Trends and Disparities in Sepsis and Acute Stroke-Related Mortality Rates among Adults in the United States (1999-2023): A CDC Wonder Analysis

Trends and Disparities in Sepsis and Acute Stroke-Related Mortality Rates among Adults in the United States (1999-2023): A CDC Wonder Analysis | 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 Trends and Disparities in Sepsis and Acute Stroke-Related Mortality Rates among Adults in the United States (1999-2023): A CDC Wonder Analysis Eiman Amir, Minahil Tariq, Maham Sattar, Muhammad Awais Raza, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7771530/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Sepsis and stroke are the leading causes of death in the United States with stroke accounting for 1 out of every 20 deaths each year. Sepsis increases the risk of stroke by causing hypercoagulable state, triggering inflammation, endothelial dysfunction and disseminated intravascular coagulation (DIC) resulting in microthrombi formation, hypoperfusion of the brain leading to stroke. This study aims at analyzing the trends and disparity in sepsis and stroke related mortality rates in the United States from 1999–2023. Methods This retrospective study uses CDC WONDER database from 1999–2023 for Sepsis and Stroke to analyze mortality trends using CDC-10 code (A40-41) for sepsis and (160–164) for stroke. Age adjusted mortality rates (AAMR) per 100,000 were obtained and analyzed for overall mortality, gender, age, race and ethnicity, states, urbanization and census region. Join point analysis regression analyzed AAMR and annual percent change (APC). Results From 1999–2023 sepsis and stroke accounted for 209,719 deaths in the United States. Majority of deaths occurred in medical facilities (77.8%) with AAMR of 4.59 in 1999 followed by decrease to 3.04 in 2023. Higher AAMR's are observed in Males, Older age groups, Blacks, Hispanics and Non-metropolitan areas. States in the top 95th percentile included District of Columbia, Mississippi and Oklahoma which had five to six times higher AAMR's than states in 5th percentile. Peaks in mortality trends of demographic factors were observed, coinciding with Covid-19 pandemic. Conclusions: Disparity among Males, Old age, Black, Non-metropolitan, South and several states in mortality highlights the need for future studies to identify risk factors. Timely diagnosis, prompt treatment, effective use of technology and telemedicine can reduce morbidity and mortality. Sepsis Stroke Mortality rates disparity CDC WONDER Age-adjusted mortality Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction According to the World Health Organization, a stroke is defined as 'rapidly developed clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than vascular origin 1 . Stroke is a severe debilitating disease leading to disability and death. It is the third leading cause of death and the fourth leading cause of DALYs (Disability-Adjusted Life-Years) 2 . In 2021, there were 7.25 million deaths due to stroke worldwide while in the United States in the year 2022, 1 of every 20 deaths was due to stroke 3 . There have been many definitions of sepsis with the most widely used as ‘body's systemic inflammatory response syndrome (SIRS) to infection’ but in 2016 a new definition was proposed as ‘dysregulated immune response to infection leading to organ dysfunction 4 . There were 48.9 million cases of sepsis worldwide in 2017 with 11.0 million deaths directly related to sepsis 5 . It presents a major challenge for healthcare, as it is often underdiagnosed; in fact, 1 in 3 patients who die in hospitals had sepsis. Sepsis is not uncommon, affecting approximately 1.7 million U.S. adults each year 6 . Sepsis, particularly when it progresses to septic shock, is a common cause of atrial fibrillation 7 . Atrial fibrillation, in turn, increases the risk of thromboembolic events, particularly cardioembolic stroke 8 . Consequently, sepsis—due to various mechanisms such as circulatory collapse, coagulation disorders, and systemic inflammation—can lead to stroke 9 . Similarly, patients admitted to the ICU for ischemic stroke have an increased risk of developing sepsis during their hospital stay 10 . In patients with hemorrhagic stroke, increased mortality and poorer medical outcomes within the first three months are linked to sepsis, making it one of the earliest medical complications following a stroke 11 . Given the strong association between sepsis and stroke, particularly during long duration of hospital admission, a thorough study related to the temporal trends