Impact on Cognitive Prognosis in Patients with Septic Encephalopathy related to Fluid Resuscitation: A Prospective Cohort Study

Impact on Cognitive Prognosis in Patients with Septic Encephalopathy related to Fluid Resuscitation: A Prospective Cohort Study | 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 Article Impact on Cognitive Prognosis in Patients with Septic Encephalopathy related to Fluid Resuscitation: A Prospective Cohort Study Qing Yu, Wen Lai, Zuqing Xu, Lumei Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8811454/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Objective Septic encephalopathy (SAE) is a common cerebral dysfunction associated with septic shock, which can lead to neurological and cognitive impairments. Early and adequate fluid resuscitation during septic shock not only reduces the risk of mortality but also significantly improves medium-to-long-term neurological outcomes for patients with SAE. This study investigated the relationship between fluid resuscitation and cognitive prognosis in SAE patients via TCD(Transcranial Doppler ultrasonography), with implications for early intervention. Methods In this prospective cohort study, 150 patients with septic shock were enrolled and categorised into SAE and non-SAE groups on the basis of clinical diagnostic criteria. SAE patients received standardised fluid resuscitation and were stratified into successful resuscitation and unsuccessful resuscitation subgroups. TCD was performed 24 hours, 48 hours, 1 week, and 2 weeks after admission to evaluate cerebral perfusion. Cognitive function was assessed on day 30 using the Mini-Mental State Examination (MMSE). Results TCD effectively identified SAE in septic shock patients. Significant differences in TCD-negative detection rates were observed between the successful and unsuccessful resuscitation subgroups at 48 hours, 1 week, and 2 weeks (p < 0.05). Statistically distinct MMSE scores were also noted at the 30-day follow-up. Conclusion Effective fluid resuscitation in septic shock patients has positive implications for neurological recovery and medium-to-long-term cognitive improvement. TCD exhibits favourable efficacy and operational feasibility in the evaluation of neurological outcomes for prognostic purposes, thus supporting its integration into clinical decision-making protocols. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Septic encephalopathy Transcranial Doppler ultrasonography Septic shock Cognitive prognosis Fluid resuscitation Figures Figure 1 Figure 2 Figure 3 Background Septic shock, which is a life-threatening condition frequently encountered in intensive care units, can lead to systemic multiple organ dysfunction syndrome (MODS), including acute renal failure, cardiac dysfunction, and disseminated intravascular coagulation (DIC). According to the Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock (SSC guidelines) and related studies, the mortality rate associated with septic shock exceeds 40% upon diagnosis [ 1 ][ 2 ][ 3 ]. In China, the mortality rate for sepsis and septic shock ranges from 29% to 32% [ 4 ][ 5 ], thus underscoring the critical severity of the disease. From a clinical perspective, patients who are recovering from septic shock frequently exhibit delirium, sleep‒wake cycle disturbances, transient or persistent cognitive dysfunction, incoherent speech, and even aggressive behaviours [ 6 ]. Notably, even in patients without prior neurological or psychiatric disorders, multiple studies have confirmed that septic shock induces infection-related impairments in cerebral blood flow and metabolic function [ 7 ][ 8 ], ultimately leading to neurocognitive deficits, which are collectively termed sepsis-associated encephalopathy (SAE). SAE is a diagnosis of exclusion, with neurologists attributing neurological or psychiatric symptoms to SAE only after ruling out cerebrovascular accidents, meningitis, or other conditions. Although most patients experience symptom resolution as infections subside and organ function recovers, the diagnosis of SAE remains challenging because of the absence of direct diagnostic biomarkers or definitive imaging findings. Recent studies have suggested that early-stage SAE may be detected via biomarkers such as amyloid-β (S100-β), neuron-specific enolase (NSE), and interleukin-8 (IL-8) in the blood or cerebrospinal fluid [ 2 ], as well as via noninvasive monitoring tools such as transcranial Doppler ultrasound (TCD), electroencephalography (EEG), and the bispectral index (BIS), to identify reduced cerebral perfusion. Among these tools, TCD offers significant advantages in evaluating cerebral haemodynamic changes, thereby providing critical diagnostic insights. Previous research has shown that the PI (Pulsatility Index) and RI (Resistance Index) in SAE patients are significantly greater than those in non-SAE patients, and the cut-off values of PI and RI for the diagnosis of SAE are 1.16 and 0.65, with specificities being 96.8% and 96.8%, respectively. These findings suggest that TCD could be valuable for the early diagnosis of SAE[ 9 ]. Research has indicated that effective fluid resuscitation promotes recovery from acute organ injury and improves mid-to-long-term cognitive outcomes in septic shock patients. Its pathophysiological mechanisms involve systemic inflammatory responses and abnormal cerebral perfusion triggered by infection [ 12 ][ 13 ]. Existing evidence suggests that the efficacy of fluid resuscitation may profoundly influence the mid-to-long-term prognosis of SAE [ 14 ][ 15 ][ 16 ]. However, prior studies have been limited by the lack of dynamic, real-time monitoring methods for assessing SAE severity during disease progression, resulting in incomplete evaluations of therapeutic outcomes. In this study, we proposed the use of serial TCD assessments in septic shock patients to systematically evaluate the effects of various fluid resuscitation strategies on mid- to long-term SAE prognosis. This investigation aimed to elucidate potential associations between fluid resuscitation and neurological recovery. Additionally, TCD may serve as a noninvasive, real-time tool for the early detection of cerebral hypoperfusion, thus enabling timely clinical interventions. We further explored the correlations between TCD-derived cerebral haemodynamic parameters and the severity of neurological impairment and assessed cognitive recovery during rehabilitation. This prospective cohort study aimed to determine the value of TCD in predicting medium- to long-term cognitive impairment in sepsis-associated encephalopathy patients. Materials and Methods This study was reviewed and approved by the Ethics Committee of Shenzhen Longhua District Central Hospital and complies with the requirements of the Declaration of Helsinki. All the participants signed a Informed consent form and were deidentified. The reporting of this study conforms to the STROBE guidelines[3]. In this study, patients with infectious diseases who were admitted to the intensive care unit (ICU) of Longhua District Central Hospital between January 2022 and June 2024 were assessed using the Sequential Organ Failure Assessment (SOFA) score at admission. Participants who met the Sepsis 3.0 diagnostic criteria for septic shock [18] were consecutively enrolled. The exclusion criteria were as follows: 1. Patients who died within 72 hours of septic shock diagnosis; 2. Patients whose families opted to discontinue standardised treatment during the therapeutic course; 3. Age < 18 years; 4. Pregnant women; 5. Patients with traumatic brain injury; 6. Patients with a history of large-area cerebral infarction; 7. Patients with severe sequelae of intracerebral haemorrhage and acute cerebral infarction; 8. Patients with meningitis, encephalitis, or metabolic encephalopathy; 9. Other individuals with significant preexisting cognitive impairments. All the enrolled septic shock patients received standardised 3-hour bundle therapy, including antibiotic treatment, goal-directed fluid resuscitation (20–30 ml/kg saline with lactated Ringer’s solution in the first 3 hours after diagnosis), oxygen therapy or ventilatory support, and other interventions to correct electrolyte imbalances[14]. Serum lactate levels were measured 6 hours after resuscitation, with a 30% reduction from preresuscitation levels defined as adequate resuscitation[18][19]. Participants whose lactate reduction rate exceeded 20% from baseline were classified into the successful resuscitation group or the SR group, while participants whose lactate reduction rate was less than 20% or whose lactate level was elevated were classified into the unsuccessful resuscitation group or the UR group. Given that sepsis-associated encephalopathy (SAE) is a diagnosis of exclusion, patients who met the following criteria were enrolled in the SAE group[20]: 1. Septic shock patients who present with new episodes of disturbance of consciousness and cognitive dysfunction. 