Intraspinal pressure is not elevated after traumatic spinal cord injury in a porcine model sham-controlled trial.

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Mathias Møller Møller Thygesen, Seyar Entezari, Nanna Kaae Houlind, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4453192/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Dec, 2024 Read the published version in Neurocritical Care → Version 1 posted 4 You are reading this latest preprint version Abstract Introduction It has been suggested that intraspinal pressure (ISP) below the dura is elevated following traumatic spinal cord injury (TSCI). The dura can maintain the pressure, a hence a subdural compartment syndrome has been hypothesized to develop regardless of bony decompression. This study aimed to evaluate whether a such intradural compartment syndrome develops during the first 72 hours in a porcine TSCI model. Methods First, in a randomized sham controlled-trial design, longitudinal ISP measurements were performed over a period of 72 h from onset of TSCI. TSCI was inflicted by a weight-drop contusion regime: 75 g rod, 75 mm free fall, 5 min compression of the spinal cord. Second, in a sham controlled dose-response design longitudinal ISP measurements were performed over a period of 16 h from onset of TSCI, using two other contusion regimes: 75 g, 125 mm free fall, 5 min compression; and 75 g, 75 mm, 240 min compression. Animals were kept sedated for the entire course of the study using propofol, fentanyl and midazolam. Results ISP increased in TSCI and sham animals alike, but we found no significant increase in ISP following TSCI compared to the sham group, and we found no relationship between the ISP increase and the severity or duration of the TSCI impact. Conclusion These findings suggest that the subdural swelling of the spinal cord following TSCI is not responsible for the ISP increase measured in our TSCI model, but that the ISP increase was caused by the surgical procedure or the reconstitution of normal CSF pressure. Spinal Cord Injuries Pressure Critical Care Trauma Figures Figure 1 Figure 2 Figure 3 Introduction The mechanical forces exerted directly to the spinal cord during traumatic spinal cord injury (TSCI) causes irreversible damage to the tracts of the spinal cord and disrupt blood vessels and cell membranes 1 – 4 . Furthermore, the primary insult initiates a secondary cascade that leads to progressive cell death and spinal cord damage due to the concomitant immunological response and edema 2 , 5 – 7 . The developed edema is hypothesized to produce a subdural compartment syndrome by an increased intraspinal pressure (ISP) causing hypoperfusion 8 – 11 . Given that scenario, today’s standard care, bony decompression, may not suffice in preserving adequate perfusion of the spinal cord 12 . This mechanism has been the basis for guidelines recommending admission of TSCI patients to critical care for maintaining spinal cord perfusion using therapeutic hypertension 13 – 15 . Previous studies have found that ISP gradually increases during the acute phase despite bony decompression 10 , 16 – 20 . Furthermore, elevated ISP has been correlated with worse outcome 21 . Motivated by these findings, several studies have subsequently intervened in TSCI, with the aim of preserving perfusion, by the means of expansive duroplasty 22 , therapeutic hypertension 12 or drainage 10 , 23 . ISP increase following TSCI is a premise for these interventions. It has never been evaluated against a stand-alone laminectomy. I It is unknown whether the surgical intervention (the laminectomy and probe placement) itself contributes to ISP increase. The aims of this two-part study were as follows: sub study one: To investigate the development of ISP after onset of TSCI and compare it with the development after a sham laminectomy procedure; and sub study two: To investigate whether larger impacts or longer duration of compression produces higher ISP compared with less impact and shorter duration of compression. Methods Study design and overview The study was conducted in two sub-studies: a primary trial, and a subsequent dose-response study. Sub study one was performed as a sham-controlled trial in a developed TSCI model. The study inflicted TSCI using a 75 g rod falling 75 mm whilst sustaining compression for 5 min. Following, ISP was measured for 72 h. Sub study two was designed to evaluate the effects on ISP of varying degrees of impact and compression duration. This study was conducted using different injury regimens as described below and measured ISP for 16 h after onset of injury. The duration time (16 h) was based on our findings in sub study one, showing a peak ISP at 8–14 h. Animals Danish female Landrace pigs weighing 38–42 kg were included. The study was approved by the Danish Animal Research Inspectorate (approval no. 2020-15-0201-00687). Anesthesia and intensive care protocol A detailed description of the experimental TSCI animal model was described previously 24 . The animal was intubated and sedated during a period of 72 h, sustained by propofol (10 mg/mL Propofol B, Braun), fentanyl (50 ug/mL Fentanyl,) and midazolam (1 mg/mL Midazolam Hameln). Infusion rates were titrated to clinical effect, evaluated by hourly clinical examinations of snout and ciliary reflexes, along with reactions to painful stimuli. When hypotension occurred, defined as mean arterial blood pressure (MAP) below 65 mmHg, administration of crystalloid fluids and noradrenaline were initiated. Mechanical ventilation, fluids and nutrition administration were adjusted according to hourly control of ventilator metrics, urine output and vital parameters. Further, arterial blood gasses were obtained every third hour, and any derangement was corrected accordingly. For sub study one, the animal was positioned in the recumbent position and repositioned every 24th hour. For sub study two, the animal was kept in prone position during the 16 h. Surgical procedure and probe placement A 2.5 level laminectomy was performed at the thoracic level 8 following subperiosteal dissection of the paravertebral musculature. Before inflicting injury, a subdural ISP probe (Sophysa Pressio catheter) was placed under microscopic magnification. A scalpel was used to produce a 2 mm incision in the dura. The ISP probe was tunneled through a distal opening in the skin and advanced through the dural incision. The probe tip was placed directly at the injury site. A single suture was placed in the dura to avoid leaking of cerebrospinal fluid (CSF). The probe was fixed using purse string suture around the muscular tunnel within the surgical wound and in the surface skin. Injury protocols and groups TSCI was inflicted as described in a previous study 25 , using a 75 g round tipped rod falling in a cylinder that controls the trajectory. An overview of groups and procedures is shown in Fig. 1 . For sub study one, the TSCI injury regime included a rod fall of 75 mm and compression time of 5 min. For sub study two, two additional regimes were tested: a 75 mm fall and 240 min of compression, and a 125 mm fall and 5 min of compression. ISP probe and data acquisition The ISP probe was connected to a pressure monitor (Sophysa Pressio II), connected to a critical care unit (CCU) monitor (Phillips Intellivue MX500). The software ICM+ (University of Cambridge) 26 registered data from the ICU monitor. To automatically filter out artefacts from manipulations (flushing or blood sampling) with the arterial line, MAP values above 180 mmHg were filtered out, and last observation was carried forward. End tidal CO 2 was registered every hour and plasma sodium levels were measured every third hour. Analyses and statistics Both studies were analyzed using plots of means and 95% confidence intervals and mixed models. All means are presented with 95% confidence intervals. Raw data are plotted as spaghetti plots, and the means and 95%CI for are plotted for each group. The results of the statistical model were plotted as margins plots. The mixed model computed ISP as the dependent variable, and group and time from TSCI (repeated) were considered explanatory variables. Time was binned into 6-hour blocks. For sub study one, the first 30 min were excluded to remove the artefacts from the direct impact and the surgical closure. For sub study two, the first 4.5 h were filtered out for the same reasons. The assumptions for the model, independence and equal standard deviations and correlations in the groups, were tested prior to fitting. Diagnostic plots of residuals and fitted values were constructed before accepting the model (Supplementary files 1 and 2 for sub study one and sub study two, respectively). Data from sub study one was included in sub study two but limited to 16 h of follow up. Plots of plasma sodium concentration and arterial pressure of CO 2 (pCO 2 ) were plotted as well, since they were potential confounders, but were not included in the model due to a lack of replicates. A significance level of 5% was used. Due to observations of changes in ISP following change in positioning, we examined the absolute difference in ISP before and after repositioning. Results Sub