of the aforementioned diseases is crucial. With stroke and sepsis being one of the leading causes of mortality in both the developed and developing countries, urgent attention to determine their correlation is imperative. While many previous studies have conceptualized these two conditions in relation to the cardiovascular system, none have yet analyzed their mortality trends. Similarly, although stroke has been studied within the domain of cardiovascular diseases, our study focuses specifically on the relationship between acute events of stroke and sepsis. The following CDC analysis aims to bridge this gap in the literature. Methodology Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database (CDC WONDER) was used in this retrospective study to determine deaths occurring in the USA due to sepsis and acute stroke 12 . Data was extracted from the Multiple Cause of Death (final) database for the years 1999–2023. The International Classification of Diseases (ICD), 10th Revision (ICD-10), codes A-40, A-41 were used for septicemia while codes I-60, I-61, I-62, I-63, and I-64 were used for acute stroke events. Codes I-65 through I-69 were excluded as they represent long-term complications of stroke, allowing us to focus solely on acute events. Data was extracted for patients aged ≥ 15, as data for those under 15 was deemed unreliable. Data were analyzed for overall mortality and further stratified by gender, race, urbanization, states, and census regions. Races were categorized into Hispanic and non-Hispanic, which included Americans, Whites, Blacks, and Asians. We studied mortality for the age range of 15 to 85+, as data for patients under 15 was not available on CDC WONDER. Ages were grouped in 20-year increments: young adults (15–34), early middle-aged adults (35–54), middle-aged adults (55–64), and older adults (75–85+). Census regions were divided into Northeast, Midwest, West, and South, as defined by the Census Bureau. Overall mortality was studied by extracting the number of deaths per year and Age adjusted mortality rates (AAMR) was calculated using the 2000 United States standard population. The Joinpoint Regression Program (version 4.9.0.0) from National Cancer Institute was used for data analysis 13 . Annual Percentage change (APC), Average Annual Percentage Change (AAPC) and 95% Confidence Interval for AAMRs were calculated. For determining segment joints by connecting join points, the Monte Carlo Permutation test was employed. Changes in APCs and slopes were assessed on the basis of difference from zero by 2-tailed t-test. Statistical significance was determined using asterisks and was set as p ≤ 0.05. Results From 1999–2023, sepsis and stroke accounted for 209,719 deaths in the U.S., with 102,682 in males and 107,117 in females. (See Supplementary Table 1,2) The majority of deaths occurred in medical facilities ( 77.8% ) followed by nursing homes ( 12.17% ), hospice facilities ( 4.34% ) and decedent’s homes ( 4.12% ). 1. Annual trends for Sepsis and Stroke related AAMR : The AAMR for sepsis and stroke related deaths was 4.59 in 1999 and 3.04 in 2023. (APC: -1.6674*, 95% CI: -2.3496 to -0.9804, p value:<0.001). Overall AAMR was 3.17 (APC: -1.6676*, 95% CI: -2.3496 to -0.9804, p-value:<0.001). (See Fig. 1 , Supplementary Tables 3 and 4A) 2. AAMR stratified by Gender : Males have higher AAMRs than females throughout the study period. Overall AAMR for males is 3.09 (APC: -1.5726*, 95% CI: -2.4700 to -0.6668, p value: <0.001) and for females is 2.74 (APC: -1.6356*, 95% CI: -2.0903 to -0.1787, p value: <0.001). In 1999, the AAMR for females was 4.09 which significantly decreased in 2012 to 2.26 (APC: -4.8158*, 95% CI: -5.3817 to -4.2464, p value: <0.001). This was followed by an increase till 2023, where the AAMR rose to 2.62 (APC:2.2601*, 95%CI: 1.4322 to 3.0948, p value: <0.001). Similarly, AAMR for males in 1999 was 5.35 , followed by a decrease till 2010 to 3.03 (APC: -5.2821*, 95%CI: -5.7256 to -4.8366, p value: <0.001). There was a slight increase in AAMR in 2018 to 3.14 (APC:1.1228*, 95% CI: 0.1842 to 2.0702, p value:0.223). Then from 2018 to 2021, there was a significant increase in AAMR, rising to 3.99 (APC:7.2909*, 95%CI: 0.6889 to 14.3249, p value:0.032). However, from 2021 to 2023, AAMR declined to 3.6 (APC: -4.1087, 95%CI: -9.4902 to 1.5927, p value: 0.141). (See Fig. 2 , Supplementary Tables 3 and 4A) 3. AAMR stratified by Age Group : Young adults showed no significant trends during this period. In 1999, AAMR was 0.05 , which slightly increased to 0.1 by 2023 (APC:2.8605*, 95%CI: 1.3515 