2. Participants with preexisting psychiatric disorders or cognitive impairment were excluded. 3. Participants with central nervous system (CNS) pathologies, including cerebral infarction, intracranial haemorrhage, CNS infections, and other CNS injuries, were excluded on the basis of cranial computed tomography (CT) or magnetic resonance imaging (MRI) findings. 4. Participants with evidence of epileptic seizures were excluded. 5. Participants with metabolic/toxic encephalopathies such as hepatic encephalopathy, hypoglycaemic encephalopathy, uraemic encephalopathy, drug intoxication, and other systemic metabolic causes of altered mental status were excluded. 6. Participants were assessed under conditions of relatively stable haemodynamics and adequate oxygen supply prior to sedative administration using the confusion assessment method for the intensive care unit (CAM-ICU), and those with positive results were diagnosed with SAE. Patients were stratified into SAE and non-SAE groups. For the patients in the non-SAE group, transcranial Doppler ultrasound (TCD) was performed at treatment initiation (0 h) to establish a baseline for normal cerebral perfusion among patients with septic shock. For the patients in the SAE group, TCD assessments were performed at the following predefined intervals: 1. baseline (0 h); 2. 24 hours post-treatment; 3. 48 hours post-treatment; 4. 1 week post-treatment; 5. 2 weeks post-treatment. During the TCD examinations, the patients were placed in a supine position with the headrest elevated to 0°. A portable ultrasound device (Mindray, Shenzhen, China) equipped with a phased-array transducer was used to measure the haemodynamic parameters of the proximal M1 segment of the bilateral middle cerebral arteries (MCAs) via the temporal window. The higher flow values from either MCA were recorded, including the following parameters: 1. peak systolic velocity ( Vs ); 2. end-diastolic velocity (Vd); 3. mean velocity (Vm); 4. pulsatility index (PI); 5. resistance index (RI). Vm was calculated as follows: Vm = (Vs + 2×Vd)/3 ; PI was calculated as follows: PI = (Vs - Vd)/Vm ; and the RI was calculated as follows: RI = (Vs - Vd)/Vs . PI values > 1.16 and RI values > 0.65 indicated TCD positivity, thereby suggesting reduced cerebral perfusion. Moreover, PI values < 1.16 and RI values < 0.65 indicated TCD negativity, thereby suggesting adequate cerebral perfusion. To ensure consistency, all the TCD measurements and data recordings were performed by 3 trained operators. At 30 days post-treatment, the cognitive function of the patients in the SAE group was systematically evaluated using the Mini-Mental State Examination (MMSE). Patients with MMSE scores < 23 points were defined as having cognitive impairment. The statistical analysis was performed using SPSS 27 software. One-way ANOVA was employed for comparisons among three groups of measurement data, whereas independent samples t tests were used for comparisons between two groups. Paired samples t tests were utilised for within-group comparisons. A P value < 0.05 was considered to indicate statistical significance. Categorical data are presented as counts, with intergroup comparisons being analysed via chi-square tests. A significance level of P < 0.05 was applied for all statistical comparisons. Results The overall cohort included 150 septic shock participants; 95 participants were diagnosed with SAE and 55 were diagnosed with non-SAE. The detailed baseline characteristics of the sepsis cohorts are shown in Table 1. A total of 150 septic shock patients who met the inclusion criteria were enrolled in this study. Data from all the groups were subjected to homoscedasticity checking and were found to conform to a normal distribution. On the basis of the sepsis-associated encephalopathy (SAE) diagnostic criteria proposed by Papadopoulos et al., 95 patients were classified into the SAE group, whereas 45 patients were categorised into the non-SAE group. Following fluid resuscitation therapy, 66 patients (69.5%) in the SAE group were classified into the successful resuscitation group or the SR group, whereas 29 patients (30.5%) were classified into the unsuccessful resuscitation group or the UR group (Fig. 1 ). Transcranial Doppler ultrasound (TCD) findings at 0 h (Table 2) revealed that cerebral perfusion was better in the non-SAE group (PI = 0.983 ± 0.127; RI = 0.619 ± 0.014) than in the SAE group (p 0.05). The TCD findings at 24 hours post-treatment demonstrated that both the SR group and the UR group exhibited inadequate cerebral perfusion (p > 0.05). At the 48-hour, 1-week and 2-week follow-ups, the patients in the SR group demonstrated better cerebral perfusion than the patients in the UR group did (p 1.16 and RI > 0.65 were used as cut-off values to define positive TCD results, we obtained the number of patients with TCD-positive and TCD-negative results (Table 3). At 24 hours, 63 out of 66 patients (95.45%) in the SR group demonstrated TCD-positive results, whereas all 29 UR patients (100%) exhibited TCD positivity ( P > 0.05). At 48 hours post-treatment, 50 patients (75.76%) in the SR group remained TCD-positive, whereas all 29 UR patients (100%) retained their TCD-positive status ( P > 0.05). By 1 week post-treatment, TCD positivity persisted in 21 patients (31.82%) in the SR group, with 32 patients (48.48%) demonstrating negative results. By contrast, 12 UR patients (41.38%) remained TCD-positive, with 5 patients (17.24%) exhibiting negative results and 13 patients being excluded because of mortality. The intergroup difference was statistically significant ( P < 0.05). At 2 weeks post-treatment, the percentage of patients with TCD positivity decreased to 5 patients (7.58%) in the SR group, with 46 patients (70.91%) achieving normalisation. Among the UR patients, 10 patients (34.48%) remained TCD-positive, with 6 patients (20.69%) converting to a negative status and 13 patients being excluded because of mortality. A significant intergroup disparity persisted ( P < 0.05). The cognitive function assessment using the Mini-Mental State Examination (MMSE) at 30 days post-treatment (by a cut-off value ≤ 23 for cognitive impairment) revealed that 12 out of 39 survivors (30.8%) in the SR group exhibited cognitive deficits, whereas 10 survivors (52.6%) in the UR group demonstrated these deficits. This difference was statistically significant ( P < 0.05) (Table 3). Compared with non-SAE patients, SAE patients demonstrated significantly greater cognitive decline at 30 days post-treatment ( P < 0.05). This deterioration remained statistically significant when directly compared with non-SAE controls ( P < 0.05) (Fig. 3 ). Discussion In this study, SAE was an exclusive diagnosis established primarily through the CAM-ICU scale