The influence of different arterial carbon dioxide levels on the cerebrovascular autoregulation curve in a porcine cranial window model.

The influence of different arterial carbon dioxide levels on the cerebrovascular autoregulation curve in a porcine cranial window model. | 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 The influence of different arterial carbon dioxide levels on the cerebrovascular autoregulation curve in a porcine cranial window model. sofie dietvorst, Bavo Kempen, Veerle De Sloovere, Nikky Corthout, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4493125/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Apr, 2025 Read the published version in Neurocritical Care → Version 1 posted 4 You are reading this latest preprint version Abstract Introduction: Cerebrovascular autoregulation (CA) is the ability to maintain adequate cerebral blood flow (CBF) over a wide range of arterial blood pressure (ABP). Carbon dioxide (PaCO₂) is a potent vasodilator, but its precise influence on CA remains incompletely understood. Methods: A porcine cranial window model, in which CBF can be measured directly in the pial arterioles while ABP is mechanically manipulated, is used to investigate the effect of PaCO₂ on CA capacity. Hypercapnia and hypocapnia were induced in 12 male piglets each by adjusting the respiratory rate. Once stable PaCO₂ levels of resp 60 mmHg and 25 mmHg respectively were achieved, ABP was gradually increased in half of the animals or decreased in the other half beyond limits of CA by inflating a balloon in the aorta or inferior caval vein. Results: Before ABP manipulation, hypercapnia already induced a significant vasodilation (+33.9%) and increase in CBF (+20.5%) whereas hypocapnia did not alter diameter or CBF. Both hyper- and hypocapnia significantly reduced the ability to adjust arteriolar diameters in response to changes in ABP. Conclusion: During hypo- as well as hypercapnia, narrowing of the CA range with a shorter plateau between upper and lower limit of autoregulation was observed, compared to normocapnia. Cerebrovascular autoregulation Cerebrovascular resistance Arterial carbon dioxide pressure Porcine cranial window model Ventilation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The ability of the brain to maintain an adequate cerebral blood flow (CBF) despite variations in cerebral perfusion pressure (CPP) is known as cerebrovascular autoregulation (CA). The Lassen curve, first described in 1959, is a plot of CBF against arterial blood pressure (ABP) and demonstrates a plateau of autoregulation where CBF remains constant as long as the ABP is between 50–150 mmHg. 1 This wide plateau, known as the zone of active CA, is defined between the lower and upper limits of autoregulation (LLA, ULA). Recent data have questioned the existence of such a wide and universal zone of active CA, demonstrating a narrower plateau, which also depends on the baseline ABP. 2–5 The active adjustment of cerebrovascular resistance (CVR) by the myogenic response is one of the primary regulators of CA, but there are also contributions from the cholinergic, sympathetic, and other systems. 6 While the large extracranial and intracranial arteries account for approximately 40% of total CVR, the major component of resistance capacity is located more distally in the pial arterioles (approximately 20%) and in the penetrating arterioles and capillaries (approximately 40%). 7–12 We have developed a method to directly determine arteriolar red blood cell (RBC) flux in a piglet cranial window model by combining the direct measurement of vessel diameter and RBC velocity in pial arterioles in response to changes in ABP. 13 This method has been validated against laser Doppler flow (LDF) measurements in our own experiments and in the piglet model experiments of Brady et al. 14 With this method, we found that there is a zone of relatively stable CBF to the left of baseline ABP, where vasodilation effectively counteracts arterial hypotension and with a simultaneous maximum vasodilation across different arteriolar sizes, resulting in a sharp LLA. However, as ABP increases from baseline, smaller arterioles (with thinner smooth muscle cell layers) are unable to maintain vasoconstriction while larger arterioles still constrict, resulting in a more gradual increase of CBF above baseline ABP without sharp ULA ( Fig. 1 ). 13,15 When the ability to adjust CVR is impaired, CPP becomes the main regulator of CBF, putting the brain at risk of hypo- or hyperperfusion. Such CA deficiency has been described in association with acute brain injuries, but also with altered metabolic states. Mild hypocapnia is used as a treatment for intracranial hypertension in severe traumatic brain injury (TBI) and is classified as Tier 2 therapy in the SIBICC algorithms. 16 The effects of PaCO 2 levels on CVR and cerebral blood volume (CBV) are well-known, where hypocapnia induces vasoconstriction. PaCO₂ has a direct effect on CVR, rather than pH, since the active H+-ions cannot transfer over the blood-brain-barrier. This has been extensively demonstrated in prior animal studies. 12,17–19 However, the physiological impact of varying PaCO 2 levels on CA is less clear. 17,20–22 It has been hypothesized in a review by Meng and Gelb 23 that in a hypercapnic setting, the plateau of the CA curve would shift upwards because of a higher overall CBF and be narrowed because the LLA shifts to the right and the ULA to the left. Hypocapnia on the other hand would be associated with a lowering of the CBF plateau, while the LLA remains unchanged and insufficient data exist to describe a change in ULA when PaCO 2 is lowered. However, it was also stated that the data on which these hypotheses were based are fragmented and lack consistency. 23 In view of the importance of CA in the pathophysiology of brain injury, and as PaCO 2 manipulations are potentially applied as a treatment in these patients, clarification of the impact of PaCO 2 changes on the CA curve is highly relevant in clinical practice. The aim of the current study is to investigate the effect of modifying PaCO 2 levels on the CA curve in the cranial window piglet model developed in our laboratory. Material and Methods Ethical considerations All animal care and procedures were approved by the Ethics Committee of the Animal Research Centre, KU Leuven (Ethical Approval: P107-2019) in accordance with the Belgian Royal Decree (29 May 2013) and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. All animal procedures were conducted under veterinary supervision according to the guidelines imposed by the Ethics Committee and in compliance with the ARRIVE guidelines. Experiment setup The experiments were performed using the porcine cranial window model described by Klein et al. 13 6-week-old male piglets (domestic pigs, Zootechnical Centre KULeuven) were anesthetized by intravenous propofol, pancuronium, midazolam and fentanyl. At the start of the experiment, animals were intubated and mechanically ventilated. Volume-controlled mechanical ventilation (Cato® Dräger) was initiated with a tidal volume (TV) of 10ml/kg, positive expiratory pressure (PEEP) of 5 cmH 2 O, inspiratory:expiratory (I:E) ratio of 1:2 and peak pressure below 30cmH₂O; the respiratory rate (RR) was set at 20–26/min and adjusted to maintain an end-tidal carbon dioxide (ETCO 2 ) tension of 40mmHg during surgical instrumentation. Baseline normocapnia was considered a value of PaCO₂ of 40mmHg. Next, an arterial line was placed in the left femoral artery for continuous ABP monitoring, placed 5 cm above the diaphragm. For non-pharmacologic blood pressure manipulations, a balloon catheter was inserted via the right femoral artery (for the hypertensive experiments) or right femoral vein (for the hypotensive experiments) and positioned at the level of the diaphragm. Inflation of a balloon in the descending aorta will induce hypertension by increasing afterload, and inflation of a balloon