84-716d9d35c985","added_by":"auto","created_at":"2026-01-19 13:46:25","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":79583,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/ea2816629039a06de9d513dd.jpg"},{"id":100561319,"identity":"25cf74b0-fc11-41f7-bae7-dd236fc8483d","added_by":"auto","created_at":"2026-01-19 08:43:59","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":78380,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/9da0869dc29d26a300aa2422.jpg"},{"id":100561476,"identity":"a0feabb9-3bec-4233-b328-dea85695207b","added_by":"auto","created_at":"2026-01-19 08:44:05","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":76178,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/308adbaac0fe9bf7cdf773dc.jpg"},{"id":100597280,"identity":"fbfef281-9105-411d-b3b6-568766389ead","added_by":"auto","created_at":"2026-01-19 14:16:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1325265,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8541637/v1/3b342c1e-0257-4d53-abcf-6afa1643c964.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Aortic Occlusion with REBOA Reverses Cerebral Ischaemia Induced by Haemorrhagic Shock","fulltext":[{"header":"Background","content":"\u003cp\u003eIn recent years, the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) as a less invasive procedure compared to aortic cross-clamping via thoracotomy (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) has increased as an adjunct resuscitative method and a bridge to damage control surgery, primarily in trauma settings involving haemodynamically unstable patients (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe main function of REBOA in HS is to preserve the remaining blood to the upper part of the body, i.e. to the brain, the lungs, and the heart. Additionally, REBOA reduces ongoing bleeding distal to the occlusion until definitive haemostasis is achieved (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eREBOA increases blood pressure proximal to the occlusion zone (proximal mean arterial pressure (pMAP)); consequently, it might be lifesaving and mitigates cerebral damage and neurological sequelae following the reduction of cerebral perfusion in patients with HS (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, aortic occlusion (AO) might raise PBP to supraphysiological levels, and potentially disturb cerebral autoregulation (CA) causing cerebral damage (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe unique CA mechanism maintains a stable cerebral blood flow (CBF) in the intact brain despite fluctuations in blood pressure (BP). This mechanism ensures adequate CBF when the mean arterial pressure (MAP) is within the range of 50\u0026ndash;150 mmHg. Any changes in MAP outside this may cause cerebral ischaemia or cerebral oedema (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDue to the sudden elevation of PBP after AO, total REBOA (tREBOA) has been regarded by some authors as contraindicated in TBI and elevated ICP, as theoretically, the supraphysiological PBP caused by AO may exacerbate cerebral oedema and increase intracranial haemorrhage (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral animal studies in aortic and thoracic surgery have investigated the effects of AO on the brain using aortic cross-clamping. However, most of these studies were conducted on normovolemic animals (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). A few recent animal studies have focused on the cerebral effects of AO by REBOA in hypovolemic scenarios, primarily in trauma settings. These studies have mainly concentrated on haemodynamic and radiological changes in the brain (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCerebral microdialysis (CMD) is a validated method for monitoring chemical events and metabolic changes in cerebral tissue before they manifest in the blood (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Different neurochemical markers are used to detect early abnormal metabolic changes such as in the case of ischaemia, mitochondrial dysfunction, and cellular damage. Under normal conditions, glucose is the primary substrate for brain energy metabolism. The lactate/pyruvate ratio (LPR) indicates changes in the cellular redox state, and indicator for ischaemia (\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, the impact of thoracic AO in hypovolemic shock by REBOA on CM has not yet been described. However, we found two authors who have studied the metabolic changes in the spinal cord by inserting a MD probe into the lumbar spinal cord during AO in normovoleumic pigs. They reported changes in energy-related metabolites reflecting considerable ischaemia in the spinal cord tissue (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe purpose of this paper is to fill the knowledge gap regarding the impact of total AO by tREBOA on CM, in animals with HS.\u003c/p\u003e \u003cp\u003eThe first aim is to describe the changes in CM during total AO during HS in animals with normal and elevated ICP, and the second aim is to study whether there is a difference between CM in the two groups. The null hypothesis is that there are more pronounced cerebral metabolic changes in the group with elevated ICP, indicating that REBOA should not be used in individuals with suspected raised ICP or severe head injury.