and clinical history. The TCD positivity rate was significantly higher in SAE patients than in non-SAE patients. The results at 0 h revealed that SAE not only resulted in functional cognitive decline but also resulted in pathological reductions in cerebral perfusion. During standardized bundle therapy for septic shock, four TCD assessments were performed. The 24 h post-treatment TCD results demonstrated no significant difference in cerebral perfusion between the SR and UR patients. These findings might suggest delayed cerebral haemodynamic recovery during the initial 24 hours of bundle therapy, which is potentially attributable to the acute-phase pathophysiology of septic shock [ 21 ][ 22 ]. Despite systemic perfusion improvements, persistent microthrombus formation in the microcirculation may perpetuate circulatory disturbances, compounded by high-dose vasopressor requirements during this critical phase, which may exacerbate cerebral vasoconstriction. Significant intergroup differences in TCD parameters were observed at 48 hours, 1 week, and 2 weeks post-treatment. The results revealed that the lower PI and RI values in the SR group indicate better cerebrovascular autoregulation and lower vascular resistance, suggesting better cerebral perfusion supply. By contrast, the higher PI and RI values in the UR group reflect increased cerebrovascular resistance, impaired vascular autoregulation, and consequently reduced cerebral perfusion[ 23 ]. These findings indicate that effective fluid resuscitation not only reduces lactate levels (which represent a marker of systemic microcirculation improvement) but also promotes cerebral perfusion recovery. This phenomenon may be correlated with lower vasopressor doses in responders, thus mitigating cerebral vascular resistance and enhancing perfusion. When intragroup comparisons were conducted, we observed that cerebral perfusion in the SR group gradually improved between 0 hours and 2 weeks, whereas that in the UR group did not significantly improve during the first 0–48 hours, with perfusion only beginning to recover between 48 hours and 2 weeks. These findings suggest that adequate and effective fluid resuscitation during the early stages of septic shock significantly enhances cerebral perfusion in SAE patients during the early phases. This improvement may be associated with fluid resuscitation promoting microthrombolysis and microcirculatory restoration. Notably, patients with improved cerebral perfusion require a shorter duration of mechanical ventilation and thus shorter sedation/analgesia time, thus leading to decreased ICU times and healthcare costs. These outcomes underscore the critical role of protocolised bundle therapy in septic shock management. In this study, a 20% reduction in serum lactate levels within 6 hours served as the threshold for adequate resuscitation. Although lactate does not directly quantify tissue perfusion, it reflects cellular hypoxia [ 24 ]. An elevated lactate concentration (> 4 mmol/L) predicts an increased risk of mortality in septic shock patients [ 25 ][ 26 ], with a lactate clearance > 20% within 6 hours being associated with improved survival [ 27 ]. Paediatric studies have further demonstrated that persistent hyperlactataemia (≥ 4 mmol/L) at 4 hours post-resuscitation is correlated with a 5.5-fold increased risk of MODS within 24 hours [ 28 ]. Randomised trials have confirmed that lactate-guided resuscitation significantly reduces the risk of mortality [ 29 ][ 30 ]. Our findings extend this evidence, linking effective lactate clearance to enhanced cerebral perfusion and superior neurocognitive outcomes. Furthermore, rigorous inflammatory control may attenuate blood–brain barrier disruption and neuronal injury by reducing the levels of circulating lipopolysaccharides, proinflammatory cytokines, and endotoxins [ 24 ]. At 30 days post-treatment, MMSE scores ≤ 23 (indicating moderate-to-severe cognitive impairment) were analysed in survivors. Although SAE is often considered reversible, up to 40% of septic shock survivors exhibit mild-to-moderate neurological deficits within 1 year post-discharge [ 31 ][ 32 ]. Prolonged ICU stays, post-sepsis anxiety/depression [ 33 ][ 34 ], and posttraumatic stress may confound mild cognitive assessments. To minimise false positives, we focused on moderate-to-severe impairments. Notably, compared with UR patients, SR patients exhibited significantly higher MMSE-negative rates ( P < 0.05), thereby aligning with acute-phase TCD trends. These findings suggest that protocolised resuscitation not only optimises acute cerebral perfusion but also mitigates midterm neurocognitive sequelae. Conversely, impaired cerebral perfusion is correlated with midterm cognitive deficits, which are likely mediated by hypoxic-ischaemic injury to the metabolically vulnerable limbic system (a region that is critical for cognition, emotional regulation, and memory) [ 35 ][ 36 ][ 37 ]. The susceptibility of the limbic system to hypoperfusion [ 38 ] aligns with MRI evidence of ischaemic injury in shock states, thereby explaining why preserved cerebral perfusion predicts favourable neurological outcomes. Limitations This study has several limitations. First, the single-centre design may limit the representativeness of the sample size and the generalisability of the findings. In the absence of a multivariable assessment, current evidence is insufficient to support the use of TCD findings as a predictor of cognitive outcomes in patients with SAE. Future studies should incorporate assessments such as NSE or S-100β to substantiate the correlation between TCD findings and neuronal damage. Second, after patients with severe sequelae of intracerebral haemorrhage or cerebral infarction were excluded, an increased rate of successful fluid resuscitation and reduced 30-day mortality rate were observed, which may be attributed to their preexisting compromised vascular status. However, these exclusion criteria may introduce bias in the diagnosis of SAE severity within the SR and UR subgroups. Third, the short follow-up duration limited the comprehensive evaluation of long-term neurological and cognitive outcomes. Thus, multicentre, double-blind studies with extended follow-up periods, multimodal imaging and validated neuropsychological assessments are needed in the future to holistically evaluate the impact of fluid resuscitation on SAE progression. Conclusion This study demonstrated that protocolised bundle therapy might significantly reduce neurological injury in septic shock patients by providing adequate cerebral perfusion. Monitoring cerebral perfusion via TCD might provide actionable insights for optimising resuscitation strategies. Declarations Ethics approval and consent to participate( Ethics Approval Number: 2021-156-01) Approved by the Medical and Health Institutions of Longhua District, Shenzhen. Availability of supporting data. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Competing interests. The authors declare that they have no competing interests. Funding. The Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen Key Medical Discipline Construction Fund of Shenzhen Longhua District Authors' contributions. Qing Yu: Conceptualisation, Writing, Data analysis,Original Draft Preparation—language review and editing Wen Lai: TCD assessment, Data collection,Figure editing, Zuqing Xu: Fact checking, Reference collection, and Language review Lumei Fan: Figure and table editing, Data analysis Acknowledgements. We would like to express our sincere gratitude to several individuals who made significant contributions to the completion of this thesis. First, we are grateful to all the patients for sharing their medical data and providing their cooperation. Additionally, we would like to thank all the medical staff for sharing ideas and collaborating during treatment. Finally, we would like to thank the tech support team from Mindray for their patience and professionalism. 