in the inferior caval vein will induce hypotension by decreasing venous return. For cranial monitoring, two small cranial burr holes were made posterior to the coronal suture on the right side, and ICP-PbO 2 and laser Doppler flow (LDF) probes were inserted in the brain and onto the dural surface respectively. Anterior to the coronal suture, a round craniotomy was made for placement of a cranial window, which is cemented to the skull after the dura is opened. The cranial window consists of a steel ring with a glass cover slip in the middle. Through holes in the steel ring, we can fill the space between the glass and the brain with artificial cerebrospinal fluid. Pial arterioles were observed through the glass of the cranial window with an epifluorescence microscope (SMZ18 with P2-SHR Plan Apo 1x, Nikon), illuminated with a solid-state light engine (SOLA SM2, Lumencor), and captured with a high-speed digital CMOS camera (Orca Flash 4.0 V2, Hamamatsu) controlled by NIS-Elements software (Nikon). A green-fluorescent filter (P2-EFL GFP-B Filter Cube 470–535nm, Nikon) was used. Images were acquired at 170–200 frames per second and digitally stored for offline analysis. Twenty-four piglets were randomized into four groups of six animals each. Group 1 combines hypercapnia and gradual arterial hypotension, group 2 hypercapnia and arterial hypertension, group 3 hypocapnia and arterial hypotension, group 4 hypocapnia and arterial hypertension. Before starting the experiment, baseline measurements of pial arteriol diameter, ICP-PbO 2 and LDF were taken at normocapnia (PaCO₂ 40mmHg). First, ventilation was gradually adjusted over 1.5 hours to reach a stable value of altered PaCO₂. For the hypercapnic experiments, PaCO₂ was increased to 60 mmHg by hypoventilation (RR range 13–15/min). For the hypocapnic experiments, the pigs were hyperventilated (RR range 35–42/min) to a PaCO 2 of 25 mmHg. 24 These values of PaCO₂ were based on a set of five exploratory experiments, performed to investigate what the range of PaCO₂ is that could be reached by changing RR. During the change in ventilation, RBCs were fluorescently labelled with carboxyfluorescein diacetate succinimidyl ester (CFSE, Thermofisher Scienitific). The RBCs were reinjected into the arterial compartment 15 minutes after reaching a stable level of PaCO₂. Again, baseline measurements of pial arteriole diameter, ICP-PbO 2 and LDF were taken at the altered level of PaCO₂, but now we could also track the labeled RBCs and calculate their velocity. Second, ABP was manipulated into the desired direction of arterial hypotension or hypertension, by slowly inflating a venous or aortic balloon respectively, as described above. The real starting point of the experiment is when the inflation of the balloon was started. The balloon was gradually inflated by means of an infusion pump which was programmed to inflate the balloon (maximum volume of 1.5ml) over 120 minutes. Figure 2 shows an overview of the timeline of each experiment. Pial arteriolar flux was calculated using vessel diameter and RBC velocity (tracking of RBC labeled with CFSE) in the formula: \(F=V*A=V* \pi *{r}^{2}= V* \pi *{(D/2)}^{2}.\) LLA (in hypotensive experiments) resp. ULA (in hypertensive experiments) was calculated using segmental linear regression to define breakpoints in the relation between pial arteriolar flux and CPP. The arteriolar flux and CA curve from 8 previous experiments, performed in normocapnia (PaCO₂ 40mmHg), were used as a reference for comparison. At the end of each experiment, the animal was euthanized with pentobarbital. Statistical analysis Analyses were performed using Excel (Microsoft, Washington, US) and R statistical software (R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ ). Comparison of baseline data within one experiment from normo- to hyper- or hypocapnia was done using paired t-testing. Pooling of data of diameters, velocity and calculated CBF was done using R (packages tidyverse, lubridate, imputeTS), the graphs were constructed with the use of ggplot2. Segmented linear regression was used to estimate the breakpoints of autoregulation (R, package segmented), to estimate the change in slope of CBF. Results Before the experiment was started, the piglet was brought from normocapnia to either hyper- or hypocapnia. Table 1 summarizes the mean values and standard deviations (SD) for arteriolar diameters, ABP, LDF and arterial pH during normocapnia compared to hypercapnia or hypocapnia respectively, using paired t-testing. Baseline pial arteriole diameters measured in normocapnic state range from 40 to 150µm, normal distribution was confirmed (by histogram and quantile-quantile plots). Hypercapnia significantly increased the diameter of all arterioles by 33.9% (SD 22.6%) and increased CBF by 20.5% (SD 22.4%) as measured by LDF. Hypercapnia significantly decreased pH, whereas hypocapnia only significantly increased pH without a measurable effect on arteriolar diameter or CBF. Plots of calculated pial arteriolar flux against CPP and color coded per animal are provided in Fig. 3 . In the further analyses, data for both arterial hypotension and hypertension are pooled per ventilation condition to obtain plots over the full range of CPP, and changes induced by altered ABP are expressed as percentage of change with respect to the pooled hyper- or hypocapnia data at normotension At PaCO 2 of 60 mmHg, changes in ABP could only induce limited changes in arteriolar diameter. As a result, changes of calculated pial arteriolar flux were mainly determined by changes of RBC velocity in response to ABP change. However, compared with baseline normocapnic normotension, vasodilation across the CPP range in hypercapnia was substantial ( Fig. 4 ) Similarly, at PaCO 2 of 25 mmHg, pial arteriolar flux was mainly determined by RBC velocity because of limited adjustment of arteriolar diameter in response to ABP manipulation. Arteriolar diameters changes were also limited when compared with baseline normocapnic normotension ( Fig. 5 ). Over all experiments, LDF values correlated well with calculated pial arteriolar flux (intraclass correlation coefficient of 0.808, p < 0.001, 95%-Confidence Interval of 0.644 < ICC < 0.892). The LLA and ULA breakpoints of CA, determined by segmented regression, for hypercapnia are at 83mmHg and 98.81mmHg respectively and for hypocapnia at 87.16mmHg and 97.57mmHg respectively. In Fig. 6 , the relative changes in pial arteriolar flux in response to ABP changes in hyper- and hypocapnia from the current study are confronted with the pial arteriolar flux and ABP data from 8 previous experiments in normocapnia (LLA at 63.03mmHg and ULA at 133.70mmHg)( 10 , 12 ), showing substantial narrowing of the CA plateau in both hyper- and hypocapnia.When calculating the breakpoints of these curves with segmented regression, Discussion In the current study, the effect of altered levels of PaCO₂ on pial arteriolar diameters and RBC velocity in response to ABP manipulation was investigated.,We found that hypercapnia at 60mmHg resulted in substantial vasodilation over the entire range of CPP. In this setting, the ability to adjust arteriolar diameters to ABP changes was significantly reduced. Hypocapnia at 25mmHg did not clearly influence arteriolar diameters, which was not expected based on previous experiments. 