study one ISP increased from baseline for both groups (Fig. 2 a and 2 b). During the 72-hour course, the maximum ISP was 13.3 mmHg [2.6, 24.0] for the TSCI group and 12.5 mmHg [8.0, 17.1] for the sham group (Fig. 2 b). MAP was kept above 65 mmHg during the 72-hour study (Fig. 2 c). The arterial gasses found the animals to be marginally hypo-ventilated for the beginning of the experiments, whilst returning to normo-ventilation over the course of the study (Fig. 2 d). The mean plasma sodium levels were kept within reference ranges for the entire study for both groups (Fig. 2 e). The mixed model found no statistically significant effect of TSCI as compared to sham (coefficient: 1.90, p = 0.249), but found a significant effect of time in the time blocks between 12 h and 42 h regardless of groups. This finding means that ISP is increased as compared with the baseline regardless of the group. The mixed model statistics found the mean ISP of the TSCI group to be insignificantly higher than the sham group throughout the study (Fig. 2 F), with the highest absolute difference at any time block being 2.36 mmHg at 54 h. The maximum ISP reached by any TSCI individual was 27.8 mmHg and for any sham individual 24.6 mmHg (Fig. 2 a). During the 72-hour period from onset of TSCI, the animal was repositioned multiple times. The mean change in ISP following a repositioning was 1.42 mmHg but ranged from 0.099 mmHg to 2.90 mmHg. Study two ISP increased from baseline for all the groups (Fig. 3 a and 3 b). During the 16-hour course, the maximum group mean ISP was 10.1 mmHg [6.30, 13.9] for the sham group, 13.2 mmHg [7.97, 18.5] for the 75 mm, 5 min group; 14.3 mmHg [4.35, 24.3] for the 125 mm, 5 min group and 11.5 mmHg [4.08, 18.9] for the 75 mm, 240 min group. MAP was kept stable above 65 mmHg during the study (Fig. 3 c). We found that the animals normo-ventilated during the study (Fig. 3 d). The mean plasma sodium levels were kept within reference ranges during the entire study period for both groups (Fig. 3 e). The mixed model found no statistically significant main effect of different trauma regimes (75 mm 5 min coefficient: 0.03, p = 0.99; 125 mm 5 min coefficient: 1.96, p = 0.47; 75 mm 240 min coefficient: -2.76, p = 0.31). Meaning that ISP did not increase significantly differently between groups. There were significant interactions of time block 12 hours and the 75 mm 240 min group (95% CI 0.28, 4.55, p = 0.03) and time block 16 hours (95% CI 0.81, 5.08, p = 0.01). However, this was caused by the fact that the 75 mm 240 min group started out with a lower ISP, as seen both in the margins plot (Fig. 3 f) and from the main effect of -22.76 (95% CI -8.35, 2.83, p = 0.31). The predicted ISP of the 75 mm 420 min group was never higher than the sham group (Fig. 3 f). The maximum ISP reached by any individual was 24.62 mmHg in the sham group, 20.26 mmHg in the 75 mm, 5 min group, 24.6 mmHg the 125 mm, 5 min group and 18.1 mmHg in the 75 mm, 240 min group. Discussion In sub study one, we observed no significant difference in the increase of ISP following TSCI compared to the sham operated group. The absolute mean difference in ISP between TSCI and sham was not higher than the mean difference in ISP following repositioning. In sub study two, we observed no effect of increasing impact nor duration of the compression compared to the regime of sub study one and the sham operated group. The animals were kept physiologically stable throughout the course of the respective sub studies. We observed an increase in ISP for both sham and TSCI animals. The increase was higher in the TSCI groups. However, the absolute difference between the highest ISP in both groups was 0.8 mmHg which is lower than considered clinically significant. Following these findings, a subsequent study applying increased TSCI impact severity and duration was conducted (sub study two). Neither of these regimes produced significant ISP rises compared to sham or inter- injury regimes. We decided upon a large falling height (125 mm) and prolonged compression (4 hours). The large falling height produced substantial macroscopic injury, in which hematoma below dura was evident. For one animal subjected to the 125 mm falling height, we observed an ISP in the range of 20–25 mmHg, but generally, the increased falling height and longer compression failed to produce further elevation of ISP compared to lower falling heights and short duration of compression. The mixed model of sub study two, found a positive and significant interaction effect of the 75 mm 240 min group. This means that the 75 mm 240 min group had ISP significantly increased compared with sham over time. It is imperative to state that it did not find the ISP of the 75 mm 240 min group to be higher than the sham. Since this group started out at a markedly lower ISP than the sham, the finding merely suggests, that the group increases towards the sham; not above. The reason for this could be the removal of the rod after 240 min. It was evident that the cord was completely compressed, in turn reducing the subdural tissue volume. The dura would quickly expand, leaving the pressure at zero or even negative. Previous TSCI studies investigating ISP have shown divergent results. Human studies have shown increased ISP in human TSCI 20 , 27 . In one study, the ISP increase was evaluated against a control group (12 mmHg), consisting of patients suspected of normal pressure hydrocephalus having their CSF pressures measured, using a lumbar catheter 8 . The authors found a significant difference in mean ISP (approximately 10 mmHg). Two porcine studies found elevated ISP after onset of TSCI 16 , 17 . The first study applied intraparenchymal probes and found a 220% increase in ISP compared to baseline (10.5 mmHg vs 23 mmHg). This study did not have a control group. However, in another study applying the same model to evaluate the effect of duroplasty, the control group (TSCI minus duroplasty) mean ISP was only just above 10 mmHg 16 . This is comparable to ISP observed in our study. The pathophysiological processes associated with TSCI may differ between pigs and humans, and both our results and previous results suggest that our TSCI porcine model does not reach the anticipated compartment syndrome 16 . Perhaps the development of high ISP is a multifactorial process including contributions from both the subdural and extradural compartments, and other factors, that we do not have control of in this study. This argument would explain the observed pressures in both ends of the spectrum in two different studies 16 , 17 , and why we observed one animal with high ISP (20–25 mmHg). Further, a multifactorial mechanism may explain the human findings, where not all patients seem to develop high ISP 8 . Another explanation of our model not producing a subdural compartment syndrome, could be the anatomical differences between cervical and thoracic regions of the spine. We opted for a thoracic injury to reduce the risk of an unstable model due to autonomic complications. The cervical spinal cord is larger in the traverse plane and might fill the dura more readily. It cannot be excluded as one of the factors driving a compartment syndrome and may explain why our model found different ISP increases compared to those reported in human studies with cervical patients 8 , 22 . Another difference between our study and earlier studies is the use of general anesthesia throughout the study. In TBI, anesthesia, using propofol and midazolam will lower cerebral metabolism, in turn lowering intracranial pressure (ICP) 28 . Since our animals were anesthetized for the entire study, we cannot exclude a diminished ISP rise in TSCI compared to sham using anesthesia. However, a general and close to similar increase in ISP was found in both sham and TSCI. Following, anesthesia should selectively diminish the trauma effects to introduce bias. Considering our knowledge from TBI, it is known that hyperventilation decreases ICP through vasoconstriction and hence a decreased intracranial volume of blood 28 . In our study, animals were kept normo-ventilated. One way of mitigating ICP increase in TBI is through plasma sodium concentration increase. Despite meticulous corrections, two TSCI animals had sodium levels above reference at the late stage of the experiments. The group mean plasma sodium concentration was within the reference range. We find it less likely, that minor divergence in plasma sodium could account for the lack of ISP increase in the TSCI group alone. Despite not observing differences in ISP between groups, we did observe an overall ISP rise from baseline for all groups. These finding suggest that the ISP rise, or at least a part of it, is not dependent on TSCI, but is rather the result of the surgical procedure and/or probe placement. First, the surgical procedure itself produces concomitant edema and minor hemorrhage in the soft tissue above the spinal column could cause external dural pressure. This may explain the observed slow pressure buildup during the first 12–24 hours. To evaluate this mechanism, supplementary studies measuring the epidural pressure should be conducted. Second, the probe is located