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Supplementary Files table1.xlsx table2.xlsx table3.xlsx STROBEchecklistcohort.docx AJEEditingCertificate.pdf consentform.pdf Ethicsapproval.pdf data.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Apr, 2026 Reviews received at journal 04 Apr, 2026 Reviews received at journal 30 Mar, 2026 Reviews received at journal 28 Mar, 2026 Reviewers agreed at journal 21 Mar, 2026 Reviewers agreed at journal 21 Mar, 2026 Reviews received at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 19 Mar, 2026 Editor assigned by journal 19 Mar, 2026 Editor invited by journal 02 Mar, 2026 Submission checks completed at journal 17 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8811454","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":609925666,"identity":"e171d987-5117-41dc-80e6-fbb8259dac78","order_by":0,"name":"Qing Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYLCChAoJOX4Q4wEDgwFxWj6csTCWbGBgbEggVgvjzLaKxA0HiNVicCN5422eMxKJm4/3mD9IqLAxZmA/fHQDfi1pxdY8FRLG286cMWxIOJNmxsCTlnYDv5YcM2mgLbLbbuQYNiS2HbZhkOAxI6yFt02CcfMMUrRIzmyTUNwgAdFiRlCL5JlnxRYfzkgYS5w5VjgD6BdjNkJ+4TuevPFGQkWdHH9784YPHypsDPvZDx/Dq0XhAIOBBIoIGz7lICDfgK5lFIyCUTAKRgE6AACWcU/Yt3mriQAAAABJRU5ErkJggg==","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Qing","middleName":"","lastName":"Yu","suffix":""},{"id":609925667,"identity":"83aead43-fa6a-4657-9fe0-795b0a6000e2","order_by":1,"name":"Wen Lai","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Lai","suffix":""},{"id":609925668,"identity":"6d75cd2f-1beb-4ed9-ba61-29cb12bec706","order_by":2,"name":"Zuqing Xu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Zuqing","middleName":"","lastName":"Xu","suffix":""},{"id":609925669,"identity":"f2ee4e48-0e8c-466b-8e1d-386213c6e8d9","order_by":3,"name":"Lumei Fan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lumei","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2026-02-07 01:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8811454/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8811454/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105350791,"identity":"ca715418-ae3f-4603-b5fa-b9ac5b9bb1a1","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":168413,"visible":true,"origin":"","legend":"\u003cp\u003eAmong 251 patients who were diagnosed with septic shock between 1st January, 2022, and 1st June, 2024, 81 patients were excluded on the basis of predefined criteria, resulting in 150 enrolled participants. Using the CAM-ICU scale and TCD findings, patients were stratified into two groups: the SAE group (n=95) and the non-SAE group (n=45). The patients in the SAE group were further categorised into the SR subgroup (n=66) and UR subgroup (n=29) on the basis of their lactate clearance rates following BUNDEL therapy.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/3297fd86f8471b60a8696537.jpg"},{"id":105565700,"identity":"519123c3-94bf-4e3e-a01d-e0d3e9e2c825","added_by":"auto","created_at":"2026-03-27 12:54:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":466924,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical analysis revealed no significant intergroup differences in PI (A) and RI (B) values between the SR and UR cohorts during the initial 24-hour period. However, from 48 hours to 2 weeks, compared with the UR group, the SR group presented significantly lower PI and RI values, with the magnitude of these differences progressively increasing over time. Intragroup analysis revealedthat within the SR cohort, all the comparisons from 0 hours to 2 weeks were statistically significant (p\u0026lt;0.05), indicating a consistent temporal reduction in the PI and RI values. By contrast, in the UR group, neither the PI nor the RI differed significantly between 0 hours and 48 hours; however, all the other intragroup comparisons were statistically significant. An asterisk (*) indicates a statistically significant difference.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/3c16c0c4c431a6f7e8538f22.jpg"},{"id":105350800,"identity":"edbd9321-2f92-47c0-826a-d0a310ab8f44","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":68100,"visible":true,"origin":"","legend":"\u003cp\u003ePatients in both the SR and UR groups underwent 4 TCD assessments at 24 hours, 48 hours, 1 week and 2 weeks. The percentages of patients with negative TCD results at different time points are shown in the figure, and the results of the TCD tests conducted at 1 week and 2 weeks were significantly different (red asterisk). The percentage of patients with MMSE scores less than 27 also significantly differed between the SR and UR groups (red asterisk).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/4eb93f9c821999ab1de7a75f.jpg"},{"id":105569935,"identity":"e25e2a6a-b5de-40a7-93ef-a53e63fb6702","added_by":"auto","created_at":"2026-03-27 13:13:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1203817,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/bbfb4d76-ef28-4a5d-8518-68c7a49f6b36.pdf"},{"id":105564621,"identity":"a1571c36-66a6-4684-8c48-e1784ae5ec83","added_by":"auto","created_at":"2026-03-27 12:50:14","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11070,"visible":true,"origin":"","legend":"","description":"","filename":"table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/c0dfe69d9362bb26bb50122b.xlsx"},{"id":105564639,"identity":"9baa20a5-1299-4267-b47c-0a7ce0729930","added_by":"auto","created_at":"2026-03-27 12:50:18","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":9942,"visible":true,"origin":"","legend":"","description":"","filename":"table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/dd197330049af9a667d60fb3.xlsx"},{"id":105350795,"identity":"48c3e6a1-db69-43c8-be2c-d6837cbbc897","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10625,"visible":true,"origin":"","legend":"","description":"","filename":"table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/cd4ac6d1f6c3590f237b9304.xlsx"},{"id":105565407,"identity":"c9d06aa7-eadb-4495-931d-376ab963d7a7","added_by":"auto","created_at":"2026-03-27 12:53:09","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":32736,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklistcohort.docx","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/e3ec343ec7eb477460d8880f.docx"},{"id":105565896,"identity":"04fe9e7e-9f80-489f-93a6-db87478fba97","added_by":"auto","created_at":"2026-03-27 12:54:42","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":81163,"visible":true,"origin":"","legend":"","description":"","filename":"AJEEditingCertificate.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/4d0e5dbb449dab2037c2aac1.pdf"},{"id":105350789,"identity":"1a9f409d-d843-46c9-b2ff-c44cbbcdf52e","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":227422,"visible":true,"origin":"","legend":"","description":"","filename":"consentform.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/8a91557046ad25748ea4540e.pdf"},{"id":105350788,"identity":"6decad94-5e27-40f3-9f22-675ddf63a340","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":416300,"visible":true,"origin":"","legend":"","description":"","filename":"Ethicsapproval.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/b748ed60392ca76f11e7380e.pdf"},{"id":105350796,"identity":"0a13daa7-8bf1-4501-b741-a72a5c149ac9","added_by":"auto","created_at":"2026-03-25 05:50:51","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":35267,"visible":true,"origin":"","legend":"","description":"","filename":"data.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8811454/v1/fb0a243ebf7a510ae8138131.