20,25 However, it did also substantially reduce the vasoreactivity in response to ABP changes As a result, in both hyper- and hypocapnia, the CA plateau was narrower compared to the CA plateau obtained in normocapnia in the same experimental model. Contrary to the hypotheses formulated by Meng et al 23 , in the present study the LLA was shifted to the right in both hyper- and hypocapnia, and the ULA was shifted to the left in both settings. Our LDF measurements demonstrated that CBF increased in hypercapnia, from which can be deduced that the CBF plateau not only narrowed but also shifted upward in hypercapnia. CBF remained unchanged in hypocapnia compared to normocapnia. Findings congruent to ours were observed by other researchers using a piglet model. Ringer et al found that the combination of arterial hypotension and hypocapnia led to a decrease in cerebral perfusion, metabolic alterations and early ischemia as measured by MRI. 26 In a piglet model by Nusbaum et al, hypercapnia induced an increase in the value of LLA as measured by the pressure reactivity index (PRx) and LDF. 27 In situations where the capacity to adjust CVR is altered, CBF is predominantly determined by RBC velocity, which is almost linearly related to CPP. Only in the hypercapnia experiments, we did observe a plateau in RBC velocity at CPP roughly between 70–100 mmHg, which is not well understood at present. A more direct relationship between CBF and CPP makes the brain more susceptible to secondary damage from hypo- or hyperperfusion. As hyperventilation is still used as a therapy in the intensive care unit to manage elevated ICP, hyperventilation-induced hypocapnia may tip the delicate balance towards ischemia even at CPP values that are deemed accurate. 28–32 One difficulty encountered in the attempt to document the influence of PaCO 2 on CBF and CA, is that also pH in the perivascular interstitium plays a role in therelation between PaCO 2 and pial arteriolar diametersThis was described by Muizelaar et al in 1988, who reported a significant change in diameter due to hypocapnia (acquired by hyperventilation) in rabbits, but metabolic compensation for the aberrant pH over the next 24 hours abolished these changes, rendering peri-arterial pH the main driver of CVR. 20 The influence of pH on CVR in pial arterioles has been confirmed in humans. 33 Although pH seems to be most important in altering CVR andit being mainly dependent on the diffusion of CO₂ across the arterial wall, pH is also subject to metabolic compensation. Thus, not only the interaction with central chemoreceptors, but also the general acid-base relationship in the body will influence CBF. 34,35 This also means that our findings are only valid in a context of altered PaCO 2 before metabolic compensation. Although the present study provides new insights into how PaCO₂ affects CA capacity in a large animal model, the study has several limitations. First, CFSE is susceptible to bleaching and therefore time-limited. The installment of hyper- or hypoventilation needs to be done in a stepwise fashion and takes time. Therefore, CFSE-labeled RBCs were only injected after stable hyper- or hypocapnia was achieved. As a result we were unable to obtain RBC velocity and hence to calculate pial arteriolar flux absolute reference values in the setting of normocapnia before alteration of PaCO 2 was started. Consequently, we cannot directly compare the height of the plateau of CBF in hyper- or hypocapnia with CBF in normocapnia in the same animal using absolute values from the calculated arteriolar flux method. LDF enabled us to assess the relative change in CBF under different PaCO₂ conditions in the same animals. While this demonstrated increased CBF in hypercapnia, it demonstrated no measurable change from normocapnia to hypocapnia. This seems to conflict with previous experiments reporting a decreased CBF under hypocapnia. 20,23,32,36 Second, we pooled the data to compare CA curves, thereby eliminating individual variations. From previous experiments, we know that there can be substantial individual variation in the width and position of the CA plateau. 13,15 Additionally, although the breakpoint estimation method applied on the CBF-CPP graph allows the identification of the LLA and ULA, we found in previous experiments that the transition from active to deficient CA for increasing ABP was very gradual, leading to the statistical identification of more than one ULA. 15 Since the CA plateau was significantly narrowed here, only one ULA was retrieved in the current experiments. Third, the experimental protocol included ABP manipulation in the direction of either arterial hypertension or hypotension beyond the limits of CA, subjecting the animals to hyper- or hyperperfusion. For that reason, we did not use the same animal to test both hypo- and hypertension. Fourth, we used ventilation settings to alter the levels of PaCO 2 , by adjusting the RR in hyper- and hypocapnia and increasing dead space ventilation in hypercapnia. We kept the tidal volume (TV) constant but changed the RR, since it has been shown that mechanical hyperventilation with low RR and high TV generally reduces blood flow at tissue level. 37,38 By increasing RR with a constant TV, there are no changes in cardiac output (CO), which is important in our model where we want to mimic normal physiology as much as possible. 38 In some animals at hypocapnia, we reached a thoracic peak pressure of 30cmH₂O by hyperventilating. Such high intrathoracic pressure can potentially alter the basic cardiopulmonary physiology, detectable by increased central venous pressure (CVP) and ICP. 37,39 However, in our experiments such increases of ICP were not observed. During the experiments and RR changes we monitored the animals with arterial blood gases. PaO 2 was maintained between 180–200 mmHg during hyper- or hypoventilation. An alternative would have been to add inhaled CO₂, but the method chosen here seemed to be closer to the normal physiology. Fifth, anesthetic agents can influence CBF, ICP, cerebral metabolism, synaptic neurotransmitter balance, intracellular calcium, intracellular signaling cascades and scavenging of free radicals. This multitude of influences leads to complex effects on brain physiology in different pathological conditions. 40,41 Because of their presumed effect on CBF, we specifically avoided to use inhalation anesthetics and focused on total intravenous anesthesia, as is the common practice in neurosurgical procedures and the neuro-ICU. Propofol is stated to preserve CA in healthy individuals both at low and high concentrations. 42 Opioids as fentanyl may result in a modest decrease of cerebral metabolism and ICP, and these effects depend on concomitant registration of other drugs/anesthetics. 42 The protocol for anesthesia of the animals was optimized by a senior neuro-anesthesiologist, who was involved in the experimental procedures as well. While the cranial window piglet model lends itself to the investigation of CA under different physiological and supraphysiological circumstances, further research is most certainly required to fully map and understand this protective mechanism and how it responds to external stimuli. The current study enables to conclude that CA is a fragile mechanism, that largely disappears under non-compensated hyper- and hypocapnia. Conclusion In the context of the continuing uncertainty about the influence of altered PaCO 2 on CA as outlined in the review of Meng et al 23 , the present study aimed at investigating different settings of PaCO 2 and CPP in a piglet cranial window model. First, we found that hypercapnia results in significant pial arteriolar vasodilation across the entire ABP spectrum and results in increased CBF. Second, both hyper- and hypocapnia altered the capacity to adjust pial arteriolar CVR to changes in ABP, thereby reducing the protective capacity of CA. Third, the CBF plateau of active CA was narrowed due to a rightward shift of LLA and a leftward shift of ULA in both hyper- and hypocapnia. Declarations Acknowledgements Sincere thanks to Stéphanie De Vleeschauwer, who works as a veterinarian for the large animal facility of KU Leuven. Sincere thanks to medical students Charlotte Deprez, Floor Vanelderen, Robin Van Lerberghe and Aline Vervekken, who contributed to the experimental work. Disclosure/conflict of interest Bavo Kempen is sponsored by FWO (1S12523N). Geert Meyfroidt is a consultant for Neural Analytics and is funded by the Flemish Government (Research Foundation – Flanders (FWO)) as Senior Clinical Researcher (1843123N). References Lassen N. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39(2):183–238. Brassard P, Labrecque L, Smirl JD, et al. Losing the dogmatic view of cerebral autoregulation. Physiol Rep. 2021;9(15). 10.14814/phy2.14982 . Drummond JC. Blood Pressure and the Brain. Anesth Analg. 2019;128(4):759–71. 10.1213/ANE.0000000000004034 . Willie CK, Tzeng YC, Fisher Ja, Ainslie PN. Integrative regulation of human brain blood flow. J Physiol. 2014;592:841–59. 10.1113/jphysiol.2013.268953 . Claassen JAHR, Thijssen DHJ, Panerai RB, Faraci FM. Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation. Physiol Rev. 2021;101(4):1487–559. 10.1152/physrev.00022.2020 . Hamner J, Tan C. 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Cole CD, Gottfried ON, Gupta DK, Couldwell WT. TOTAL INTRAVENOUS ANESTHESIA. Neurosurgery. 2007;61:369–78. 10.1227/01.neu.0000303996.74526.30 . Tables Table 1 is available in the Supplementary Files section. Supplementary Files Table1.jpg Table 1. Effects of alteration of PaCO 2 from 40 mmHg to 60 or 25 mmHg on mean arteriolar diameter, mean arterial blood pressure, cerebral blood flow measured by LDF, arterial pH and values of PaCO₂ from arterial blood gas in 12 animals per PaCO 2 experimental condition. Statistical comparison using two-way paired t-test. MAP = mean arterial blood pressure, SD = standard deviation, LDF = laser doppler flow, aBG = arterial blood gas. Cite Share Download PDF Status: Published Journal Publication published 11 Apr, 2025 Read the published version in Neurocritical Care → Version 1 posted Reviewers agreed at journal 11 Jun, 2024 Reviewers invited by journal 08 Jun, 2024 Editor assigned by journal 03 Jun, 2024 First submitted to journal 31 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-4493125","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312071020,"identity":"df92e740-fee5-4a2e-9e3a-e9c4b943686a","order_by":0,"name":"sofie dietvorst","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-9926-4529","institution":"KUL Bio-medical Sciences Group: Katholieke Universiteit Leuven Groep Biomedische Wetenschappen","correspondingAuthor":true,"prefix":"","firstName":"sofie","middleName":"","lastName":"dietvorst","suffix":""},{"id":312071021,"identity":"81aaee58-090e-4d8b-82f9-d42e7fa1ea22","order_by":1,"name":"Bavo Kempen","email":"","orcid":"","institution":"Katholieke Universiteit Leuven Hospital: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven","correspondingAuthor":false,"prefix":"","firstName":"Bavo","middleName":"","lastName":"Kempen","suffix":""},{"id":312071022,"identity":"0d8c58f9-2e08-45d0-ba8f-98ca610d56ce","order_by":2,"name":"Veerle De Sloovere","email":"","orcid":"","institution":"Katholieke Universiteit Leuven Hospital: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven","correspondingAuthor":false,"prefix":"","firstName":"Veerle","middleName":"","lastName":"De Sloovere","suffix":""},{"id":312071023,"identity":"c45c353e-88ac-4e17-b7c4-58fa13c30efe","order_by":3,"name":"Nikky Corthout","email":"","orcid":"","institution":"Katholieke Universiteit Leuven","correspondingAuthor":false,"prefix":"","firstName":"Nikky","middleName":"","lastName":"Corthout","suffix":""},{"id":312071024,"identity":"97bf9a5c-5c81-47f4-be13-aaae71b3a4c9","order_by":4,"name":"Geert Meyfroidt","email":"","orcid":"","institution":"Katholieke Universiteit Leuven Hospital: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven","correspondingAuthor":false,"prefix":"","firstName":"Geert","middleName":"","lastName":"Meyfroidt","suffix":""},{"id":312071025,"identity":"f84247e8-520f-40ba-a860-dc54e7434d6e","order_by":5,"name":"Bart Depreitere","email":"","orcid":"","institution":"Katholieke Universiteit Leuven Hospital: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven","correspondingAuthor":false,"prefix":"","firstName":"Bart","middleName":"","lastName":"Depreitere","suffix":""}],"badges":[],"createdAt":"2024-05-28 21:11:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4493125/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4493125/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12028-025-02250-z","type":"published","date":"2025-04-11T16:05:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58964785,"identity":"9e3041a3-ce8d-45c2-803e-397b728a2ddb","added_by":"auto","created_at":"2024-06-24 17:54:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39213,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eAdapted from Klein et al. The curves represent pooled data of 10 hypertensive and 10 hypotensive piglets in normocapnia, presented as change from baseline (%Δ) in pial arteriolar flux, pial arteriolar diameter, and RBC velocity as a function of cerebral perfusion pressure (CPP). Arteriolar diameter is shown in green, RBC velocity in blue and pial arteriolar flux in red. When lowering CPP, there is a clear vasodilation to about 140% compared to diameter measurements when normotensive. Due to this compensation, there is a zone with relatively stable CBF, which we call the plateau of CA.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/ad9e1b52e21d20fac9f57ad2.jpg"},{"id":58964504,"identity":"ba08a952-da8f-4fdb-bd15-ec65dcea357c","added_by":"auto","created_at":"2024-06-24 17:46:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26098,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eOverview of the timeline of an experiment. After induction and sedation is started, we place the invasive ABP monitoring, the arterial/venous balloon catheter and the cranial window is cemented to the skull. Next, the ventilation is changed to adjust the level of PaCO₂. When the arterial blood gas shows a stable level of PaCO₂, the CFSE-labeled RBCs are injected. The actual experiment is started when the balloon is then gradually inflated to allow a slow of raise or fall in in- or decrease ABP, while cranial monitoring is continuing.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/db71afa8a771fca137586908.jpg"},{"id":58964009,"identity":"9b62b727-47fa-42ed-9514-f34942b3bbd9","added_by":"auto","created_at":"2024-06-24 17:38:01","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141448,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eChange from baseline (%Δ) of pial arteriolar flux plotted against CPP. Baseline is before the start of arterial blood pressure manipulation after installment of altered PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e. Each color represents a different animal. A) Experiments under hypercapnia (PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e 60mmHg). \u0026nbsp;B) Experiments under hypocapnia (PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e 25mmHg).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure3a.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/a6164935122208eebc0d4fb7.jpeg"},{"id":58964014,"identity":"f2e6e2d0-e1b1-48f5-b4ca-0b948b784f6a","added_by":"auto","created_at":"2024-06-24 17:38:01","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":83509,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eChange from baseline (%Δ) of pial arteriolar flux (red), pial arteriolar diameter (light green) and RBC velocity (blue). Baseline is before the start of arterial blood pressure manipulation after installment of hypercapnia (PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e = 60 mmHg). The dark green curve demonstrates the proportional change in diameter compared to the normocapnic state before alteration of PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e. The shaded zones in gray express the 95% confidence interval of the graphs. Pooled data from 12 piglets assigned to hypercapnia condition. \u0026nbsp;\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/1ab2a36f7c6e5f531089d922.jpg"},{"id":58964013,"identity":"b6488074-0084-4e8d-a9df-a5deca07cf44","added_by":"auto","created_at":"2024-06-24 17:38:01","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":83601,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eChange