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics\u003c/h2\u003e \u003cp\u003e The study was approved by the Animal Experimental Ethics Committee at Ume\u0026aring; University, Sweden (A 32\u0026ndash;19). And conducted in accordance with Directive 2010/63/EU on the protection of animals used for scientific purposes, and the \u003cem\u003eGuide for the Care and Use of Laboratory Animals\u003c/em\u003e, National Research Council, Washington, DC, USA, 1996.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy overview\u003c/h3\u003e\n\u003cp\u003eWe studied two groups of animals with nine pigs in each, both males and females: The normal ICP group (NICPG), and the elevated ICP group (EICPG). The experiment comprised five phases illustrated in Fig.\u0026nbsp;1: the preparation phase, stabilisation phase, bleeding phase, occlusion phase, and lastly the termination phase (Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eAnimal preparation\u003c/h3\u003e\n\u003cp\u003eFor detailed information about the general experimental setup and protocol, see Bader et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eAnaesthesia\u003c/h3\u003e\n\u003cp\u003eThe animals were sedated with ketamine and atropine sulphate, whereafter anaesthesia was started using sodium pentobarbital. Anaesthesia was maintained using fentanyl, midazolam, and sodium pentobarbital. After sedation, the animals were tracheostomised and mechanically ventilated. Ringer\u0026rsquo;s acetate was given as fluid maintaining a central venous pressure of 5\u0026ndash;10 mmHg.\u003c/p\u003e\n\u003ch3\u003eGeneral monitoring and surgical preparation\u003c/h3\u003e\n\u003cp\u003eOxygen saturation was measured by pulse oximetry and heart rate was monitored by ECG. The CVP, PBP and the distal blood pressure in the femoral artery were monitored with the zero reference at heart level.\u003c/p\u003e \u003cp\u003eA REBOA was inserted via the right femoral artery. Confirmation of the balloon\u0026rsquo;s adequate placement in the aortic zone 1 was obtained under tactile guidance.\u003c/p\u003e \u003cp\u003eSaturation and ABP were documented every five minutes until the end of the experiment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCerebral monitoring\u003c/h2\u003e \u003cp\u003eAfter anaesthesia and overall monitoring were established, the animal was placed in a prone position. The head was shaved, cleaned, and disinfected. The cranial bone was exposed with a paramedian incision 6 cm long on the left side. A 3 mm burr hole was drilled frontally. Next, the dura was opened sharply, and haemostasis secured by diathermy. A four-lumen bolt (H QFlow 500 Titanium, Hemedex, Waltham, MA, USA) was placed in the burr hole.\u003c/p\u003e \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 10 mm into the brain, and connected to an ICP monitor (PSO-4000 Pressio 2, Sophysa, Orsay, France). ICP was continuously measured and manually recorded every five minutes. CPP was calculated according to the formula CPP\u0026thinsp;=\u0026thinsp;MAP\u0026thinsp;\u0026minus;\u0026thinsp;ICP.\u003c/p\u003e \u003cp\u003eTo simulate an acute epidural haematoma in EICPG, an extra 6 mm burr hole was drilled on the right side of the skull, where a Foley catheter (Ch12) was inserted into the epidural space. The balloon was inflated with saline to mimic an epidural haematoma.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMicrodialysis\u003c/h3\u003e\n\u003cp\u003eA microdialysis catheter (70Brain Catheter, mdialysis 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 (mdialysis Stockholm etc) using a microdialysis pump (CMA 107; CMA/ Microdialysis etc) 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. Samples were first stored at \u0026ndash; 6\u0026deg;C and transferred to a \u0026ndash; 20\u0026deg;C freezer. The microdialysis samples were analysed for glucose, lactate, and pyruvate using a CMA 600 Analyser (CMA Microdialysis AB, Stockholm, Sweden).\u003c/p\u003e\n\u003ch3\u003eStudy design and experimental protocol\u003c/h3\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStabilisation phase (60 minutes)\u003c/h2\u003e \u003cp\u003eIn a supine position with 15\u0026deg; table inclination, the animal was immobilised, keeping the head and heart on the same level; hence, the zero level of the PBP equals that of the ICP. Antibiotic prophylaxis with Cefuroxime 750 mg (MIP Pharma GmbH, Blieskastel, Germany) was given, and the 60-minutes stabilisation phase initiated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eBleeding phase (30 minutes)\u003c/h2\u003e \u003cp\u003eBlood volume for each animal was estimated at 8% of the animal\u0026rsquo;s body weight. Over 30 minutes 40% of the animal\u0026rsquo;s estimated blood volume was drained from the left femoral artery. The bleeding was calculated in ml/min according to the equation: Bleeding speed\u0026thinsp;=\u0026thinsp;Estimated blood volume / 30.\u003c/p\u003e \u003cp\u003eIntravenous infusion of 5000 IE Heparin (Heparin LEO Pharma AB; Malm\u0026ouml;, Sweden) was administered before the bleeding started, and Adrenaline (Mylan, Canonsburg, Pennsylvania, USA) was given if needed to keep the MAP around 40 mmHg and to simulate the physiological stress response.