intimately against the spinal cord and could theoretically produce spinal cord edema following placement by inflicting a minimal trauma. Disregard it would be minimal and we find this mechanism to be likely. Third, the subarachnoid space is sparse, and probe volume may contribute to ISP increase by occupying part of the subarachnoid space. If this mechanism was true, one would expect an abrupt pressure increase to a steady state during seconds. This is not observed in our data; contrary, a gradual buildup of pressure is observed during the first 12 hours. Finally, the observed rise may represent the reconstitution of the normal CSF pressure. During probe placement, CSF leaks through the incision in the dura is unavoidable. After placement, a watertight dural closure was performed. This could allow for a gradual reconstitution of CSF. Following, a pressure buildup could be observed. Despite different reports on the reference range and upper normal level for CSF pressure in humans, there is consensus on the pressure not being zero and probably in the range of 4–30 mmHg 29 , 30 . This range includes the ISPs we have observed in the present study. Conclusions In this randomized trial, in a porcine model, we found no significant increase in ISP following TSCI compared to sham surgery. ISP increase was not statistically dependent on severity or duration of TSCI impact. ISP increased in TSCI and sham animal alike, suggesting that the ISP increase measured in our model, was either attributed to the surgery itself, or caused by reconstitution of a normal CSF pressure. Declarations Summary of disclosures: No potential conflicts of interests were identified for this study within the group of the authors. Original research Requirements for submission The manuscript complies with all instructions to authors Authors We hereby confirm that authorship requirements have been met and the final manuscript was approved by all authors Publications elsewhere This manuscript has not been published elsewhere and is not under consideration by another journal Ethics The study was approved by the Danish Animal Research Inspectorate (approval no. 2020-15-0201-00687). Availability of data and materials The dataset supporting the conclusions of this article is included within the article and its Supplementary files (Supplementary file 3). Competing interests The authors declare that they have no conflicts of interest. Funding This study was funded by Offerfonden (“The Victims Foundation” under Ministry of Justice of Denmark), The Riisfort Foundation, AP Møller Mærsk Foundation, The Dagmar Marshalls Foundation and Aarhus University. Authors' contributions MMT: Conceptualization, Data curation, Investigation, Formal analysis, Funding Acquisition, Methodology, Software, Visualization, Writing – Original Draft. SE: Investigation, Writing – review & editing NH Investigation, Writing – review & editing THN: Investigation, Writing – review & editing NØO Investigation, Writing – review & editing TDN: Investigation, Formal analysis, Writing – review & editing MS Investigation, Writing – review & editing AT: Supervision, Software, Writing – review & editing MR: Supervision, Writing – review & editing HBE: Investigation, Writing – review & editing DO: Investigation, Methodology, Supervision Writing – review & editing SED: Supervision, Methodology, Resources, Writing – review & editing LT: Supervision, Methodology, Writing – review & editing MP Investigation, Supervision, Methodology, Resources, Project administration, Writing – review & editing MMR: Conceptualization, Investigation, Supervision, Methodology, Resources, Project administration, Funding acquisition, Writing – review & editing References Aguayo AJ, Rasminsky M, Bray GM, et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 1991;331(1261):337-43, doi:10.1098/rstb.1991.0025 Silver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol 2015;7(3):a020602, doi:10.1101/cshperspect.a020602 Cajal Ry. Degeneration and regeneration of the nervous system. oxford university press, 1928. Oxford University Press: 1928. Zorner B, Schwab ME. Anti-Nogo on the go: from animal models to a clinical trial. Ann N Y Acad Sci 2010;1198 Suppl 1(E22-34, doi:10.1111/j.1749-6632.2010.05566.x Popovich PG, Guan Z, McGaughy V, et al. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 2002;61(7):623-33 Popovich PG, Guan Z, Wei P, et al. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999;158(2):351-65, doi:10.1006/exnr.1999.7118 Fleming JC, Norenberg MD, Ramsay DA, et al. The cellular inflammatory response in human spinal cords after injury. Brain 2006;129(Pt 12):3249-69, doi:10.1093/brain/awl296 Werndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study*. Crit Care Med 2014;42(3):646-55, doi:10.1097/ccm.0000000000000028 Saadoun S, Werndle MC, Lopez de Heredia L, et al. The dura causes spinal cord compression after spinal cord injury. Br J Neurosurg 2016;30(5):582-4, doi:10.3109/02688697.2016.1173191 Kwon BK, Curt AN, Belanger LM, et al. Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: A prospective randomized trial - Clinical article. Journal of Neurosurgery: Spine 2009;10(3):181-193, doi:10.3171/2008.10.SPINE08217 Grassner L, Winkler PA, Strowitzki M, et al. Increased intrathecal pressure after traumatic spinal cord injury: an illustrative case presentation and a review of the literature. Eur Spine J 2017;26(1):20-25, doi:10.1007/s00586-016-4769-9 Werndle MC, Saadoun S, Phang I, et al. Measurement and optimisation of spinal cord perfusion pressure in acute spinal cord injury. Br J Neurosurg 2013;27(5):556, doi:10.3109/02688697.2013.833786 Fehlings MG, Tetreault LA, Wilson JR, et al. A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury and Central Cord Syndrome: Recommendations on the Timing (≤24 Hours Versus >24 Hours) of Decompressive Surgery. Global Spine J 2017;7(3 Suppl):195s-202s, doi:10.1177/2192568217706367 Hadley MN, Walters BC, Grabb PA, et al. Management of acute central cervical spinal cord injuries. Neurosurgery 2002;50(3 Suppl):S166-72, doi:10.1097/00006123-200203001-00025 Walters BC, Hadley MN, Hurlbert RJ, et al. Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 update. Neurosurgery 2013;60(CN_suppl_1):82-91, doi:10.1227/01.neu.0000430319.32247.7f Streijger F, Kim KT, So K, et al. Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model. J Neurotrauma 2021;38(21):2937-2955, doi:10.1089/neu.2021.0084 Streijger F, So K, Manouchehri N, et al. Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model. J Neurotrauma 2017;34(24):3336-3350, doi:10.1089/neu.2017.5034 Phang I, Werndle MC, Saadoun S, et al. Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: injured spinal cord pressure evaluation study. J Neurotrauma 2015;32(12):865-74, doi:10.1089/neu.2014.3668 Varsos GV, Werndle MC, Czosnyka ZH, et al. Intraspinal pressure and spinal cord perfusion pressure after spinal cord injury: an observational study. J Neurosurg Spine 2015;23(6):763-71, doi:10.3171/2015.3.Spine14870 Phang I, Papadopoulos MC. Intraspinal Pressure Monitoring in a Patient with Spinal Cord Injury Reveals Different Intradural Compartments: Injured Spinal Cord Pressure Evaluation (ISCoPE) Study. Neurocrit Care 2015;23(3):414-8, doi:10.1007/s12028-015-0153-6 Saadoun S, Chen SL, Papadopoulos MC. Intraspinal pressure and spinal cord perfusion pressure predict neurological outcome after traumatic spinal cord injury. Journal of Neurology Neurosurgery and Psychiatry 2017;88(5):452-+, doi:10.1136/jnnp-2016-314600 Phang IS, Werndle MC, Varsos G, et al. Injured spinal cord pressure evaluation (iscope) study: Expansion duroplasty reduces spinal cord pressure in acute spinal cord injury. J Neurotrauma 2014;31(5):A28, doi:10.1089/neu.2014.9937 Theodore N, Martirosyan N, Hersh AM, et al. Cerebrospinal Fluid Drainage in Patients with Acute Spinal Cord Injury: A Multi-Center Randomized Controlled Trial. World Neurosurg 2023, doi:10.1016/j.wneu.2023.06.078 Thygesen M, Entezari S, Houlind N, et al. A 72-hour sedated porcine model of traumatic spinal cord injury Brain and Spine 2024; Thygesen MM, Entezari S, Houlind N, et al. A 72-hour sedated porcine model of traumatic spinal cord injury. Brain and Spine 2024;102813, doi:https://doi.org/10.1016/j.bas.2024.102813 Smielewski P, Czosnyka M, Steiner L, et al. ICM+: software for on-line analysis of bedside monitoring data after severe head trauma. Acta Neurochir Suppl 2005;95(43-9, doi:10.1007/3-211-32318-x_10 Hogg FRA, Gallagher MJ, Chen SL, et al. Predictors of Intraspinal Pressure and Optimal Cord Perfusion Pressure After Traumatic Spinal Cord Injury. Neurocrit Care 2019;30(2):421-428, doi:10.1007/s12028-018-0616-7 Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017;80(1):6-15, doi:10.1227/neu.0000000000001432 Whiteley W, Al-Shahi R, Warlow CP, et al. CSF opening pressure: reference interval and the effect of body mass index. Neurology 2006;67(9):1690-1, doi:10.1212/01.wnl.0000242704.60275.e9 Bø SH, Lundqvist C. Cerebrospinal fluid opening pressure in clinical practice - a prospective study. J Neurol 2020;267(12):3696-3701, doi:10.1007/s00415-020-10075-3 Supplementary Files Supplementaryfile1.tif Supplementary file 1 · Supplementary file 2 · Tag Image File Format (TIFF) · Diagnostic plots from the mixed model on sub study one. · Residuals are not showing a tend to be skewed over levels of each explanatory variable or the fitted values. The QQ plot of the residuals suggests a normal distribution. Supplementaryfile2.tif Supplementary file 2 · Supplementary file 2 · Tag Image File Format (TIFF) · Supplementary figure 2: Diagnostic plots from the mixed model on sub study one. · Residuals are not showing a tend to be skewed over levels of each explanatory variable or the fitted values. The QQ plot of the residuals suggests a normal distribution. supplementaryfile3.csv Supplementary file 3 · Supplementary file 1 · Comma separated file · Dataset · Raw dataset containing data that were used for the analyses of the study. Cite Share Download PDF Status: Published Journal Publication published 11 Dec, 2024 Read the published version in Neurocritical Care → Version 1 posted Reviewers agreed at journal 28 May, 2024 Reviewers invited by journal 27 May, 2024 Editor assigned by journal 23 May, 2024 First submitted to journal 22 May, 2024 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4453192","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307432239,"identity":"e411a4e8-a7e4-47f6-a40d-5737449032e3","order_by":0,"name":"Mathias Møller Møller Thygesen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYJACZgYGGwY+ZgiHcQYRGhibGRjSGNhI1XKYgY2BWC267eePPy5sOy/Pxs57gOFnG4PszAYCWszOJDM2z2y7bdjGzJfA2NvGYDybkC1mB4BaeNtuJ7Ax8xgw8LYxJM4jqOX8Y5CWc2AtjH+J0nIDbMsBsBZmkC2EHXbjseFsnnPJQL/wGByWOSdhTNj75xMffOYps5Pn5z9j+PBNmY3sjAOErAEBRmikABVLEKMeBP4Qq3AUjIJRMApGJAAA5dk46V2+ITkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6544-8450","institution":"Aarhus University","correspondingAuthor":true,"prefix":"","firstName":"Mathias","middleName":"Møller Møller","lastName":"Thygesen","suffix":""},{"id":307432240,"identity":"95935bae-7090-4890-a47c-c31b47d2d396","order_by":1,"name":"Seyar Entezari","email":"","orcid":"","institution":"Aarhus University Department of Clinical Medicine: Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"prefix":"","firstName":"Seyar","middleName":"","lastName":"Entezari","suffix":""},{"id":307432241,"identity":"e21e94c8-b9bb-48c2-92ff-b9649e5fb341","order_by":2,"name":"Nanna Kaae Houlind","email":"","orcid":"","institution":"Aarhus University Department of Clinical Medicine: Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"prefix":"","firstName":"Nanna","middleName":"Kaae","lastName":"Houlind","suffix":""},{"id":307432242,"identity":"d0e9820d-3d23-4dde-a73a-64d095bb73a5","order_by":3,"name":"Teresa Haugaard Nielsen","email":"","orcid":"","institution":"Aarhus University Department of Clinical Medicine: Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"prefix":"","firstName":"Teresa","middleName":"Haugaard","lastName":"Nielsen","suffix":""},{"id":307432243,"identity":"372f2afb-7ce9-4c70-a511-0ae1d95e673b","order_by":4,"name":"Nicholas Østergaard Olsen","email":"","orcid":"","institution":"Aarhus University Department of Clinical Medicine: Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"Østergaard","lastName":"Olsen","suffix":""},{"id":307432244,"identity":"d33f6ae6-e1cf-4de3-90b0-3358e15a7b85","order_by":5,"name":"Tim Damgaard Nielsen","email":"","orcid":"","institution":"Aarhus University Department of Clinical Medicine: Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"prefix":"","firstName":"Tim","middleName":"Damgaard","lastName":"Nielsen","suffix":""},{"id":307432245,"identity":"8e8f9891-1f75-49e1-8960-003439bc0e01","order_by":6,"name":"Mathias Skov","email":"","orcid":"","institution":"Aarhus University: Aarhus Universitet","correspondingAuthor":false,"prefix":"","firstName":"Mathias","middleName":"","lastName":"Skov","suffix":""},{"id":307432246,"identity":"b55df4f8-8230-43d2-9ec2-040ad7d1c9de","order_by":7,"name":"Alp Tankisi","email":"","orcid":"","institution":"Aarhus University Hospital: Aarhus Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Alp","middleName":"","lastName":"Tankisi","suffix":""},{"id":307432247,"identity":"95e23da7-d101-4942-b2be-db9f895a77b7","order_by":8,"name":"Mads Rasmussen","email":"","orcid":"","institution":"Aarhus University Hospital: Aarhus Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Mads","middleName":"","lastName":"Rasmussen","suffix":""},{"id":307432248,"identity":"76b4a68b-59ea-48d7-835f-1ffb287210ff","order_by":9,"name":"Halldór Bjarki Einarsson","email":"","orcid":"","institution":"Aalborg University Hospital: Aalborg Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Halldór","middleName":"Bjarki","lastName":"Einarsson","suffix":""},{"id":307432249,"identity":"37546992-616f-4861-98aa-a4449619dc1e","order_by":10,"name":"Dariusz Orlowski","email":"","orcid":"","institution":"Aarhus University: Aarhus Universitet","correspondingAuthor":false,"prefix":"","firstName":"Dariusz","middleName":"","lastName":"Orlowski","suffix":""},{"id":307432250,"identity":"42ef6712-ce47-44da-ab9f-170356434814","order_by":11,"name":"Stig Dyrskog","email":"","orcid":"","institution":"Aarhus University Hospital: Aarhus Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Stig","middleName":"","lastName":"Dyrskog","suffix":""},{"id":307432251,"identity":"42b40ade-f0d4-4184-83f6-a0028f6f646a","order_by":12,"name":"Line Thorup","email":"","orcid":"","institution":"Aarhus University Hospital: Aarhus Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Line","middleName":"","lastName":"Thorup","suffix":""},{"id":307432252,"identity":"2f7536c1-6693-4953-be11-639a2b00d73d","order_by":13,"name":"Michael Pedersen","email":"","orcid":"","institution":"Aarhus University: Aarhus Universitet","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Pedersen","suffix":""},{"id":307432253,"identity":"d7f474e3-5cdf-4d95-ac44-8e2a53bb30c3","order_by":14,"name":"Mikkel Mylius Rasmussen","email":"","orcid":"","institution":"Aarhus University Hospital: Aarhus Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Mikkel","middleName":"Mylius","lastName":"Rasmussen","suffix":""}],"badges":[],"createdAt":"2024-05-21 08:13:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4453192/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4453192/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12028-024-02181-1","type":"published","date":"2024-12-11T15:57:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58170262,"identity":"39fd425a-1b64-4c43-83d7-172c6f90957c","added_by":"auto","created_at":"2024-06-12 03:37:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":424506,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy overview:\u003c/strong\u003e Graphical illustration of the timeline, intervention regimes and group-sizes of the two sub studies.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/aaebe48ef37692cc08d13a88.jpg"},{"id":58170263,"identity":"ddd6e51c-4294-4d2d-8c61-70677d3bcffc","added_by":"auto","created_at":"2024-06-12 03:37:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":564663,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime-data of sub-study 1: (A) \u003c/strong\u003eRaw data on ISP for each animal in the study, during the 72 hours from onset of TSCI. \u003cstrong\u003e(B)\u003c/strong\u003e Mean ISP for each group. \u003cstrong\u003e(C)\u003c/strong\u003e Mean MAP for each group. \u003cstrong\u003e(D)\u003c/strong\u003e Mean pCO2 for each group. \u003cstrong\u003e(E)\u003c/strong\u003e Mean plasma sodium for each group. \u003cstrong\u003e(F)\u003c/strong\u003e Graphical representation, in the form of margins plots of the mixed model. The graphs depict the modelled mean of each group at each time block of 6 hours. Lines depict the group mean; ranges and error bars depict 95% Confidence intervals. Orange: TSCI; Blue: Sham.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/19d29347a95730411640048c.jpg"},{"id":58170261,"identity":"924ee88d-2a8c-48c7-b055-08f806e05c7a","added_by":"auto","created_at":"2024-06-12 03:37:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":520505,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime-data of sub-study 2: (A) \u003c/strong\u003eRaw data on ISP for each animal in the study, during the 16 hours after onset of TSCI. \u003cstrong\u003e(B)\u003c/strong\u003e Mean ISP for each group. \u003cstrong\u003e(C)\u003c/strong\u003e Mean MAP for each group. \u003cstrong\u003e(D)\u003c/strong\u003e Mean pCO2 for each group. \u003cstrong\u003e(E)\u003c/strong\u003e Mean plasma sodium for each group. \u003cstrong\u003e(F)\u003c/strong\u003e Graphical representation, in the form of margins plots of the mixed model. The graphs depict the modelled mean of each group at each time block of 6 hours. Lines depict the group mean; ranges and error bars depict 95% confidence intervals. Blue: sham; Orange: 75 mm 5 min regime; Green: 125 mm 5 min regime; Dark grey: 75 mm 240 min.