from baseline (%Δ) of pial arteriolar flux (red), pial arteriolar diameter (light green) and RBC velocity (blue). Baseline is before the start of arterial blood pressure manipulation after installment of hypocapnia (PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e = 25 mmHg). The dark green curve demonstrates the proportional change in diameter compared to the normocapnic state before alteration of PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e. The shaded zones in gray express the 95% confidence interval of the graphs. Pooled data from 12 piglets assigned to hypercapnia condition. \u0026nbsp;\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/738bfcdece7f951a865a40d4.jpg"},{"id":58964502,"identity":"fbdb057e-4e9f-4bdf-8aa9-84106c6bffd2","added_by":"auto","created_at":"2024-06-24 17:46:01","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":105597,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eChange from baseline (%Δ) of pial arteriolar flux plotted against CPP. Baseline is before the start of arterial blood pressure manipulation. Normocapnic experiments are represented in black, hypercapnic (60 mmHg) in red and hypocapnic (25 mmHg) in green. Pooled data from 12 piglets under hypercapnia, 12 piglets under hypocapnia and 8 piglets under normocapnia. The shaded zones in gray express the 95% confidence interval of the graphs. The breakpoints (LLA and ULA), calculated by segmented regression, are shown as dotted lines (normocapnic in black, hypercapnic in red and hypocapnic in green).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/95e7d7f40009bb19b0a124b2.jpg"},{"id":80558732,"identity":"978461b2-2f66-4a1b-b362-13f8d9d15882","added_by":"auto","created_at":"2025-04-14 16:16:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":958665,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/e765340d-d0ba-42da-9b12-6b1019f8a158.pdf"},{"id":58964010,"identity":"08cc21a2-6680-41d3-8ca2-5f4ce5065f55","added_by":"auto","created_at":"2024-06-24 17:38:01","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":86981,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTable 1. Effects of alteration of PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e from 40 mmHg to 60 or 25 mmHg on mean arteriolar diameter, mean arterial blood pressure, cerebral blood flow measured by LDF, arterial pH and values of PaCO₂ from arterial blood gas in 12 animals per PaCO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e\u003cem\u003e experimental condition. Statistical comparison using two-way paired t-test. MAP = mean arterial blood pressure, SD = standard deviation, LDF = laser doppler flow, aBG = arterial blood gas.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Table1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4493125/v1/bf3eebdb3c7a6ecc2e93bbf9.jpg"}],"financialInterests":"","formattedTitle":"The influence of different arterial carbon dioxide levels on the cerebrovascular autoregulation curve in a porcine cranial window model.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe ability of the brain to maintain an adequate cerebral blood flow (CBF) despite variations in cerebral perfusion pressure (CPP) is known as cerebrovascular autoregulation (CA). The Lassen curve, first described in 1959, is a plot of CBF against arterial blood pressure (ABP) and demonstrates a plateau of autoregulation where CBF remains constant as long as the ABP is between 50\u0026ndash;150 mmHg.\u003csup\u003e1\u003c/sup\u003e This wide plateau, known as the zone of active CA, is defined between the lower and upper limits of autoregulation (LLA, ULA). Recent data have questioned the existence of such a wide and universal zone of active CA, demonstrating a narrower plateau, which also depends on the baseline ABP.\u003csup\u003e2\u0026ndash;5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe active adjustment of cerebrovascular resistance (CVR) by the myogenic response is one of the primary regulators of CA, but there are also contributions from the cholinergic, sympathetic, and other systems.\u003csup\u003e6\u003c/sup\u003e While the large extracranial and intracranial arteries account for approximately 40% of total CVR, the major component of resistance capacity is located more distally in the pial arterioles (approximately 20%) and in the penetrating arterioles and capillaries (approximately 40%).\u003csup\u003e7\u0026ndash;12\u003c/sup\u003e We have developed a method to directly determine arteriolar red blood cell (RBC) flux in a piglet cranial window model by combining the direct measurement of vessel diameter and RBC velocity in pial arterioles in response to changes in ABP.\u003csup\u003e13\u003c/sup\u003e This method has been validated against laser Doppler flow (LDF) measurements in our own experiments and in the piglet model experiments of Brady et al.\u003csup\u003e14\u003c/sup\u003e With this method, we found that there is a zone of relatively stable CBF to the left of baseline ABP, where vasodilation effectively counteracts arterial hypotension and with a simultaneous maximum vasodilation across different arteriolar sizes, resulting in a sharp LLA. However, as ABP increases from baseline, smaller arterioles (with thinner smooth muscle cell layers) are unable to maintain vasoconstriction while larger arterioles still constrict, resulting in a more gradual increase of CBF above baseline ABP without sharp ULA \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003csup\u003e13,15\u003c/sup\u003e When the ability to adjust CVR is impaired, CPP becomes the main regulator of CBF, putting the brain at risk of hypo- or hyperperfusion. Such CA deficiency has been described in association with acute brain injuries, but also with altered metabolic states.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMild hypocapnia is used as a treatment for intracranial hypertension in severe traumatic brain injury (TBI) and is classified as Tier 2 therapy in the SIBICC algorithms.\u003csup\u003e16\u003c/sup\u003e The effects of PaCO\u003csub\u003e2\u003c/sub\u003e levels on CVR and cerebral blood volume (CBV) are well-known, where hypocapnia induces vasoconstriction. PaCO₂ has a direct effect on CVR, rather than pH, since the active H+-ions cannot transfer over the blood-brain-barrier. This has been extensively demonstrated in prior animal studies.\u003csup\u003e12,17\u0026ndash;19\u003c/sup\u003e However, the physiological impact of varying PaCO\u003csub\u003e2\u003c/sub\u003e levels on CA is less clear.\u003csup\u003e17,20\u0026ndash;22\u003c/sup\u003e It has been hypothesized in a review by Meng and Gelb\u003csup\u003e23\u003c/sup\u003e that in a hypercapnic setting, the plateau of the CA curve would shift upwards because of a higher overall CBF and be narrowed because the LLA shifts to the right and the ULA to the left. Hypocapnia on the other hand would be associated with a lowering of the CBF plateau, while the LLA remains unchanged and insufficient data exist to describe a change in ULA when PaCO\u003csub\u003e2\u003c/sub\u003e is lowered. However, it was also stated that the data on which these hypotheses were based are fragmented and lack consistency.\u003csup\u003e23\u003c/sup\u003e In view of the importance of CA in the pathophysiology of brain injury, and as PaCO\u003csub\u003e2\u003c/sub\u003e manipulations are potentially applied as a treatment in these patients, clarification of the impact of PaCO\u003csub\u003e2\u003c/sub\u003e changes on the CA curve is highly relevant in clinical practice. The aim of the current study is to investigate the effect of modifying PaCO\u003csub\u003e2\u003c/sub\u003e levels on the CA curve in the cranial window piglet model developed in our laboratory.