\u003c/p\u003e \u003cp\u003eDuring this phase, the epidural Foley balloon in the EICPG was injected slowly with saline, aiming at an ICP of 25\u0026ndash;30 mmHg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eOcclusion phase (90 minutes)\u003c/h2\u003e \u003cp\u003eOnce hypovolemia was achieved with MAP around 40 mmHg, the REBOA was inflated with saline (tREBOA) until ABP in the femoral artery disappeared (T\u0026thinsp;=\u0026thinsp;0 minutes) and the tREBOA was kept inflated for 90 minutes.\u003c/p\u003e \u003cp\u003eAfter AO we administered intravenously 500 ml of 6% hydroxyethyl starch in sodium chloride (Voluven Fresenius Kabi, Homburg, Germany) to mimic prehospital treatment of haemorrhagic shock.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTermination\u003c/h2\u003e \u003cp\u003eAfter 90 minutes of total AO, at a rate of 1 ml/min, the balloon was deflated, whereafter the animal was euthanized with a lethal intravenous injection of potassium chloride 40 mmol (Kaliumklorid; B. Braun Medical AB, Danderyd, Sweden) and sodium pentobarbital 400 mg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eThe outcomes pMAP, ICP, CPP, CL, CP and LPR were compared within and between study groups (EICPG, NICPG) at every 5- minute time point from \u0026minus;\u0026thinsp;30 until 90 minutes after AO with a random intercept linear mixed model. Study groups and time points and the interaction (group x time points) were used as fixed factors. All outcomes except pMAP and CPP were evaluated on the natural log scale, which showed better normal distribution assumptions for the standardised residuals. Sensitivity analyses were performed by excluding outliers if the standardised residual was greater than 3 (in absolute value). Association measures were mean differences with 95% confidence intervals (CI), and on the log scale, mean ratios (95% CI). A mean ratio of 1.20 interprets as the mean being 20% higher for exposed vs. unexposed. To reduce the risk of false-positive findings due to multiple testing because of many time points, a P-value below 0.01 was considered statistically significant. All analyses were performed with STATA release 17 (StataCorp, College Station, TX).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eEighteen pigs (thirteen female and five male) with a mean weight of 48.6 kg with (SD\u0026thinsp;=\u0026thinsp;6.9) were included in statistical analysis.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003eProximal Mean Arterial Pressure (pMAP)\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eDuring the bleeding phase in NICPG, pMAP showed a statistically significant decrease from initial mean 95 mmHg to baseline mean 49 mmHg before AO, mean difference 46 (95% CI 29\u0026ndash;63; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), then increased rapidly after AO, peaking 20 minutes later up to 159 mmHg and remaining elevated throughout the experiment.\u003c/p\u003e \u003cp\u003eA similar pattern was observed in the EICPG; however, pMAP reached its peak of 168 mmHg 15 minutes post-AO.\u003c/p\u003e \u003cp\u003eNo statistically significant difference in pMAP was observed between groups during the bleeding phase. However, the pMAP in the EICPG was statistically significantly higher than in the NICPG from 15 minutes post-AO onward at multiple time points (Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eIntracranial Pressure (ICP):\u003c/h2\u003e \u003cp\u003eIn the NICPG, ICP remained stable with a mean of around 15 mmHg throughout the experiment.\u003c/p\u003e \u003cp\u003eIn the EICPG, inflation of the epidural balloon led to a significant rise in ICP from 17 mmHg to 29 mmHg prior to AO (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). After AO, ICP further increased, reaching a maximum of 38 mmHg at 5 minutes post-AO, though this was not statistically significant compared to pre-AO baseline (P\u0026thinsp;\u0026gt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eICP was statistically significantly higher in EICPG than in NICPG from 5 minutes before AO until the end of the experiment (Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCerebral Perfusion Pressure (CPP):\u003c/h2\u003e \u003cp\u003eIn the NICPG, CPP declined from 78 mmHg to 32 mmHg during the bleeding phase (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), then rose rapidly after AO, peaking at 115 mmHg after 20 minutes. It remained statistically significantly elevated compared to pre-AO baseline for the rest of the experiment.\u003c/p\u003e \u003cp\u003eIn the EICPG, CPP dropped to 16 mmHg pre-AO and rose to a peak of 124 mmHg 15 minutes post-AO, staying statistically significantly above baseline thereafter.\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference in CPP between the groups, except at one time point (5 minutes post-AO), where EICPG had significantly lower CPP than NICPG (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCerebral Lactate (CL):\u003c/h2\u003e \u003cp\u003eIn the NICPG, CL gradually increased during the bleeding phase from 0.71 mmol/L to 1.13 mmol/L pre-AO (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and continued to rise slowly during the occlusion phase, though not statistically significant on any time point.\u003c/p\u003e \u003cp\u003eIn the EICPG, CL started to increase earlier than in NICPG and reached statistically significant elevated levels from 55 minutes into the timeline.