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact on Cognitive Prognosis in Patients with Septic Encephalopathy related to Fluid Resuscitation: A Prospective Cohort Study","fulltext":[{"header":"Background","content":"\u003cp\u003eSeptic shock, which is a life-threatening condition frequently encountered in intensive care units, can lead to systemic multiple organ dysfunction syndrome (MODS), including acute renal failure, cardiac dysfunction, and disseminated intravascular coagulation (DIC). According to the \u003cem\u003eSurviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock\u003c/em\u003e (SSC guidelines) and related studies, the mortality rate associated with septic shock exceeds 40% upon diagnosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn China, the mortality rate for sepsis and septic shock ranges from 29% to 32% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], thus underscoring the critical severity of the disease. From a clinical perspective, patients who are recovering from septic shock frequently exhibit delirium, sleep‒wake cycle disturbances, transient or persistent cognitive dysfunction, incoherent speech, and even aggressive behaviours [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, even in patients without prior neurological or psychiatric disorders, multiple studies have confirmed that septic shock induces infection-related impairments in cerebral blood flow and metabolic function [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], ultimately leading to neurocognitive deficits, which are collectively termed sepsis-associated encephalopathy (SAE).\u003c/p\u003e \u003cp\u003eSAE is a diagnosis of exclusion, with neurologists attributing neurological or psychiatric symptoms to SAE only after ruling out cerebrovascular accidents, meningitis, or other conditions. Although most patients experience symptom resolution as infections subside and organ function recovers, the diagnosis of SAE remains challenging because of the absence of direct diagnostic biomarkers or definitive imaging findings. Recent studies have suggested that early-stage SAE may be detected via biomarkers such as amyloid-β (S100-β), neuron-specific enolase (NSE), and interleukin-8 (IL-8) in the blood or cerebrospinal fluid [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], as well as via noninvasive monitoring tools such as transcranial Doppler ultrasound (TCD), electroencephalography (EEG), and the bispectral index (BIS), to identify reduced cerebral perfusion. Among these tools, TCD offers significant advantages in evaluating cerebral haemodynamic changes, thereby providing critical diagnostic insights. Previous research has shown that the PI (Pulsatility Index) and RI (Resistance Index) in SAE patients are significantly greater than those in non-SAE patients, and the cut-off values of PI and RI for the diagnosis of SAE are 1.16 and 0.65, with specificities being 96.8% and 96.8%, respectively. These findings suggest that TCD could be valuable for the early diagnosis of SAE[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearch has indicated that effective fluid resuscitation promotes recovery from acute organ injury and improves mid-to-long-term cognitive outcomes in septic shock patients. Its pathophysiological mechanisms involve systemic inflammatory responses and abnormal cerebral perfusion triggered by infection [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Existing evidence suggests that the efficacy of fluid resuscitation may profoundly influence the mid-to-long-term prognosis of SAE [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, prior studies have been limited by the lack of dynamic, real-time monitoring methods for assessing SAE severity during disease progression, resulting in incomplete evaluations of therapeutic outcomes.\u003c/p\u003e \u003cp\u003eIn this study, we proposed the use of serial TCD assessments in septic shock patients to systematically evaluate the effects of various fluid resuscitation strategies on mid- to long-term SAE prognosis. This investigation aimed to elucidate potential associations between fluid resuscitation and neurological recovery. Additionally, TCD may serve as a noninvasive, real-time tool for the early detection of cerebral hypoperfusion, thus enabling timely clinical interventions. We further explored the correlations between TCD-derived cerebral haemodynamic parameters and the severity of neurological impairment and assessed cognitive recovery during rehabilitation. This prospective cohort study aimed to determine the value of TCD in predicting medium- to long-term cognitive impairment in sepsis-associated encephalopathy patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis study was reviewed and approved by the Ethics Committee of Shenzhen Longhua District Central Hospital and complies with the requirements of the Declaration of Helsinki. All the participants signed a Informed consent form and were deidentified. The reporting of this study conforms to the STROBE guidelines[3].\u003c/p\u003e\n\u003cp\u003eIn this study, patients with infectious diseases who were admitted to the intensive care unit (ICU) of Longhua District Central Hospital between January 2022 and June 2024 were assessed using the Sequential Organ Failure Assessment (SOFA) score at admission. Participants who met the Sepsis 3.0 diagnostic criteria for septic shock [18] were consecutively enrolled. The exclusion criteria were as follows:\u003c/p\u003e\n\u003cp\u003e1. Patients who died within 72 hours of septic shock diagnosis;\u003c/p\u003e\n\u003cp\u003e2. Patients whose families opted to discontinue standardised treatment during the therapeutic course;\u003c/p\u003e\n\u003cp\u003e3. Age\u0026thinsp;\u0026lt;\u0026thinsp;18 years;\u003c/p\u003e\n\u003cp\u003e4. Pregnant women;\u003c/p\u003e\n\u003cp\u003e5. Patients with traumatic brain injury;\u003c/p\u003e\n\u003cp\u003e6. Patients with a history of large-area cerebral infarction;\u003c/p\u003e\n\u003cp\u003e7. Patients with severe sequelae of intracerebral haemorrhage and acute cerebral infarction;\u003c/p\u003e\n\u003cp\u003e8. Patients with meningitis, encephalitis, or metabolic encephalopathy;\u003c/p\u003e\n\u003cp\u003e9. Other individuals with significant preexisting cognitive impairments.\u003c/p\u003e\n\u003cp\u003eAll the enrolled septic shock patients received standardised 3-hour bundle therapy, including antibiotic treatment, goal-directed fluid resuscitation (20\u0026ndash;30 ml/kg saline with lactated Ringer\u0026rsquo;s solution in the first 3 hours after diagnosis), oxygen therapy or ventilatory support, and other interventions to correct electrolyte imbalances[14]. Serum lactate levels were measured 6 hours after resuscitation, with a 30% reduction from preresuscitation levels defined as adequate resuscitation[18][19]. Participants whose lactate reduction rate exceeded 20% from baseline were classified into the successful resuscitation group or the SR group, while participants whose lactate reduction rate was less than 20% or whose lactate level was elevated were classified into the unsuccessful resuscitation group or the UR group.\u003c/p\u003e\n\u003cp\u003eGiven that sepsis-associated encephalopathy (SAE) is a diagnosis of exclusion, patients who met the following criteria were enrolled in the SAE group[20]:\u003c/p\u003e\n\u003cp\u003e1. Septic shock patients who present with new episodes of disturbance of consciousness and cognitive dysfunction.\u003c/p\u003e\n\u003cp\u003e2. Participants with preexisting psychiatric disorders or cognitive impairment were excluded.\u003c/p\u003e\n\u003cp\u003e3. Participants with central nervous system (CNS) pathologies, including cerebral infarction, intracranial haemorrhage, CNS infections, and other CNS injuries, were excluded on the basis of cranial computed tomography (CT) or magnetic resonance imaging (MRI) findings.\u003c/p\u003e\n\u003cp\u003e4. Participants with evidence of epileptic seizures were excluded.