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthical considerations\u003c/h2\u003e \u003cp\u003e All animal care and procedures were approved by the Ethics Committee of the Animal Research Centre, KU Leuven (Ethical Approval: P107-2019) in accordance with the Belgian Royal Decree (29 May 2013) and the European Directive 2010/63/EU on the protection of animals used for scientific purposes. All animal procedures were conducted under veterinary supervision according to the guidelines imposed by the Ethics Committee and in compliance with the ARRIVE guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eExperiment setup\u003c/h2\u003e \u003cp\u003eThe experiments were performed using the porcine cranial window model described by Klein et al.\u003csup\u003e13\u003c/sup\u003e 6-week-old male piglets (domestic pigs, Zootechnical Centre KULeuven) were anesthetized by intravenous propofol, pancuronium, midazolam and fentanyl. At the start of the experiment, animals were intubated and mechanically ventilated. Volume-controlled mechanical ventilation (Cato\u0026reg; Dr\u0026auml;ger) was initiated with a tidal volume (TV) of 10ml/kg, positive expiratory pressure (PEEP) of 5 cmH\u003csub\u003e2\u003c/sub\u003eO, inspiratory:expiratory (I:E) ratio of 1:2 and peak pressure below 30cmH₂O; the respiratory rate (RR) was set at 20\u0026ndash;26/min and adjusted to maintain an end-tidal carbon dioxide (ETCO\u003csub\u003e2\u003c/sub\u003e) tension of 40mmHg during surgical instrumentation. Baseline normocapnia was considered a value of PaCO₂ of 40mmHg.\u003c/p\u003e \u003cp\u003eNext, an arterial line was placed in the left femoral artery for continuous ABP monitoring, placed 5 cm above the diaphragm. For non-pharmacologic blood pressure manipulations, a balloon catheter was inserted via the right femoral artery (for the hypertensive experiments) or right femoral vein (for the hypotensive experiments) and positioned at the level of the diaphragm. Inflation of a balloon in the descending aorta will induce hypertension by increasing afterload, and inflation of a balloon in the inferior caval vein will induce hypotension by decreasing venous return.\u003c/p\u003e \u003cp\u003eFor cranial monitoring, two small cranial burr holes were made posterior to the coronal suture on the right side, and ICP-PbO\u003csub\u003e2\u003c/sub\u003e and laser Doppler flow (LDF) probes were inserted in the brain and onto the dural surface respectively. Anterior to the coronal suture, a round craniotomy was made for placement of a cranial window, which is cemented to the skull after the dura is opened. The cranial window consists of a steel ring with a glass cover slip in the middle. Through holes in the steel ring, we can fill the space between the glass and the brain with artificial cerebrospinal fluid. Pial arterioles were observed through the glass of the cranial window with an epifluorescence microscope (SMZ18 with P2-SHR Plan Apo 1x, Nikon), illuminated with a solid-state light engine (SOLA SM2, Lumencor), and captured with a high-speed digital CMOS camera (Orca Flash 4.0 V2, Hamamatsu) controlled by NIS-Elements software (Nikon). A green-fluorescent filter (P2-EFL GFP-B Filter Cube 470\u0026ndash;535nm, Nikon) was used. Images were acquired at 170\u0026ndash;200 frames per second and digitally stored for offline analysis.\u003c/p\u003e \u003cp\u003eTwenty-four piglets were randomized into four groups of six animals each. Group 1 combines hypercapnia and gradual arterial hypotension, group 2 hypercapnia and arterial hypertension, group 3 hypocapnia and arterial hypotension, group 4 hypocapnia and arterial hypertension. Before starting the experiment, baseline measurements of pial arteriol diameter, ICP-PbO\u003csub\u003e2\u003c/sub\u003e and LDF were taken at normocapnia (PaCO₂ 40mmHg).\u003c/p\u003e \u003cp\u003eFirst, ventilation was gradually adjusted over 1.5 hours to reach a stable value of altered PaCO₂. For the hypercapnic experiments, PaCO₂ was increased to 60 mmHg by hypoventilation (RR range 13\u0026ndash;15/min). For the hypocapnic experiments, the pigs were hyperventilated (RR range 35\u0026ndash;42/min) to a PaCO\u003csub\u003e2\u003c/sub\u003e of 25 mmHg.\u003csup\u003e24\u003c/sup\u003e These values of PaCO₂ were based on a set of five exploratory experiments, performed to investigate what the range of PaCO₂ is that could be reached by changing RR. During the change in ventilation, RBCs were fluorescently labelled with carboxyfluorescein diacetate succinimidyl ester (CFSE, Thermofisher Scienitific). The RBCs were reinjected into the arterial compartment 15 minutes after reaching a stable level of PaCO₂. Again, baseline measurements of pial arteriole diameter, ICP-PbO\u003csub\u003e2\u003c/sub\u003e and LDF were taken at the altered level of PaCO₂, but now we could also track the labeled RBCs and calculate their velocity.\u003c/p\u003e \u003cp\u003eSecond, ABP was manipulated into the desired direction of arterial hypotension or hypertension, by slowly inflating a venous or aortic balloon respectively, as described above. The real starting point of the experiment is when the inflation of the balloon was started. The balloon was gradually inflated by means of an infusion pump which was programmed to inflate the balloon (maximum volume of 1.5ml) over 120 minutes. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows an overview of the timeline of each experiment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePial arteriolar flux was calculated using vessel diameter and RBC velocity (tracking of RBC labeled with CFSE) in the formula: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(F=V*A=V* \\pi *{r}^{2}= V* \\pi *{(D/2)}^{2}.\\)\u003c/span\u003e\u003c/span\u003e LLA (in hypotensive experiments) resp. ULA (in hypertensive experiments) was calculated using segmental linear regression to define breakpoints in the relation between pial arteriolar flux and CPP. The arteriolar flux and CA curve from 8 previous experiments, performed in normocapnia (PaCO₂ 40mmHg), were used as a reference for comparison. At the end of each experiment, the animal was euthanized with pentobarbital.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAnalyses were performed using Excel (Microsoft, Washington, US) and R statistical software (R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/\u003c/span\u003e\u003cspan address=\"https://www.R-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Comparison of baseline data within one experiment from normo- to hyper- or hypocapnia was done using paired t-testing. Pooling of data of diameters, velocity and calculated CBF was done using R (packages tidyverse, lubridate, imputeTS), the graphs were constructed with the use of ggplot2. Segmented linear regression was used to estimate the breakpoints of autoregulation (R, package segmented), to estimate the change in slope of CBF.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBefore the experiment was started, the piglet was brought from normocapnia to either hyper- or hypocapnia. \u003cem\u003eTable\u0026nbsp;1\u003c/em\u003e summarizes the mean values and standard deviations (SD) for arteriolar diameters, ABP, LDF and arterial pH during normocapnia compared to hypercapnia or hypocapnia respectively, using paired t-testing. Baseline pial arteriole diameters measured in normocapnic state range from 40 to 150\u0026micro;m, normal distribution was confirmed (by histogram and quantile-quantile plots). Hypercapnia significantly increased the diameter of all arterioles by 33.9% (SD 22.6%) and increased CBF by 20.5% (SD 22.4%) as measured by LDF. Hypercapnia significantly decreased pH, whereas hypocapnia only significantly increased pH without a measurable effect on arteriolar diameter or CBF.