\u003c/p\u003e \u003cp\u003eNo statistically significant differences in CL were observed between the groups throughout the experiment (Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eCerebral Pyruvate (CP):\u003c/h2\u003e \u003cp\u003eIn the NICPG, CP increased statistically significantly at 20 minutes post-AO (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and remained elevated (Fig.\u0026nbsp;6).\u003c/p\u003e \u003cp\u003eIn the EICPG, CP remained stable during bleeding but increased statistically significantly 15 minutes after AO and stayed elevated.\u003c/p\u003e \u003cp\u003eInitial CP levels were statistically significantly lower in the EICPG compared to NICPG (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and 5 and 10 minutes after AO (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). However, in the sensitivity analysis, excluding outliers, the differences at 5 and 10 minutes after AO were no longer statistically significant. (Fig.\u0026nbsp;6).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eCerebral Lactate Pyruvate Ratio (LPR):\u003c/h2\u003e \u003cp\u003eIn the NICPG, LPR rose from mean of 26 to 47 during bleeding, (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and gradually decreased after AO, reaching a low mean level of 34 by 25 minutes post-AO but never reached statistically significantly low levels compared to pre-AO until the end of the experiment.\u003c/p\u003e \u003cp\u003eIn the EICPG, LPR also rose during bleeding and increased further 5 minutes post-AO before gradually declining and remained statistically significantly low compared to pre-AO.\u003c/p\u003e \u003cp\u003eStatistically significant differences between groups were found during the first 10 minutes post-AO only (Fig.\u0026nbsp;7).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough the human brain accounts for only about 2% of total body weight, it receives nearly 20% of the cardiac output and body energy production. Due to its limited energy reserves, even brief interruptions in CBF can rapidly result in severe neurological impairment (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). The cerebral cytoplasmic redox state, expressed by the lactate-to-pyruvate ratio (LPR), serves as a sensitive indicator of mitochondrial oxidative metabolism (\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this experimental model, we demonstrated at the cellular level that AO using tREBOA is an effective resuscitative strategy in uncontrolled HS. During HS in the normal ICP group (NICPG), LPR increased slightly due to elevated lactate and decreased pyruvate levels but returned to baseline following AO, indicating reversibility of cerebral ischaemia.\u003c/p\u003e \u003cp\u003eThe same pattern was observed in EICPG, however, LPR reached higher values with about a 20-minute delay before returning to baseline. Changes in LPR align with the changes in cerebral haemodynamic MAP and CPP. In EICPG CPP reached critically low levels by the end of bleeding phase, which might indicate an alteration of CA (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe abrupt increase in MAP induced by AO did not significantly affect cerebral metabolism in the NICPG. However, in EICPG, a transient and reversible ischaemic disturbance was observed, evidenced by an LPR peak following the supraphysiological MAP (129 mmHg) induced by AO.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to demonstrate enhanced cerebral metabolism and reversible ischaemia following HS resuscitated with tREBOA. Nevertheless, our haemodynamic findings are consistent with previous reports that described comparable effects of AO and tREBOA on MAP, ICP, and CPP in HS (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn trauma, HS frequently coexists with traumatic brain injury (TBI) and elevated ICP (\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Approximately 80% of trauma-related deaths are attributed to uncontrolled haemorrhage and 4% to TBI. (Kelly JF 2008) The coexistence of these two conditions nearly doubles morbidity and mortality compared to HS alone (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTime is a critical factor in trauma management, especially in haemodynamically unstable patients. Fluid resuscitation alone may be insufficient to restore cardiac output and cerebral perfusion. Achieving distal control of bleeding can also be challenging in cases of massive haemorrhage.\u003c/p\u003e \u003cp\u003eInflation of the tREBOA balloon in aortic zone 1 divides the arterial system into two distinct circulatory compartments: a proximal (upper body) circulation and a distal (lower body) circulation. However, minimal collateral flow persists through arterial connections between these two regions (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur animal model replicates two clinical trauma scenarios: NICPG representing uncontrolled HS resuscitated by tREBOA with a target MAP of approximately 40 mmHg, as recommended by the European Society for Intensive Care Medicine (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). And EICPG a more complex polytrauma model combining uncontrolled HS with acute ICP elevation (25 mmHg) simulating subdural or epidural haematoma, also resuscitated using tREBOA (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eNormal ICP group (NICPG)\u003c/h2\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eBleeding