\u003c/p\u003e\n\u003cp\u003e5. Participants with metabolic/toxic encephalopathies such as hepatic encephalopathy, hypoglycaemic encephalopathy, uraemic encephalopathy, drug intoxication, and other systemic metabolic causes of altered mental status were excluded.\u003c/p\u003e\n\u003cp\u003e6. Participants were assessed under conditions of relatively stable haemodynamics and adequate oxygen supply prior to sedative administration using the confusion assessment method for the intensive care unit (CAM-ICU), and those with positive results were diagnosed with SAE.\u003c/p\u003e\n\u003cp\u003ePatients were stratified into SAE and non-SAE groups. For the patients in the non-SAE group, transcranial Doppler ultrasound (TCD) was performed at treatment initiation (0 h) to establish a baseline for normal cerebral perfusion among patients with septic shock. For the patients in the SAE group, TCD assessments were performed at the following predefined intervals:\u003c/p\u003e\n\u003cp\u003e1. baseline (0 h);\u003c/p\u003e\n\u003cp\u003e2. 24 hours post-treatment;\u003c/p\u003e\n\u003cp\u003e3. 48 hours post-treatment;\u003c/p\u003e\n\u003cp\u003e4. 1 week post-treatment;\u003c/p\u003e\n\u003cp\u003e5. 2 weeks post-treatment.\u003c/p\u003e\n\u003cp\u003eDuring the TCD examinations, the patients were placed in a supine position with the headrest elevated to 0\u0026deg;. A portable ultrasound device (Mindray, Shenzhen, China) equipped with a phased-array transducer was used to measure the haemodynamic parameters of the proximal M1 segment of the bilateral middle cerebral arteries (MCAs) via the temporal window. The higher flow values from either MCA were recorded, including the following parameters:\u003c/p\u003e\n\u003cp\u003e1. peak systolic velocity (\u003cem\u003eVs\u003c/em\u003e);\u003c/p\u003e\n\u003cp\u003e2. end-diastolic velocity (Vd);\u003c/p\u003e\n\u003cp\u003e3. mean velocity (Vm);\u003c/p\u003e\n\u003cp\u003e4. pulsatility index (PI);\u003c/p\u003e\n\u003cp\u003e5. resistance index (RI).\u003c/p\u003e\n\u003cp\u003eVm was calculated as follows: \u003cem\u003eVm = (Vs\u0026thinsp;+\u0026thinsp;2\u0026times;Vd)/3\u003c/em\u003e; PI was calculated as follows: \u003cem\u003ePI = (Vs - Vd)/Vm\u003c/em\u003e; and the RI was calculated as follows: \u003cem\u003eRI = (Vs - Vd)/Vs\u003c/em\u003e. PI values\u0026thinsp;\u0026gt;\u0026thinsp;1.16 and RI values\u0026thinsp;\u0026gt;\u0026thinsp;0.65 indicated TCD positivity, thereby suggesting reduced cerebral perfusion. Moreover, PI values\u0026thinsp;\u0026lt;\u0026thinsp;1.16 and RI values\u0026thinsp;\u0026lt;\u0026thinsp;0.65 indicated TCD negativity, thereby suggesting adequate cerebral perfusion. To ensure consistency, all the TCD measurements and data recordings were performed by 3 trained operators.\u003c/p\u003e\n\u003cp\u003eAt 30 days post-treatment, the cognitive function of the patients in the SAE group was systematically evaluated using the Mini-Mental State Examination (MMSE). Patients with MMSE scores\u0026thinsp;\u0026lt;\u0026thinsp;23 points were defined as having cognitive impairment.\u003c/p\u003e\n\u003cp\u003eThe statistical analysis was performed using SPSS 27 software. One-way ANOVA was employed for comparisons among three groups of measurement data, whereas independent samples t tests were used for comparisons between two groups. Paired samples t tests were utilised for within-group comparisons. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance. Categorical data are presented as counts, with intergroup comparisons being analysed via chi-square tests. A significance level of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was applied for all statistical comparisons.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe overall cohort included 150 septic shock participants; 95 participants were diagnosed with SAE and 55 were diagnosed with non-SAE. The detailed baseline characteristics of the sepsis cohorts are shown in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eA total of 150 septic shock patients who met the inclusion criteria were enrolled in this study. Data from all the groups were subjected to homoscedasticity checking and were found to conform to a normal distribution.\u003c/p\u003e \u003cp\u003eOn the basis of the sepsis-associated encephalopathy (SAE) diagnostic criteria proposed by Papadopoulos et al., 95 patients were classified into the SAE group, whereas 45 patients were categorised into the non-SAE group. Following fluid resuscitation therapy, 66 patients (69.5%) in the SAE group were classified into the successful resuscitation group or the SR group, whereas 29 patients (30.5%) were classified into the unsuccessful resuscitation group or the UR group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTranscranial Doppler ultrasound (TCD) findings at 0 h (Table\u0026nbsp;2) revealed that cerebral perfusion was better in the non-SAE group (PI\u0026thinsp;=\u0026thinsp;0.983\u0026thinsp;\u0026plusmn;\u0026thinsp;0.127; RI\u0026thinsp;=\u0026thinsp;0.619\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014) than in the SAE group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), whereas cerebral perfusion was not significantly different between the SR group (PI\u0026thinsp;=\u0026thinsp;1.194\u0026thinsp;\u0026plusmn;\u0026thinsp;0.019; RI\u0026thinsp;=\u0026thinsp;0.702\u0026thinsp;\u0026plusmn;\u0026thinsp;0.026) and the UR group (PI\u0026thinsp;=\u0026thinsp;1.204\u0026thinsp;\u0026plusmn;\u0026thinsp;0.035; RI\u0026thinsp;=\u0026thinsp;0.712\u0026thinsp;\u0026plusmn;\u0026thinsp;0.028) (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe TCD findings at 24 hours post-treatment demonstrated that both the SR group and the UR group exhibited inadequate cerebral perfusion (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At the 48-hour, 1-week and 2-week follow-ups, the patients in the SR group demonstrated better cerebral perfusion than the patients in the UR group did (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and their cerebral perfusion gradually improved over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMoreover, when PI\u0026thinsp;\u0026gt;\u0026thinsp;1.16 and RI\u0026thinsp;\u0026gt;\u0026thinsp;0.65 were used as cut-off values to define positive TCD results, we obtained the number of patients with TCD-positive and TCD-negative results (Table\u0026nbsp;3). At 24 hours, 63 out of 66 patients (95.45%) in the SR group demonstrated TCD-positive results, whereas all 29 UR patients (100%) exhibited TCD positivity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At 48 hours post-treatment, 50 patients (75.76%) in the SR group remained TCD-positive, whereas all 29 UR patients (100%) retained their TCD-positive status (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eBy 1 week post-treatment, TCD positivity persisted in 21 patients (31.82%) in the SR group, with 32 patients (48.48%) demonstrating negative results. By contrast, 12 UR patients (41.38%) remained TCD-positive, with 5 patients (17.24%) exhibiting negative results and 13 patients being excluded because of mortality. The intergroup difference was statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAt 2 weeks post-treatment, the percentage of patients with TCD positivity decreased to 5 patients (7.58%) in the SR group, with 46 patients (70.91%) achieving normalisation. Among the UR patients, 10 patients (34.48%) remained TCD-positive, with 6 patients (20.69%) converting to a negative status and 13 patients being excluded because of mortality. A significant intergroup disparity persisted (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe cognitive function assessment using the Mini-Mental State Examination (MMSE) at 30 days post-treatment (by a cut-off value\u0026thinsp;\u0026le;\u0026thinsp;23 for cognitive impairment) revealed that 12 out of 39 survivors (30.8%) in the SR group exhibited cognitive deficits, whereas 10 survivors (52.6%) in the UR group demonstrated these deficits. This difference was statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eCompared with non-SAE patients, SAE patients demonstrated significantly greater cognitive decline at 30 days post-treatment (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). This deterioration remained statistically significant when directly compared with non-SAE controls (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, SAE was an exclusive diagnosis established primarily through the CAM-ICU scale and clinical history. The TCD positivity rate was significantly higher in SAE patients than in non-SAE patients. The results at 0 h revealed that SAE not only resulted in functional cognitive decline but also resulted in pathological reductions in cerebral perfusion.