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/dc7f07e3a4c88867494bcf88.jpg"},{"id":71552474,"identity":"693d561d-3c42-46aa-bff4-554b6495c99b","added_by":"auto","created_at":"2024-12-16 16:06:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1942114,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/708377ac-a76a-4d98-b03b-094d2e501ffe.pdf"},{"id":58170265,"identity":"c3a033a2-43ae-4942-a7e0-8f5664cbe3e3","added_by":"auto","created_at":"2024-06-12 03:37:54","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14382990,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Supplementary \u003cstrong\u003efile 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003eTag Image File Format (TIFF)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003eDiagnostic plots from the mixed model on sub study one.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Residuals are not showing a tend to be skewed over levels of each explanatory variable or the fitted values. The QQ plot of the residuals suggests a normal distribution.\u003c/p\u003e","description":"","filename":"Supplementaryfile1.tif","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/b9bda2b69478ed35193bc6c8.tif"},{"id":58170264,"identity":"28caf484-abb7-4618-bbab-27fcc0628407","added_by":"auto","created_at":"2024-06-12 03:37:54","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14382990,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Supplementary\u003cstrong\u003e file 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003eTag Image File Format (TIFF)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003eSupplementary figure 2: Diagnostic plots from the mixed model on sub study one.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Residuals are not showing a tend to be skewed over levels of each explanatory variable or the fitted values. The QQ plot of the residuals suggests a normal distribution.\u003c/p\u003e","description":"","filename":"Supplementaryfile2.tif","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/4cb8733d6b392aecdb067293.tif"},{"id":58170266,"identity":"5e196c2d-2cc9-4fa9-b53c-fade018c50ee","added_by":"auto","created_at":"2024-06-12 03:37:54","extension":"csv","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19364264,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· Supplementary file 1\u003c/p\u003e\n\u003cp\u003e· Comma separated file\u003c/p\u003e\n\u003cp\u003e· Dataset\u003c/p\u003e\n\u003cp\u003e· Raw dataset containing data that were used for the analyses of the study.\u003c/p\u003e","description":"","filename":"supplementaryfile3.csv","url":"https://assets-eu.researchsquare.com/files/rs-4453192/v1/21af6d6e3b3f29e9b655e1c8.csv"}],"financialInterests":"","formattedTitle":"Intraspinal pressure is not elevated after traumatic spinal cord injury in a porcine model sham-controlled trial.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe mechanical forces exerted directly to the spinal cord during traumatic spinal cord injury (TSCI) causes irreversible damage to the tracts of the spinal cord and disrupt blood vessels and cell membranes\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Furthermore, the primary insult initiates a secondary cascade that leads to progressive cell death and spinal cord damage due to the concomitant immunological response and edema\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The developed edema is hypothesized to produce a subdural compartment syndrome by an increased intraspinal pressure (ISP) causing hypoperfusion\u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Given that scenario, today\u0026rsquo;s standard care, bony decompression, may not suffice in preserving adequate perfusion of the spinal cord\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This mechanism has been the basis for guidelines recommending admission of TSCI patients to critical care for maintaining spinal cord perfusion using therapeutic hypertension \u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrevious studies have found that ISP gradually increases during the acute phase despite bony decompression\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\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/sup\u003e. Furthermore, elevated ISP has been correlated with worse outcome\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Motivated by these findings, several studies have subsequently intervened in TSCI, with the aim of preserving perfusion, by the means of expansive duroplasty\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, therapeutic hypertension\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e or drainage \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eISP increase following TSCI is a premise for these interventions. It has never been evaluated against a stand-alone laminectomy. I It is unknown whether the surgical intervention (the laminectomy and probe placement) itself contributes to ISP increase. The aims of this two-part study were as follows: sub study one: To investigate the development of ISP after onset of TSCI and compare it with the development after a sham laminectomy procedure; and sub study two: To investigate whether larger impacts or longer duration of compression produces higher ISP compared with less impact and shorter duration of compression.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design and overview\u003c/p\u003e \u003cp\u003eThe study was conducted in two sub-studies: a primary trial, and a subsequent dose-response study. Sub study one was performed as a sham-controlled trial in a developed TSCI model. The study inflicted TSCI using a 75 g rod falling 75 mm whilst sustaining compression for 5 min. Following, ISP was measured for 72 h. Sub study two was designed to evaluate the effects on ISP of varying degrees of impact and compression duration. This study was conducted using different injury regimens as described below and measured ISP for 16 h after onset of injury. The duration time (16 h) was based on our findings in sub study one, showing a peak ISP at 8\u0026ndash;14 h.\u003c/p\u003e \u003cp\u003eAnimals\u003c/p\u003e \u003cp\u003eDanish female Landrace pigs weighing 38\u0026ndash;42 kg were included. The study was approved by the Danish Animal Research Inspectorate (approval no. 2020-15-0201-00687).\u003c/p\u003e \u003cp\u003eAnesthesia and intensive care protocol\u003c/p\u003e \u003cp\u003eA detailed description of the experimental TSCI animal model was described previously \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The animal was intubated and sedated during a period of 72 h, sustained by propofol (10 mg/mL Propofol B, Braun), fentanyl (50 ug/mL Fentanyl,) and midazolam (1 mg/mL Midazolam Hameln). Infusion rates were titrated to clinical effect, evaluated by hourly clinical examinations of snout and ciliary reflexes, along with reactions to painful stimuli. When hypotension occurred, defined as mean arterial blood pressure (MAP) below 65 mmHg, administration of crystalloid fluids and noradrenaline were initiated. Mechanical ventilation, fluids and nutrition administration were adjusted according to hourly control of ventilator metrics, urine output and vital parameters. Further, arterial blood gasses were obtained every third hour, and any derangement was corrected accordingly. For sub study one, the animal was positioned in the recumbent position and repositioned every 24th hour. For sub study two, the animal was kept in prone position during the 16 h.\u003c/p\u003e \u003cp\u003eSurgical procedure and probe placement\u003c/p\u003e \u003cp\u003eA 2.5 level laminectomy was performed at the thoracic level 8 following subperiosteal dissection of the paravertebral musculature. Before inflicting injury, a subdural ISP probe (Sophysa Pressio catheter) was placed under microscopic magnification. A scalpel was used to produce a 2 mm incision in the dura. The ISP probe was tunneled through a distal opening in the skin and advanced through the dural incision. The probe tip was placed directly at the injury site. A single suture was placed in the dura to avoid leaking of cerebrospinal fluid (CSF). The probe was fixed using purse string suture around the muscular tunnel within the surgical wound and in the surface skin.\u003c/p\u003e \u003cp\u003eInjury protocols and groups\u003c/p\u003e \u003cp\u003eTSCI was inflicted as described in a previous study \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, using a 75 g round tipped rod falling in a cylinder that controls the trajectory. An overview of groups and procedures is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. For sub study one, the TSCI injury regime included a rod fall of 75 mm and compression time of 5 min. For sub study two, two additional regimes were tested: a 75 mm fall and 240 min of compression, and a 125 mm fall and 5 min of compression.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eISP probe and data acquisition\u003c/p\u003e \u003cp\u003eThe ISP probe was connected to a pressure monitor (Sophysa Pressio II), connected to a critical care unit (CCU) monitor (Phillips Intellivue MX500). The software ICM+ (University of Cambridge)\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e registered data from the ICU monitor. To automatically filter out artefacts from manipulations (flushing or blood sampling) with the arterial line, MAP values above 180 mmHg were filtered out, and last observation was carried forward. End tidal CO\u003csub\u003e2\u003c/sub\u003e was registered every hour and plasma sodium levels were measured every third hour.