phase\u003c/h2\u003e \u003cp\u003eIn NICPG, LPR increased significantly between the beginning and end of the bleeding phase (P\u0026thinsp;=\u0026thinsp;0.0081), indicating cerebral ischaemia. Similar findings were reported by Jakobsen et al., who observed increased LPR in anesthetised pigs during HS (MAP 40 mmHg for 60 minutes) resuscitated with autologous blood, although LPR decreased after resuscitation, it remained elevated above baseline (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). In another experiment for Jakobsen R et al published in 2016 shown that prolonged (90 min) and severe hypotension (MAP 40 mmHg) results in irreversible metabolic perturbation evaluated by CMD (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCerebral ischaemia typically results from reduced CPP or elevated ICP, leading to well-known metabolic disturbances. Oxygen deprivation during ischaemia causes an immediate rise in cytoplasmic and interstitial LPR due to a shift in the lactate dehydrogenase equilibrium (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe observed LPR elevation coincided with MAP falling below 50 mmHg, consistent with transient impairment of CA and reduced CBF (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCA maintains constant CBF across a broad CPP range, defined as MAP minus ICP. With normal ICP (5\u0026ndash;10 mmHg), CBF remains stable up to MAP values of approximately 120 mmHg. Once CPP decreases below 50 mmHg, autoregulation fails, resulting in progressive cerebral dysfunction (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). When blood flows decline to 25\u0026ndash;30 mL/100 g/min, electroencephalographic changes occur along with alterations in consciousness. With further decreasing below 20 mL/100 g/min, electroencephalogram become isoelectric, and neurons switch to anaerobic metabolism. At 10\u0026ndash;12 mL/100 g/min, neurotransmission stops, sodium-potassium pumps fail, and cytotoxic oedema develops. Finaly, at 6\u0026ndash;10 mL/100 g/min, cerebral tissue dies (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eOcclusion phase\u003c/h2\u003e \u003cp\u003eAfter 20 minutes of tREBOA resuscitation, LPR gradually declined and stabilised, simultaneous to increases in CPP and MAP. This decline indicates the recovery of cerebral metabolism and reversal of ischaemia. When cerebral oxygenation is promptly restored, LPR typically returns to near-normal levels. Lactate and pyruvate, being water-soluble, quickly equilibrate across the blood-brain barrier (BBB) and cell membranes (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eElevated ICP group (EICPG)\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section4\"\u003e \u003ch2\u003eBleeding Phase\u003c/h2\u003e \u003cp\u003eAt the end of the bleeding, ICP was artificially increased to 25\u0026ndash;30 mmHg to simulate an acute subdural haematoma, following the method described by Timaru-Kast et al. This model reliably induces reproducible ICP elevation and associated cerebral energy metabolism alterations similar to those observed in TBI (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDuring haemorrhage, LPR rose exponentially, reaching significantly higher levels than in NICPG, indicating more pronounced cerebral ischaemia. The increase in LPR corresponded with critical reductions in CPP (16 mmHg), aggravated by artificially elevated ICP (25 mmHg).\u003c/p\u003e \u003cp\u003eAccording to the Monro\u0026ndash;Kellie doctrine, intracranial volume is constant, comprising blood brain tissue, and cerebrospinal fluid. Disruption of this equilibrium through haemorrhage, ischaemia, hydrocephalus, or reperfusion injury raises ICP and can lead to reduced CPP, cerebral ischaemia, or herniation (\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn intact autoregulation, hypotension elevates ICP, whereas hypertension may have minimal impact. However, in cases of impaired autoregulation, ICP fluctuates directly with blood pressure (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIncreased ICP without compensatory hypertension reduces cerebral perfusion and may trigger the Cushing reflex, a physiological triad of hypertension, bradycardia, and irregular respiration in response to ICP\u0026thinsp;\u0026gt;\u0026thinsp;25 mmHg (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eOcclusion phase\u003c/h2\u003e \u003cp\u003eLPR was already increased by the end of bleeding phase. After AO, a further increase occurred after AO, for about 5 minutes, then decreased significantly after 20 minutes, returning to baseline within 30 minutes. This transient rise suggests reversible ischaemic stress.