\u003c/p\u003e \u003cp\u003ePlots of calculated pial arteriolar flux against CPP and color coded per animal are provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In the further analyses, data for both arterial hypotension and hypertension are pooled per ventilation condition to obtain plots over the full range of CPP, and changes induced by altered ABP are expressed as percentage of change with respect to the pooled hyper- or hypocapnia data at normotension At PaCO\u003csub\u003e2\u003c/sub\u003e of 60 mmHg, changes in ABP could only induce limited changes in arteriolar diameter. As a result, changes of calculated pial arteriolar flux were mainly determined by changes of RBC velocity in response to ABP change. However, compared with baseline normocapnic normotension, vasodilation across the CPP range in hypercapnia was substantial \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e Similarly, at PaCO\u003csub\u003e2\u003c/sub\u003e of 25 mmHg, pial arteriolar flux was mainly determined by RBC velocity because of limited adjustment of arteriolar diameter in response to ABP manipulation. Arteriolar diameters changes were also limited when compared with baseline normocapnic normotension \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e Over all experiments, LDF values correlated well with calculated pial arteriolar flux (intraclass correlation coefficient of 0.808, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 95%-Confidence Interval of 0.644\u0026thinsp;\u0026lt;\u0026thinsp;ICC\u0026thinsp;\u0026lt;\u0026thinsp;0.892).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe LLA and ULA breakpoints of CA, determined by segmented regression, for hypercapnia are at 83mmHg and 98.81mmHg respectively and for hypocapnia at 87.16mmHg and 97.57mmHg respectively. In Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, the relative changes in pial arteriolar flux in response to ABP changes in hyper- and hypocapnia from the current study are confronted with the pial arteriolar flux and ABP data from 8 previous experiments in normocapnia (LLA at 63.03mmHg and ULA at 133.70mmHg)(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), showing substantial narrowing of the CA plateau in both hyper- and hypocapnia.When calculating the breakpoints of these curves with segmented regression,\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current study, the effect of altered levels of PaCO₂ on pial arteriolar diameters and RBC velocity in response to ABP manipulation was investigated.,We found that hypercapnia at 60mmHg resulted in substantial vasodilation over the entire range of CPP. In this setting, the ability to adjust arteriolar diameters to ABP changes was significantly reduced. Hypocapnia at 25mmHg did not clearly influence arteriolar diameters, which was not expected based on previous experiments.\u003csup\u003e20,25\u003c/sup\u003e However, it did also substantially reduce the vasoreactivity in response to ABP changes As a result, in both hyper- and hypocapnia, the CA plateau was narrower compared to the CA plateau obtained in normocapnia in the same experimental model. Contrary to the hypotheses formulated by Meng et al\u003csup\u003e23\u003c/sup\u003e, in the present study the LLA was shifted to the right in both hyper- and hypocapnia, and the ULA was shifted to the left in both settings. Our LDF measurements demonstrated that CBF increased in hypercapnia, from which can be deduced that the CBF plateau not only narrowed but also shifted upward in hypercapnia. CBF remained unchanged in hypocapnia compared to normocapnia. Findings congruent to ours were observed by other researchers using a piglet model. Ringer et al found that the combination of arterial hypotension and hypocapnia led to a decrease in cerebral perfusion, metabolic alterations and early ischemia as measured by MRI.\u003csup\u003e26\u003c/sup\u003e In a piglet model by Nusbaum et al, hypercapnia induced an increase in the value of LLA as measured by the pressure reactivity index (PRx) and LDF.\u003csup\u003e27\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn situations where the capacity to adjust CVR is altered, CBF is predominantly determined by RBC velocity, which is almost linearly related to CPP. Only in the hypercapnia experiments, we did observe a plateau in RBC velocity at CPP roughly between 70\u0026ndash;100 mmHg, which is not well understood at present. A more direct relationship between CBF and CPP makes the brain more susceptible to secondary damage from hypo- or hyperperfusion. As hyperventilation is still used as a therapy in the intensive care unit to manage elevated ICP, hyperventilation-induced hypocapnia may tip the delicate balance towards ischemia even at CPP values that are deemed accurate.\u003csup\u003e28\u0026ndash;32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne difficulty encountered in the attempt to document the influence of PaCO\u003csub\u003e2\u003c/sub\u003e on CBF and CA, is that also pH in the perivascular interstitium plays a role in therelation between PaCO\u003csub\u003e2\u003c/sub\u003e and pial arteriolar diametersThis was described by Muizelaar et al in 1988, who reported a significant change in diameter due to hypocapnia (acquired by hyperventilation) in rabbits, but metabolic compensation for the aberrant pH over the next 24 hours abolished these changes, rendering peri-arterial pH the main driver of CVR.\u003csup\u003e20\u003c/sup\u003e The influence of pH on CVR in pial arterioles has been confirmed in humans.\u003csup\u003e33\u003c/sup\u003e Although pH seems to be most important in altering CVR andit being mainly dependent on the diffusion of CO₂ across the arterial wall, pH is also subject to metabolic compensation. Thus, not only the interaction with central chemoreceptors, but also the general acid-base relationship in the body will influence CBF.\u003csup\u003e34,35\u003c/sup\u003e This also means that our findings are only valid in a context of altered PaCO\u003csub\u003e2\u003c/sub\u003e before metabolic compensation.\u003c/p\u003e \u003cp\u003eAlthough the present study provides new insights into how PaCO₂ affects CA capacity in a large animal model, the study has several limitations. First, CFSE is susceptible to bleaching and therefore time-limited. The installment of hyper- or hypoventilation needs to be done in a stepwise fashion and takes time. Therefore, CFSE-labeled RBCs were only injected after stable hyper- or hypocapnia was achieved. As a result we were unable to obtain RBC velocity and hence to calculate pial arteriolar flux absolute reference values in the setting of normocapnia before alteration of PaCO\u003csub\u003e2\u003c/sub\u003e was started. Consequently, we cannot directly compare the height of the plateau of CBF in hyper- or hypocapnia with CBF in normocapnia in the same animal using absolute values from the calculated arteriolar flux method. LDF enabled us to assess the relative change in CBF under different PaCO₂ conditions in the same animals. While this demonstrated increased CBF in hypercapnia, it demonstrated no measurable change from normocapnia to hypocapnia. This seems to conflict with previous experiments reporting a decreased CBF under hypocapnia.\u003csup\u003e20,23,32,36\u003c/sup\u003e Second, we pooled the data to compare CA curves, thereby eliminating individual variations. From previous experiments, we know that there can be substantial individual variation in the width and position of the CA plateau.\u003csup\u003e13,15\u003c/sup\u003e Additionally, although the breakpoint estimation method applied on the CBF-CPP graph allows the identification of the LLA and ULA, we found in previous experiments that the transition from active to deficient CA for increasing ABP was very gradual, leading to the statistical identification of more than one ULA.\u003csup\u003e15\u003c/sup\u003e Since the CA plateau was significantly narrowed here, only one ULA was retrieved in the current experiments. Third, the experimental protocol included ABP manipulation in the direction of either arterial hypertension or hypotension beyond the limits of CA, subjecting the animals to hyper- or hyperperfusion. For that reason, we did not use the same animal to test both hypo- and hypertension. Fourth, we used ventilation settings to alter the levels of PaCO\u003csub\u003e2\u003c/sub\u003e, by adjusting the RR in hyper- and hypocapnia and increasing dead space ventilation in hypercapnia. We kept the tidal volume (TV) constant but changed the RR, since it has been shown that mechanical hyperventilation with low RR and high TV generally reduces blood flow at tissue level.