\u003c/p\u003e \u003cp\u003eDuring standardized bundle therapy for septic shock, four TCD assessments were performed. The 24 h post-treatment TCD results demonstrated no significant difference in cerebral perfusion between the SR and UR patients. These findings might suggest delayed cerebral haemodynamic recovery during the initial 24 hours of bundle therapy, which is potentially attributable to the acute-phase pathophysiology of septic shock [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e][\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Despite systemic perfusion improvements, persistent microthrombus formation in the microcirculation may perpetuate circulatory disturbances, compounded by high-dose vasopressor requirements during this critical phase, which may exacerbate cerebral vasoconstriction.\u003c/p\u003e \u003cp\u003eSignificant intergroup differences in TCD parameters were observed at 48 hours, 1 week, and 2 weeks post-treatment. The results revealed that the lower PI and RI values in the SR group indicate better cerebrovascular autoregulation and lower vascular resistance, suggesting better cerebral perfusion supply. By contrast, the higher PI and RI values in the UR group reflect increased cerebrovascular resistance, impaired vascular autoregulation, and consequently reduced cerebral perfusion[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings indicate that effective fluid resuscitation not only reduces lactate levels (which represent a marker of systemic microcirculation improvement) but also promotes cerebral perfusion recovery. This phenomenon may be correlated with lower vasopressor doses in responders, thus mitigating cerebral vascular resistance and enhancing perfusion. When intragroup comparisons were conducted, we observed that cerebral perfusion in the SR group gradually improved between 0 hours and 2 weeks, whereas that in the UR group did not significantly improve during the first 0\u0026ndash;48 hours, with perfusion only beginning to recover between 48 hours and 2 weeks. These findings suggest that adequate and effective fluid resuscitation during the early stages of septic shock significantly enhances cerebral perfusion in SAE patients during the early phases. This improvement may be associated with fluid resuscitation promoting microthrombolysis and microcirculatory restoration. Notably, patients with improved cerebral perfusion require a shorter duration of mechanical ventilation and thus shorter sedation/analgesia time, thus leading to decreased ICU times and healthcare costs. These outcomes underscore the critical role of protocolised bundle therapy in septic shock management.\u003c/p\u003e \u003cp\u003eIn this study, a 20% reduction in serum lactate levels within 6 hours served as the threshold for adequate resuscitation. Although lactate does not directly quantify tissue perfusion, it reflects cellular hypoxia [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. An elevated lactate concentration (\u0026gt;\u0026thinsp;4 mmol/L) predicts an increased risk of mortality in septic shock patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e][\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], with a lactate clearance\u0026thinsp;\u0026gt;\u0026thinsp;20% within 6 hours being associated with improved survival [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Paediatric studies have further demonstrated that persistent hyperlactataemia (\u0026ge;\u0026thinsp;4 mmol/L) at 4 hours post-resuscitation is correlated with a 5.5-fold increased risk of MODS within 24 hours [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Randomised trials have confirmed that lactate-guided resuscitation significantly reduces the risk of mortality [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e][\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Our findings extend this evidence, linking effective lactate clearance to enhanced cerebral perfusion and superior neurocognitive outcomes. Furthermore, rigorous inflammatory control may attenuate blood\u0026ndash;brain barrier disruption and neuronal injury by reducing the levels of circulating lipopolysaccharides, proinflammatory cytokines, and endotoxins [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt 30 days post-treatment, MMSE scores\u0026thinsp;\u0026le;\u0026thinsp;23 (indicating moderate-to-severe cognitive impairment) were analysed in survivors. Although SAE is often considered reversible, up to 40% of septic shock survivors exhibit mild-to-moderate neurological deficits within 1 year post-discharge [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e][\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Prolonged ICU stays, post-sepsis anxiety/depression [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e][\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and posttraumatic stress may confound mild cognitive assessments. To minimise false positives, we focused on moderate-to-severe impairments. Notably, compared with UR patients, SR patients exhibited significantly higher MMSE-negative rates (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), thereby aligning with acute-phase TCD trends. These findings suggest that protocolised resuscitation not only optimises acute cerebral perfusion but also mitigates midterm neurocognitive sequelae. Conversely, impaired cerebral perfusion is correlated with midterm cognitive deficits, which are likely mediated by hypoxic-ischaemic injury to the metabolically vulnerable limbic system (a region that is critical for cognition, emotional regulation, and memory) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e][\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e][\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The susceptibility of the limbic system to hypoperfusion [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] aligns with MRI evidence of ischaemic injury in shock states, thereby explaining why preserved cerebral perfusion predicts favourable neurological outcomes.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThis study has several limitations. First, the single-centre design may limit the representativeness of the sample size and the generalisability of the findings. In the absence of a multivariable assessment, current evidence is insufficient to support the use of TCD findings as a predictor of cognitive outcomes in patients with SAE. Future studies should incorporate assessments such as NSE or S-100β to substantiate the correlation between TCD findings and neuronal damage.\u003c/p\u003e \u003cp\u003eSecond, after patients with severe sequelae of intracerebral haemorrhage or cerebral infarction were excluded, an increased rate of successful fluid resuscitation and reduced 30-day mortality rate were observed, which may be attributed to their preexisting compromised vascular status. However, these exclusion criteria may introduce bias in the diagnosis of SAE severity within the SR and UR subgroups. Third, the short follow-up duration limited the comprehensive evaluation of long-term neurological and cognitive outcomes. Thus, multicentre, double-blind studies with extended follow-up periods, multimodal imaging and validated neuropsychological assessments are needed in the future to holistically evaluate the impact of fluid resuscitation on SAE progression.