\u003c/p\u003e \u003cp\u003eThe supraphysiologic arterial pressure up to 168 mmHg in this group can be explained by a double mechanism: The effect of AO itself on cerebral blood volume and alteration of autoregulation, and by Cushing reflex due to ICP increasing over 25 mmHg (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a study by Bader et al., the authors showed that total AO by tREBOA induces a reversible alteration of CA with positive values of the Modified-Long Pressure Reactivity Index (mL-PRx) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies demonstrated that acute hypertension caused by descending AO can elevate CBF, cause vasodilation, and disrupt the BBB (\u003cspan additionalcitationids=\"CR58 CR59 CR60 CR61 CR62 CR63\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOther experimental studies about the metabolic effects of acute hypertension induced by angiotensin on the brain showed that LPR was not affected but produced multifocal BBB leakage of Evans blue albumin (\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAutoregulation remains the brain\u0026rsquo;s primary protective mechanism against acute hypertension, adjusting cerebrovascular resistance to maintain stable flow (\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e). Yet its capacity diminishes under sudden or extreme pressure changes (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e). Mild increases in ICP activate astrocyte-mediated sympathetic responses to preserve perfusion whereas larger increases trigger the Cushing reflex (\u003cspan additionalcitationids=\"CR71\" citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThus, elevated ICP during hypertension can further impair cerebral perfusion due to dysfunction of autoregulatory and baroreflex mechanisms (\u003cspan additionalcitationids=\"CR74\" citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e). Moreover, the BBB plays a key role in regulating cerebral volume, as its low permeability to solutes such as sodium and chloride makes it a critical determinant of brain homeostasis (\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eThis study has several limitations. First, CMD provides regional measurements, reflecting metabolism only near the probe tip; localised perfusion differences may influence results. Second, anaesthesia and surgical stress can modify metabolic responses, as anaesthesia generally reduces cerebral metabolic demand. Third, fluid resuscitation, vasopressor use, glucose administration, or antibiotics may have influenced perfusion and metabolism. Fourth, the absence of sham controls. Finally, the short 90-minute observation period may have prevented detection of delayed metabolic disturbances. The limited number of animals, owing to cost and resource constraints, also restricts statistical power. Nevertheless, pigs remain the preferred translational model because of their close physiology to humans.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003etREBOA effectively restores cerebral haemodynamic and reverses cerebral ischaemia induced by HS. Even in the presence of raised ICP, tREBOA did not exacerbate metabolic injury, suggesting that its use may be neuro-protective rather than contraindicated in poly-trauma patients with concomitant head injury. These findings call attention to the potential of tREBOA to extend the \u0026ldquo;golden hour\u0026rdquo; in severe HS until definitive surgical control is achieved.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eAO\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAortic Occlusion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBBB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBlood-Brain Barrier\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Autoregulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCBF\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Blood Flow\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCH\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Hemodynamics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCL\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Lactate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCMD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Microdialysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Pyruvate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCPP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebral Perfusion Pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEICPG\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElevated Intracranial Pressure Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eHS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHaemorrhagic Shock\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eICP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntracranial Pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eLPR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLactate Pyruvate Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMAP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMean Arterial Pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNICPG\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNormal Intracranial Pressure Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003epMAP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProximal Mean Arterial Pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePRX\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePressure Reactivity Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eREBOA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResuscitative Endovascular Balloon Occlusion of the Aorta\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003etREBOA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTotal Resuscitative Endovascular Balloon Occlusion of the Aorta\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding Declaration\u003c/h2\u003e \u003cp\u003eThis study was supported by grants from the County Council of the County Council of \u0026Ouml;rebro L\u0026auml;n 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 the County Council of V\u0026auml;sterbotten RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA: S BaderB: Anders MagnusonC: C BrorssonD: N L\u0026ouml;fgrenE: F L\u0026ouml;fgrenF: P-J BlindG: M \u0026Ouml;manH: M OlivecronaA: 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.