\u003csup\u003e37,38\u003c/sup\u003e By increasing RR with a constant TV, there are no changes in cardiac output (CO), which is important in our model where we want to mimic normal physiology as much as possible.\u003csup\u003e38\u003c/sup\u003e In some animals at hypocapnia, we reached a thoracic peak pressure of 30cmH₂O by hyperventilating. Such high intrathoracic pressure can potentially alter the basic cardiopulmonary physiology, detectable by increased central venous pressure (CVP) and ICP.\u003csup\u003e37,39\u003c/sup\u003e However, in our experiments such increases of ICP were not observed. During the experiments and RR changes we monitored the animals with arterial blood gases. PaO\u003csub\u003e2\u003c/sub\u003e was maintained between 180\u0026ndash;200 mmHg during hyper- or hypoventilation. An alternative would have been to add inhaled CO₂, but the method chosen here seemed to be closer to the normal physiology. Fifth, anesthetic agents can influence CBF, ICP, cerebral metabolism, synaptic neurotransmitter balance, intracellular calcium, intracellular signaling cascades and scavenging of free radicals. This multitude of influences leads to complex effects on brain physiology in different pathological conditions.\u003csup\u003e40,41\u003c/sup\u003e Because of their presumed effect on CBF, we specifically avoided to use inhalation anesthetics and focused on total intravenous anesthesia, as is the common practice in neurosurgical procedures and the neuro-ICU. Propofol is stated to preserve CA in healthy individuals both at low and high concentrations.\u003csup\u003e42\u003c/sup\u003e Opioids as fentanyl may result in a modest decrease of cerebral metabolism and ICP, and these effects depend on concomitant registration of other drugs/anesthetics.\u003csup\u003e42\u003c/sup\u003e The protocol for anesthesia of the animals was optimized by a senior neuro-anesthesiologist, who was involved in the experimental procedures as well.\u003c/p\u003e \u003cp\u003eWhile the cranial window piglet model lends itself to the investigation of CA under different physiological and supraphysiological circumstances, further research is most certainly required to fully map and understand this protective mechanism and how it responds to external stimuli. The current study enables to conclude that CA is a fragile mechanism, that largely disappears under non-compensated hyper- and hypocapnia.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn the context of the continuing uncertainty about the influence of altered PaCO\u003csub\u003e2\u003c/sub\u003e on CA as outlined in the review of Meng et al\u003csup\u003e23\u003c/sup\u003e, the present study aimed at investigating different settings of PaCO\u003csub\u003e2\u003c/sub\u003e and CPP in a piglet cranial window model. First, we found that hypercapnia results in significant pial arteriolar vasodilation across the entire ABP spectrum and results in increased CBF. Second, both hyper- and hypocapnia altered the capacity to adjust pial arteriolar CVR to changes in ABP, thereby reducing the protective capacity of CA. Third, the CBF plateau of active CA was narrowed due to a rightward shift of LLA and a leftward shift of ULA in both hyper- and hypocapnia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSincere thanks to St\u0026eacute;phanie De Vleeschauwer, who works as a veterinarian for the large animal facility of KU Leuven. Sincere thanks to medical students Charlotte Deprez, Floor Vanelderen, Robin Van Lerberghe and Aline Vervekken, who contributed to the experimental work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure/conflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBavo Kempen is sponsored by FWO (1S12523N). Geert Meyfroidt is a consultant for Neural Analytics and is funded by the Flemish Government (Research Foundation \u0026ndash; Flanders (FWO)) as Senior Clinical Researcher (1843123N).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLassen N. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39(2):183\u0026ndash;238.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrassard P, Labrecque L, Smirl JD, et al. Losing the dogmatic view of cerebral autoregulation. Physiol Rep. 2021;9(15). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.14814/phy2.14982\u003c/span\u003e\u003cspan address=\"10.14814/phy2.14982\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrummond JC. Blood Pressure and the Brain. 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Neurosurgery. 2007;61:369\u0026ndash;78. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1227/01.neu.0000303996.74526.30\u003c/span\u003e\u003cspan address=\"10.1227/01.neu.0000303996.74526.30\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"Cerebrovascular autoregulation, Cerebrovascular resistance, Arterial carbon dioxide pressure, Porcine cranial window model, Ventilation","lastPublishedDoi":"10.21203/rs.3.rs-4493125/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4493125/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Cerebrovascular autoregulation (CA) is the ability to maintain adequate cerebral blood flow (CBF) over a wide range of arterial blood pressure (ABP). Carbon dioxide (PaCO₂) is a potent vasodilator, but its precise influence on CA remains incompletely understood.\u003c/p\u003e\n\u003cp\u003eMethods: A porcine cranial window model, in which CBF can be measured directly in the pial \u0026nbsp;arterioles while ABP is mechanically manipulated, is used to investigate the effect of PaCO₂ on CA capacity. Hypercapnia and hypocapnia were induced in 12 male piglets each by adjusting the respiratory rate. Once stable PaCO₂ levels of resp 60 mmHg and 25 mmHg respectively were achieved, ABP was gradually increased in half of the animals or decreased in the other half beyond limits of CA by inflating a balloon in the aorta or inferior caval vein.\u003c/p\u003e\n\u003cp\u003eResults: Before ABP manipulation, hypercapnia already induced a significant vasodilation (+33.9%) and increase in CBF (+20.5%) whereas hypocapnia did not alter diameter or CBF. Both hyper- and hypocapnia significantly reduced the ability to adjust arteriolar diameters in response to changes in ABP.\u003c/p\u003e\n\u003cp\u003eConclusion: During hypo- as well as hypercapnia, narrowing of the CA range with a shorter plateau between upper and lower limit of autoregulation was observed, compared to normocapnia.\u003c/p\u003e","manuscriptTitle":"The influence of different arterial carbon dioxide levels on the cerebrovascular autoregulation curve in a porcine cranial window model.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-24 17:37:56","doi":"10.21203/rs.3.rs-4493125/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-06-11T11:45:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-08T11:43:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-03T20:45:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurocritical Care","date":"2024-05-31T16:30:42+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":"6c313c25-89fd-48d8-8066-cda955ff5d48","owner":[],"postedDate":"June 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-14T16:11:31+00:00","versionOfRecord":{"articleIdentity":"rs-4493125","link":"https://doi.org/10.1007/s12028-025-02250-z","journal":{"identity":"neurocritical-care","isVorOnly":false,"title":"Neurocritical Care"},"publishedOn":"2025-04-11 16:05:54","publishedOnDateReadable":"April 11th, 2025"},"versionCreatedAt":"2024-06-24 17:37:56","video":"","vorDoi":"10.1007/s12028-025-02250-z","vorDoiUrl":"https://doi.org/10.1007/s12028-025-02250-z","workflowStages":[]},"version":"v1","identity":"rs-4493125","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4493125","identity":"rs-4493125","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}