\u003c/p\u003e \u003cp\u003eAnalyses and statistics\u003c/p\u003e \u003cp\u003eBoth studies were analyzed using plots of means and 95% confidence intervals and mixed models. All means are presented with 95% confidence intervals. Raw data are plotted as spaghetti plots, and the means and 95%CI for are plotted for each group. The results of the statistical model were plotted as margins plots. The mixed model computed ISP as the dependent variable, and group and time from TSCI (repeated) were considered explanatory variables. Time was binned into 6-hour blocks. For sub study one, the first 30 min were excluded to remove the artefacts from the direct impact and the surgical closure. For sub study two, the first 4.5 h were filtered out for the same reasons. The assumptions for the model, independence and equal standard deviations and correlations in the groups, were tested prior to fitting. Diagnostic plots of residuals and fitted values were constructed before accepting the model (Supplementary files 1 and 2 for sub study one and sub study two, respectively).\u003c/p\u003e \u003cp\u003eData from sub study one was included in sub study two but limited to 16 h of follow up. Plots of plasma sodium concentration and arterial pressure of CO\u003csub\u003e2\u003c/sub\u003e (pCO\u003csub\u003e2\u003c/sub\u003e) were plotted as well, since they were potential confounders, but were not included in the model due to a lack of replicates. A significance level of 5% was used.\u003c/p\u003e \u003cp\u003eDue to observations of changes in ISP following change in positioning, we examined the absolute difference in ISP before and after repositioning.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSub study one\u003c/p\u003e \u003cp\u003eISP increased from baseline for both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). During the 72-hour course, the maximum ISP was 13.3 mmHg [2.6, 24.0] for the TSCI group and 12.5 mmHg [8.0, 17.1] for the sham group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). MAP was kept above 65 mmHg during the 72-hour study (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The arterial gasses found the animals to be marginally hypo-ventilated for the beginning of the experiments, whilst returning to normo-ventilation over the course of the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). The mean plasma sodium levels were kept within reference ranges for the entire study for both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe mixed model found no statistically significant effect of TSCI as compared to sham (coefficient: 1.90, p\u0026thinsp;=\u0026thinsp;0.249), but found a significant effect of time in the time blocks between 12 h and 42 h regardless of groups. This finding means that ISP is increased as compared with the baseline regardless of the group. The mixed model statistics found the mean ISP of the TSCI group to be insignificantly higher than the sham group throughout the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF), with the highest absolute difference at any time block being 2.36 mmHg at 54 h. The maximum ISP reached by any TSCI individual was 27.8 mmHg and for any sham individual 24.6 mmHg (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003eDuring the 72-hour period from onset of TSCI, the animal was repositioned multiple times. The mean change in ISP following a repositioning was 1.42 mmHg but ranged from 0.099 mmHg to 2.90 mmHg.\u003c/p\u003e \u003cp\u003eStudy two\u003c/p\u003e \u003cp\u003eISP increased from baseline for all the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). During the 16-hour course, the maximum group mean ISP was 10.1 mmHg [6.30, 13.9] for the sham group, 13.2 mmHg [7.97, 18.5] for the 75 mm, 5 min group; 14.3 mmHg [4.35, 24.3] for the 125 mm, 5 min group and 11.5 mmHg [4.08, 18.9] for the 75 mm, 240 min group. MAP was kept stable above 65 mmHg during the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). We found that the animals normo-ventilated during the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). The mean plasma sodium levels were kept within reference ranges during the entire study period for both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe mixed model found no statistically significant main effect of different trauma regimes (75 mm 5 min coefficient: 0.03, p\u0026thinsp;=\u0026thinsp;0.99; 125 mm 5 min coefficient: 1.96, p\u0026thinsp;=\u0026thinsp;0.47; 75 mm 240 min coefficient: -2.76, p\u0026thinsp;=\u0026thinsp;0.31). Meaning that ISP did not increase significantly differently between groups. There were significant interactions of time block 12 hours and the 75 mm 240 min group (95% CI 0.28, 4.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) and time block 16 hours (95% CI 0.81, 5.08, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). However, this was caused by the fact that the 75 mm 240 min group started out with a lower ISP, as seen both in the margins plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef) and from the main effect of -22.76 (95% CI -8.35, 2.83, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31). The predicted ISP of the 75 mm 420 min group was never higher than the sham group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef).\u003c/p\u003e \u003cp\u003eThe maximum ISP reached by any individual was 24.62 mmHg in the sham group, 20.26 mmHg in the 75 mm, 5 min group, 24.6 mmHg the 125 mm, 5 min group and 18.1 mmHg in the 75 mm, 240 min group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn sub study one, we observed no significant difference in the increase of ISP following TSCI compared to the sham operated group. The absolute mean difference in ISP between TSCI and sham was not higher than the mean difference in ISP following repositioning. In sub study two, we observed no effect of increasing impact nor duration of the compression compared to the regime of sub study one and the sham operated group. The animals were kept physiologically stable throughout the course of the respective sub studies.\u003c/p\u003e \u003cp\u003eWe observed an increase in ISP for both sham and TSCI animals. The increase was higher in the TSCI groups. However, the absolute difference between the highest ISP in both groups was 0.8 mmHg which is lower than considered clinically significant.\u003c/p\u003e \u003cp\u003eFollowing these findings, a subsequent study applying increased TSCI impact severity and duration was conducted (sub study two). Neither of these regimes produced significant ISP rises compared to sham or inter- injury regimes. We decided upon a large falling height (125 mm) and prolonged compression (4 hours). The large falling height produced substantial macroscopic injury, in which hematoma below dura was evident. For one animal subjected to the 125 mm falling height, we observed an ISP in the range of 20\u0026ndash;25 mmHg, but generally, the increased falling height and longer compression failed to produce further elevation of ISP compared to lower falling heights and short duration of compression.\u003c/p\u003e \u003cp\u003eThe mixed model of sub study two, found a positive and significant interaction effect of the 75 mm 240 min group. This means that the 75 mm 240 min group had ISP significantly increased compared with sham over time. It is imperative to state that it did not find the ISP of the 75 mm 240 min group to be higher than the sham. Since this group started out at a markedly lower ISP than the sham, the finding merely suggests, that the group increases towards the sham; not above. The reason for this could be the removal of the rod after 240 min. It was evident that the cord was completely compressed, in turn reducing the subdural tissue volume. The dura would quickly expand, leaving the pressure at zero or even negative.\u003c/p\u003e \u003cp\u003ePrevious TSCI studies investigating ISP have shown divergent results. Human studies have shown increased ISP in human TSCI\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In one study, the ISP increase was evaluated against a control group (12 mmHg), consisting of patients suspected of normal pressure hydrocephalus having their CSF pressures measured, using a lumbar catheter\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The authors found a significant difference in mean ISP (approximately 10 mmHg). Two porcine studies found elevated ISP after onset of TSCI\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The first study applied intraparenchymal probes and found a 220% increase in ISP compared to baseline (10.5 mmHg vs 23 mmHg). This study did not have a control group. However, in another study applying the same model to evaluate the effect of duroplasty, the control group (TSCI minus duroplasty) mean ISP was only just above 10 mmHg\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. This is comparable to ISP observed in our study.