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003e- This study was supported by grants from the County Council of the County Council of \u0026Ouml;rebro L\u0026auml;n 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 the County Council of V\u0026auml;sterbotten RV- 969834 (2021-10-11), RV- 941769 (2020-10-10) RV-849041 (2018-10-07). We are also grateful for the help given by PO Medica AB (Spars\u0026ouml;r, Sweden) for providing the Sophysa ICP monitoring equipment.- AI-assisted writing disclosure:An AI-based language tool was used to improve grammar and clarity. All scientific content, data analysis, interpretation, and conclusions are the sole responsibility of the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWhite JM, Cannon JW, Stannard A, Markov NP, Spencer JR, Rasmussen TE. Endovascular balloon occlusion of the aorta is superior to resuscitative thoracotomy with aortic clamping in a porcine model of hemorrhagic shock. Surgery. 2011;150(3):400\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHughes CW. Use of an intra-aortic balloon catheter tamponade for controlling intra-abdominal hemorrhage in man. 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Hypertension. 1998;31(1):68\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSomers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension. 1988;11(6 Pt 2):608\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982;16(3):163\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJD F. Volume regulation of the central nervous system. In: A T, editor. Edema. New York: Raven; 1984. pp. 383\u0026ndash;404.\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":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-trauma-and-emergency-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejot","sideBox":"Learn more about [European Journal of Trauma and Emergency Surgery](http://link.springer.com/journal/68)","snPcode":"68","submissionUrl":"https://submission.nature.com/new-submission/68/3","title":"European Journal of Trauma and Emergency Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Resuscitative Endovascular Balloon Occlusion of the Aorta, REBOA, haemorrhagic shock, cerebral microdialysis, metabolism, LPR, ischemia","lastPublishedDoi":"10.21203/rs.3.rs-8541637/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8541637/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\nIn recent years, the use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) as a less invasive procedure compared to aortic cross-clamping via thoracotomy (1) has increased as an adjunct resuscitative method and a bridge to damage control surgery, primarily in trauma settings involving haemodynamically unstable patients (2-4).\nThe main function of REBOA in HS is to preserve the remaining blood to the upper part of the body, i.e. to the brain, the lungs, and the heart. Additionally, REBOA reduces ongoing bleeding distal to the occlusion until definitive haemostasis is achieved (5).\nREBOA increases blood pressure proximal to the occlusion zone (proximal mean arterial pressure (pMAP)); consequently, it might be lifesaving and mitigates cerebral damage and neurological sequelae following the reduction of cerebral perfusion in patients with HS (6, 7).","manuscriptTitle":"Aortic Occlusion with REBOA Reverses Cerebral Ischaemia Induced by Haemorrhagic Shock","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 08:30:53","doi":"10.21203/rs.3.rs-8541637/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-28T10:27:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-28T09:48:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-23T18:20:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"316892519764781588515121709489764819020","date":"2026-01-16T06:42:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333354149111426429157931204858895685735","date":"2026-01-13T17:33:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-13T13:28:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-10T22:48:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-10T08:09:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Trauma and Emergency Surgery","date":"2026-01-07T12:35:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-trauma-and-emergency-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejot","sideBox":"Learn more about [European Journal of Trauma and Emergency Surgery](http://link.springer.com/journal/68)","snPcode":"68","submissionUrl":"https://submission.nature.com/new-submission/68/3","title":"European Journal of Trauma and Emergency Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2d641a0e-0af3-49f0-b895-f0b066cdcf46","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-07T11:09:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 08:30:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8541637","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8541637","identity":"rs-8541637","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}