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrated that protocolised bundle therapy might significantly reduce neurological injury in septic shock patients by providing adequate cerebral perfusion. Monitoring cerebral perfusion via TCD might provide actionable insights for optimising resuscitation strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics\u0026nbsp;approval and consent to participate(\u003cstrong\u003eEthics Approval Number:\u0026nbsp;\u003c/strong\u003e2021-156-01)\u003cbr\u003eApproved by the Medical\u0026nbsp;and\u0026nbsp;Health\u0026nbsp;Institutions\u0026nbsp;of\u0026nbsp;Longhua\u0026nbsp;District,\u0026nbsp;Shenzhen.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eAvailability of supporting data.\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eCompeting interests.\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eFunding.\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe\u0026nbsp;Scientific\u0026nbsp;Research\u0026nbsp;Projects\u0026nbsp;of\u0026nbsp;Medical\u0026nbsp;and\u0026nbsp;Health\u0026nbsp;Institutions\u0026nbsp;of\u0026nbsp;Longhua\u0026nbsp;District,\u0026nbsp;Shenzhen\u003c/p\u003e\n\u003cp\u003eKey Medical Discipline Construction Fund of Shenzhen Longhua District\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003eAuthors' contributions.\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eQing Yu: Conceptualisation, Writing, Data analysis,Original Draft Preparation—language review and editing\u003c/p\u003e\n\u003cp\u003eWen Lai: TCD assessment, Data collection,Figure editing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZuqing Xu: Fact checking, Reference collection, and Language review\u003c/p\u003e\n\u003cp\u003eLumei Fan: Figure and table editing, Data analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe\u0026nbsp;would\u0026nbsp;like\u0026nbsp;to\u0026nbsp;express\u0026nbsp;our\u0026nbsp;sincere\u0026nbsp;gratitude\u0026nbsp;to\u0026nbsp;several\u0026nbsp;individuals\u0026nbsp;who\u0026nbsp;made significant contributions to\u0026nbsp;the\u0026nbsp;completion\u0026nbsp;of\u0026nbsp;this\u0026nbsp;thesis. First,\u0026nbsp;we are grateful to all the patients for sharing their medical data and providing their cooperation.\u0026nbsp;Additionally, we would like to thank all the medical\u0026nbsp;staff\u0026nbsp;for sharing ideas and collaborating during treatment. Finally, we would like to thank the tech\u0026nbsp;support team from Mindray for their patience and professionalism.\u003c/p\u003e\n\u003cp\u003eThis thesis\u0026nbsp;would\u0026nbsp;not\u0026nbsp;have\u0026nbsp;been\u0026nbsp;possible\u0026nbsp;without\u0026nbsp;the\u0026nbsp;support\u0026nbsp;and\u0026nbsp;assistance\u0026nbsp;of\u0026nbsp;these\u0026nbsp;wonderful\u0026nbsp;people.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCecconi, M., Evans, L., Levy, M. \u0026amp; Rhodes, A. Sepsis and septic shock. Lancet. ;392(10141):75\u0026ndash;87. doi: 10.1016/S0140-6736(18)30696-2. Epub 2018 Jun 21. PMID: 29937192. 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PMID: 25027645; PMCID: PMC4105508.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are 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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Septic encephalopathy, Transcranial Doppler ultrasonography, Septic shock, Cognitive prognosis, Fluid resuscitation","lastPublishedDoi":"10.21203/rs.3.rs-8811454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8811454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eSeptic encephalopathy (SAE) is a common cerebral dysfunction associated with septic shock, which can lead to neurological and cognitive impairments. Early and adequate fluid resuscitation during septic shock not only reduces the risk of mortality but also significantly improves medium-to-long-term neurological outcomes for patients with SAE. This study investigated the relationship between fluid resuscitation and cognitive prognosis in SAE patients via TCD(Transcranial Doppler ultrasonography), with implications for early intervention.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this prospective cohort study, 150 patients with septic shock were enrolled and categorised into SAE and non-SAE groups on the basis of clinical diagnostic criteria. SAE patients received standardised fluid resuscitation and were stratified into successful resuscitation and unsuccessful resuscitation subgroups. TCD was performed 24 hours, 48 hours, 1 week, and 2 weeks after admission to evaluate cerebral perfusion. Cognitive function was assessed on day 30 using the Mini-Mental State Examination (MMSE).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTCD effectively identified SAE in septic shock patients. Significant differences in TCD-negative detection rates were observed between the successful and unsuccessful resuscitation subgroups at 48 hours, 1 week, and 2 weeks (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Statistically distinct MMSE scores were also noted at the 30-day follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEffective fluid resuscitation in septic shock patients has positive implications for neurological recovery and medium-to-long-term cognitive improvement. TCD exhibits favourable efficacy and operational feasibility in the evaluation of neurological outcomes for prognostic purposes, thus supporting its integration into clinical decision-making protocols.\u003c/p\u003e","manuscriptTitle":"Impact on Cognitive Prognosis in Patients with Septic Encephalopathy related to Fluid Resuscitation: A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-25 05:50:41","doi":"10.21203/rs.3.rs-8811454/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-06T07:41:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-04T12:04:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-30T10:28:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-28T22:20:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25277049410911141693230440878306160690","date":"2026-03-21T15:54:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324178486543385145852810710208149050221","date":"2026-03-21T14:58:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-19T14:48:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176993196615327227128379526350191573182","date":"2026-03-19T14:38:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94038887919692400228942105704451523975","date":"2026-03-19T14:27:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2267997830779479765885749711664974952","date":"2026-03-19T12:31:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-19T12:22:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-19T12:21:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-02T08:57:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-17T14:11:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-02-17T14:07:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"82313b03-1452-48f6-8597-5b75f0c9132d","owner":[],"postedDate":"March 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64903528,"name":"Health sciences/Diseases"},{"id":64903529,"name":"Health sciences/Medical research"},{"id":64903530,"name":"Health sciences/Neurology"},{"id":64903531,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-15T16:38:36+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-25 05:50:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8811454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8811454","identity":"rs-8811454","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}