\u003c/p\u003e \u003cp\u003eThe pathophysiological processes associated with TSCI may differ between pigs and humans, and both our results and previous results suggest that our TSCI porcine model does not reach the anticipated compartment syndrome\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Perhaps the development of high ISP is a multifactorial process including contributions from both the subdural and extradural compartments, and other factors, that we do not have control of in this study. This argument would explain the observed pressures in both ends of the spectrum in two different studies \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, and why we observed one animal with high ISP (20\u0026ndash;25 mmHg). Further, a multifactorial mechanism may explain the human findings, where not all patients seem to develop high ISP\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother explanation of our model not producing a subdural compartment syndrome, could be the anatomical differences between cervical and thoracic regions of the spine. We opted for a thoracic injury to reduce the risk of an unstable model due to autonomic complications. The cervical spinal cord is larger in the traverse plane and might fill the dura more readily. It cannot be excluded as one of the factors driving a compartment syndrome and may explain why our model found different ISP increases compared to those reported in human studies with cervical patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother difference between our study and earlier studies is the use of general anesthesia throughout the study. In TBI, anesthesia, using propofol and midazolam will lower cerebral metabolism, in turn lowering intracranial pressure (ICP)\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Since our animals were anesthetized for the entire study, we cannot exclude a diminished ISP rise in TSCI compared to sham using anesthesia. However, a general and close to similar increase in ISP was found in both sham and TSCI. Following, anesthesia should selectively diminish the trauma effects to introduce bias.\u003c/p\u003e \u003cp\u003eConsidering our knowledge from TBI, it is known that hyperventilation decreases ICP through vasoconstriction and hence a decreased intracranial volume of blood\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In our study, animals were kept normo-ventilated. One way of mitigating ICP increase in TBI is through plasma sodium concentration increase. Despite meticulous corrections, two TSCI animals had sodium levels above reference at the late stage of the experiments. The group mean plasma sodium concentration was within the reference range. We find it less likely, that minor divergence in plasma sodium could account for the lack of ISP increase in the TSCI group alone.\u003c/p\u003e \u003cp\u003eDespite not observing differences in ISP between groups, we did observe an overall ISP rise from baseline for all groups. These finding suggest that the ISP rise, or at least a part of it, is not dependent on TSCI, but is rather the result of the surgical procedure and/or probe placement. First, the surgical procedure itself produces concomitant edema and minor hemorrhage in the soft tissue above the spinal column could cause external dural pressure. This may explain the observed slow pressure buildup during the first 12\u0026ndash;24 hours. To evaluate this mechanism, supplementary studies measuring the epidural pressure should be conducted. Second, the probe is located intimately against the spinal cord and could theoretically produce spinal cord edema following placement by inflicting a minimal trauma. Disregard it would be minimal and we find this mechanism to be likely. Third, the subarachnoid space is sparse, and probe volume may contribute to ISP increase by occupying part of the subarachnoid space. If this mechanism was true, one would expect an abrupt pressure increase to a steady state during seconds. This is not observed in our data; contrary, a gradual buildup of pressure is observed during the first 12 hours. Finally, the observed rise may represent the reconstitution of the normal CSF pressure. During probe placement, CSF leaks through the incision in the dura is unavoidable. After placement, a watertight dural closure was performed. This could allow for a gradual reconstitution of CSF. Following, a pressure buildup could be observed. Despite different reports on the reference range and upper normal level for CSF pressure in humans, there is consensus on the pressure not being zero and probably in the range of 4\u0026ndash;30 mmHg\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. This range includes the ISPs we have observed in the present study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this randomized trial, in a porcine model, we found no significant increase in ISP following TSCI compared to sham surgery. ISP increase was not statistically dependent on severity or duration of TSCI impact. ISP increased in TSCI and sham animal alike, suggesting that the ISP increase measured in our model, was either attributed to the surgery itself, or caused by reconstitution of a normal CSF pressure.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSummary of disclosures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflicts of interests were identified for this study within the group of the authors. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal research\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRequirements for submission\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript complies with all instructions to authors\u003c/p\u003e\n\u003ch2\u003eAuthors\u003c/h2\u003e\n\u003cp\u003eWe hereby confirm that authorship requirements have been met and the final manuscript was approved by all authors\u003c/p\u003e\n\u003ch2\u003ePublications elsewhere\u003c/h2\u003e\n\u003cp\u003eThis manuscript has not been published elsewhere and is not under consideration by another journal\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEthics\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the Danish Animal Research Inspectorate (approval no. 2020-15-0201-00687).\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is included within the article and its\u0026nbsp;Supplementary\u0026nbsp;files (Supplementary\u0026nbsp;file 3).\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was funded by Offerfonden (\u0026ldquo;The Victims Foundation\u0026rdquo; under Ministry of Justice of Denmark), The Riisfort Foundation, AP M\u0026oslash;ller M\u0026aelig;rsk Foundation, The Dagmar Marshalls Foundation and Aarhus University.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions\u003c/h2\u003e\n\u003cul\u003e\n \u003cli\u003eMMT: Conceptualization, Data curation, Investigation, Formal analysis, Funding Acquisition, Methodology, Software, Visualization, Writing \u0026ndash; Original Draft.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSE: Investigation, Writing \u0026ndash; review \u0026amp; editing\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNH Investigation, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTHN: Investigation, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eN\u0026Oslash;O Investigation, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTDN: Investigation, Formal analysis, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMS Investigation, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAT: Supervision, Software, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMR: Supervision, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHBE: Investigation, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDO: Investigation, Methodology, Supervision Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSED: Supervision, Methodology, Resources, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLT: Supervision, Methodology, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMP Investigation, Supervision, Methodology, Resources, Project administration, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMMR: Conceptualization, Investigation, Supervision, Methodology, Resources, Project administration, Funding acquisition, Writing \u0026ndash; review \u0026amp; editing \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAguayo AJ, Rasminsky M, Bray GM, et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci 1991;331(1261):337-43, doi:10.1098/rstb.1991.0025\u003c/li\u003e\n\u003cli\u003eSilver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol 2015;7(3):a020602, doi:10.1101/cshperspect.a020602\u003c/li\u003e\n\u003cli\u003eCajal Ry. Degeneration and regeneration of the nervous system. oxford university press, 1928. Oxford University Press: 1928.\u003c/li\u003e\n\u003cli\u003eZorner B, Schwab ME. Anti-Nogo on the go: from animal models to a clinical trial. Ann N Y Acad Sci 2010;1198 Suppl 1(E22-34, doi:10.1111/j.1749-6632.2010.05566.x\u003c/li\u003e\n\u003cli\u003ePopovich PG, Guan Z, McGaughy V, et al. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 2002;61(7):623-33\u003c/li\u003e\n\u003cli\u003ePopovich PG, Guan Z, Wei P, et al. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999;158(2):351-65, doi:10.1006/exnr.1999.7118\u003c/li\u003e\n\u003cli\u003eFleming JC, Norenberg MD, Ramsay DA, et al. The cellular inflammatory response in human spinal cords after injury. Brain 2006;129(Pt 12):3249-69, doi:10.1093/brain/awl296\u003c/li\u003e\n\u003cli\u003eWerndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study*. Crit Care Med 2014;42(3):646-55, doi:10.1097/ccm.0000000000000028\u003c/li\u003e\n\u003cli\u003eSaadoun S, Werndle MC, Lopez de Heredia L, et al. The dura causes spinal cord compression after spinal cord injury. Br J Neurosurg 2016;30(5):582-4, doi:10.3109/02688697.2016.1173191\u003c/li\u003e\n\u003cli\u003eKwon BK, Curt AN, Belanger LM, et al. Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: A prospective randomized trial - Clinical article. Journal of Neurosurgery: Spine 2009;10(3):181-193, doi:10.3171/2008.10.SPINE08217\u003c/li\u003e\n\u003cli\u003eGrassner L, Winkler PA, Strowitzki M, et al. Increased intrathecal pressure after traumatic spinal cord injury: an illustrative case presentation and a review of the literature. Eur Spine J 2017;26(1):20-25, doi:10.1007/s00586-016-4769-9\u003c/li\u003e\n\u003cli\u003eWerndle MC, Saadoun S, Phang I, et al. Measurement and optimisation of spinal cord perfusion pressure in acute spinal cord injury. Br J Neurosurg 2013;27(5):556, doi:10.3109/02688697.2013.833786\u003c/li\u003e\n\u003cli\u003eFehlings MG, Tetreault LA, Wilson JR, et al. A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury and Central Cord Syndrome: Recommendations on the Timing (\u0026le;24 Hours Versus \u0026gt;24 Hours) of Decompressive Surgery. Global Spine J 2017;7(3 Suppl):195s-202s, doi:10.1177/2192568217706367\u003c/li\u003e\n\u003cli\u003eHadley MN, Walters BC, Grabb PA, et al. Management of acute central cervical spinal cord injuries. Neurosurgery 2002;50(3 Suppl):S166-72, doi:10.1097/00006123-200203001-00025\u003c/li\u003e\n\u003cli\u003eWalters BC, Hadley MN, Hurlbert RJ, et al. Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 update. Neurosurgery 2013;60(CN_suppl_1):82-91, doi:10.1227/01.neu.0000430319.32247.7f\u003c/li\u003e\n\u003cli\u003eStreijger F, Kim KT, So K, et al. Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model. J Neurotrauma 2021;38(21):2937-2955, doi:10.1089/neu.2021.0084\u003c/li\u003e\n\u003cli\u003eStreijger F, So K, Manouchehri N, et al. Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model. J Neurotrauma 2017;34(24):3336-3350, doi:10.1089/neu.2017.5034\u003c/li\u003e\n\u003cli\u003ePhang I, Werndle MC, Saadoun S, et al. Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: injured spinal cord pressure evaluation study. J Neurotrauma 2015;32(12):865-74, doi:10.1089/neu.2014.3668\u003c/li\u003e\n\u003cli\u003eVarsos GV, Werndle MC, Czosnyka ZH, et al. Intraspinal pressure and spinal cord perfusion pressure after spinal cord injury: an observational study. J Neurosurg Spine 2015;23(6):763-71, doi:10.3171/2015.3.Spine14870\u003c/li\u003e\n\u003cli\u003ePhang I, Papadopoulos MC. Intraspinal Pressure Monitoring in a Patient with Spinal Cord Injury Reveals Different Intradural Compartments: Injured Spinal Cord Pressure Evaluation (ISCoPE) Study. Neurocrit Care 2015;23(3):414-8, doi:10.1007/s12028-015-0153-6\u003c/li\u003e\n\u003cli\u003eSaadoun S, Chen SL, Papadopoulos MC. Intraspinal pressure and spinal cord perfusion pressure predict neurological outcome after traumatic spinal cord injury. Journal of Neurology Neurosurgery and Psychiatry 2017;88(5):452-+, doi:10.1136/jnnp-2016-314600\u003c/li\u003e\n\u003cli\u003ePhang IS, Werndle MC, Varsos G, et al. Injured spinal cord pressure evaluation (iscope) study: Expansion duroplasty reduces spinal cord pressure in acute spinal cord injury. J Neurotrauma 2014;31(5):A28, doi:10.1089/neu.2014.9937\u003c/li\u003e\n\u003cli\u003eTheodore N, Martirosyan N, Hersh AM, et al. Cerebrospinal Fluid Drainage in Patients with Acute Spinal Cord Injury: A Multi-Center Randomized Controlled Trial. World Neurosurg 2023, doi:10.1016/j.wneu.2023.06.078\u003c/li\u003e\n\u003cli\u003eThygesen M, Entezari S, Houlind N, et al. A 72-hour sedated porcine model of traumatic spinal cord injury Brain and Spine 2024;\u003c/li\u003e\n\u003cli\u003eThygesen MM, Entezari S, Houlind N, et al. A 72-hour sedated porcine model of traumatic spinal cord injury. Brain and Spine 2024;102813, doi:https://doi.org/10.1016/j.bas.2024.102813\u003c/li\u003e\n\u003cli\u003eSmielewski P, Czosnyka M, Steiner L, et al. ICM+: software for on-line analysis of bedside monitoring data after severe head trauma. Acta Neurochir Suppl 2005;95(43-9, doi:10.1007/3-211-32318-x_10\u003c/li\u003e\n\u003cli\u003eHogg FRA, Gallagher MJ, Chen SL, et al. Predictors of Intraspinal Pressure and Optimal Cord Perfusion Pressure After Traumatic Spinal Cord Injury. Neurocrit Care 2019;30(2):421-428, doi:10.1007/s12028-018-0616-7\u003c/li\u003e\n\u003cli\u003eCarney N, Totten AM, O\u0026apos;Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017;80(1):6-15, doi:10.1227/neu.0000000000001432\u003c/li\u003e\n\u003cli\u003eWhiteley W, Al-Shahi R, Warlow CP, et al. CSF opening pressure: reference interval and the effect of body mass index. Neurology 2006;67(9):1690-1, doi:10.1212/01.wnl.0000242704.60275.e9\u003c/li\u003e\n\u003cli\u003eB\u0026oslash; SH, Lundqvist C. Cerebrospinal fluid opening pressure in clinical practice - a prospective study. J Neurol 2020;267(12):3696-3701, doi:10.1007/s00415-020-10075-3\u003c/li\u003e\n\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurocritical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neca","sideBox":"Learn more about [Neurocritical Care](http://link.springer.com/journal/12028)","snPcode":"12028","submissionUrl":"https://www.editorialmanager.com/neca/default2.aspx","title":"Neurocritical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Spinal Cord Injuries, Pressure, Critical Care, Trauma ","lastPublishedDoi":"10.21203/rs.3.rs-4453192/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4453192/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt has been suggested that intraspinal pressure (ISP) below the dura is elevated following traumatic spinal cord injury (TSCI). The dura can maintain the pressure, a hence a subdural compartment syndrome has been hypothesized to develop regardless of bony decompression.\u003c/p\u003e\n\u003cp\u003eThis study aimed to evaluate whether a such intradural compartment syndrome develops during the first 72 hours in a porcine TSCI model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, in a randomized sham controlled-trial design, longitudinal ISP measurements were performed over a period of 72 h from onset of TSCI. TSCI was inflicted by a weight-drop contusion regime: 75 g rod, 75 mm free fall, 5 min compression of the spinal cord. Second, in a sham controlled dose-response design longitudinal ISP measurements were performed over a period of 16 h from onset of TSCI, using two other contusion regimes: 75 g, 125 mm free fall, 5 min compression; and 75 g, 75 mm, 240 min compression. Animals were kept sedated for the entire course of the study using propofol, fentanyl and midazolam.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eISP increased in TSCI and sham animals alike, but we found no significant increase in ISP following TSCI compared to the sham group, and we found no relationship between the ISP increase and the severity or duration of the TSCI impact.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese findings suggest that the subdural swelling of the spinal cord following TSCI is not responsible for the ISP increase measured in our TSCI model, but that the ISP increase was caused by the surgical procedure or the reconstitution of normal CSF pressure.\u003c/p\u003e","manuscriptTitle":"Intraspinal pressure is not elevated after traumatic spinal cord injury in a porcine model sham-controlled trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:37:49","doi":"10.21203/rs.3.rs-4453192/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-05-28T14:32:18+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-27T22:48:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-23T18:09:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurocritical Care","date":"2024-05-23T01:50:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurocritical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neca","sideBox":"Learn more about [Neurocritical Care](http://link.springer.com/journal/12028)","snPcode":"12028","submissionUrl":"https://www.editorialmanager.com/neca/default2.aspx","title":"Neurocritical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2037c10c-152c-42e0-b3f5-d84f41e2ba4d","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T16:02:15+00:00","versionOfRecord":{"articleIdentity":"rs-4453192","link":"https://doi.org/10.1007/s12028-024-02181-1","journal":{"identity":"neurocritical-care","isVorOnly":false,"title":"Neurocritical Care"},"publishedOn":"2024-12-11 15:57:46","publishedOnDateReadable":"December 11th, 2024"},"versionCreatedAt":"2024-06-12 03:37:49","video":"","vorDoi":"10.1007/s12028-024-02181-1","vorDoiUrl":"https://doi.org/10.1007/s12028-024-02181-1","workflowStages":[]},"version":"v1","identity":"rs-4453192","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4453192","identity":"rs-4453192","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}