to 4.3920, p value: <0.001). Early middle-aged adults showed an AAMR of 0.62 in 1999, which decreased to 0.53 in 2007(APC: -2.2084*, 95% CI: -3.9919 to -0.3918, p value:0.020). From 2007 to 2018, the AAMR slightly increased to 0.67 (APC:1.9163, 95% CI: 0.5135 to 3.3386, p value:0.010). Then, from 2018 to 2021, there was a significant increase in AAMR to 1.1 (APC:15.9190* 95% CI: 0.2593 to 34.0248, p value:0.046). However, from 2021 to 2023, the AAMR declined to 0.86 (APC: -8.9247, 95% CI: -19.5842 to 3.1479, p value:0.129). For middle aged adults, AAMR was 6.69 in 1999, decreasing significantly to 4.18 in 2011 (APC: -4.3403*, 95% CI: -4.6446 to -4.0351, p value:<0.001). There was an increase in AAMR to 4.68 in 2018. (APC: 2.1144* 95% CI:1.2581 to 2.9779, p value:<0.001). The AAMR rapidly increased to 6.18 in 2021 (APC:9.9832*, 95% CI: 5.1883 to 14.9966, p value: <0.001). From 2021 to 2023, the AAMR declined to 5.58 (APC: -3.9285*, 95% CI: -7.5857 to -0.126, p value:0.043). For older adults, the AAMR was 39.52 in 1999, decreasing to 20.28 in 2011 (APC: -5.6543, 95% CI: -6.12702 to -5.1793, p value:<0.001). From 2011 to 2023, there was a slight increase in AAMR to 20.7 (APC:0.7526, 95% CI: 0.2182 to 1.2899, p value:0.008). (See Fig. 3 , Supplementary Tables 3 and 4C) 4. AAMR stratified by Race/Ethnicity : In 1999, AAMR for Blacks was 12.45 , which decreased significantly to 5.69 in 2012 (APC: -5.9457* 95% CI: -6.3451 to -5.5446, p value:<0.001). From 2012 to 2018, there was an insignificant decrease in AAMR to 5.52 (APC: -1.1179, 95% CI: -3.0317 to 0.8336, p value:0.2376). AAMR increased significantly to 6.98 from 2018 to 2021 (APC:8.2091*, 95% CI: 0.00292 to 17.089, p value:0.049). From 2021 to 2023, AAMR declined to 6.54 (APC: -1.6847 95%CI: -8.556 to 5.7034, p value:0.622). Americans showed no trends during the study period. AAMR was 4.84 in 1999, slightly decreasing to 3.99 by 2023 (APC:0.7316, 95% CI: − 0.1141 to 1.5844, p value:0.086). For Asians , the AAMR was 4.95 in 1999, decreasing to 2.47 in 2018 (APC: -3.5685*, 95%CI: -4.1268 to -3.0069, p value: <0.001). From 2018 to 2021 AAMR increased to 3.25 (APC:11.5800, 95% CI: -4.5320 to 30.4112, p value:0.156). It then decreased to 2.47 from 2021 to 2023 (APC: -12.1307, 95% CI: -24.337 to 2.4450, p value: 0.085). In 1999, Whites had AAMR of 3.78 , which decreased significantly to 2.18 in 2011 (APC: -4.9076*, 95% CI: -5.4618 to -4.3501, p value:<0.001). From 2011 to 2023, there was a significant increase in AAMR to 2.61 (APC:2.5091*, 95%CI: 1.9168 to 3.1049, p value:<0.001). For Hispanics , AAMR was 4.77 in 1999, which decreased significantly to 2.82 in 2012 (APC: -4.4631*, 95% CI: -5.6284 to -3.2833, p value:<0.001). There was a significant rise in AAMR to 3.07 from 2012 to 2023 (APC: 1.4856*, 95%CI: -0.2615 to 2.7246, p value:0.019). (Fig. 4 , supplementary table 3 and 4A) 5. AAMR stratified by Urbanization : For Non-Metropolitan areas , AAMR was 4.46 in 1999, decreasing to 2.67 in 2011 (APC: -4.2115, 95% CI: -4.7853 to -3.6342, p value:<0.001). From 2011 to 2020, AAMR significantly increased to 3.38 (APC:2.7304, 95%CI:1.7349 to 3.7356, p value:<0.001). AAMR was 4.62 for Metropolitan areas in 1999, significantly decreasing to 2.47 in 2012 (APC: -4.7981*, 95% CI: -5.2617 to -4.3322, p value:<0.001). Subsequently, AAMR increased significantly to 3 from 2012 to 2020 (APC:2.0261*, 95% CI:1.0841 to 2.9769, p value:0.0002). From 1999 to 2012, AAMR was higher in Metropolitan areas; however, it became lower than that of Non-Metropolitan areas from 2012 to 2020. (See Fig. 5 , supplementary table 3 and 4C) 6. AAMR Trends by Census Region (1999–2023) : Northeast group: AAMR was 4.27 in 1999, decreasing to 2.36 in 2010 (APC: -5.4752*, 95% CI: -6.1273 to -4.8186, p value:<0.001). From 2010 to 2019, there was a slight decline in AAMR to 2.3 (APC: -0.2498, 95% CI: -1.4752 to 0.9908, p value:0.674). AAMR increased significantly to 2.59 from 2019 to 2023 (APC:3.6208*, 95% CI: 0.0208 to 7.3503, p value:0.048). Midwest group: In 1999, AAMR was 4.18 which decreased significantly to 2.09 in 2012 (APC: -4.6761*, 95% CI: -5.3290 to -4.0186, p value:<0.001). From 2012 to 2023, AAMR was significantly increased to 2.56 (APC:2.2527*, 95%CI: 1.3102 to 3.2039, p value:<0.001). South group: AAMR was 5.6 in 1999, significantly decreasing to 3.01 in 2011 (APC: -5.4517*, 95% CI: -5.7132 to -5.1895, p value:<0.001). From 2011 to 2018, AAMR significantly increased to 3.35 (APC:1.6417*, 95% CI: 0.8778 to 2.4114, p value:0.0003). AAMR further increased to 4.18 from 2018 to 2021 (APC: 7.8988*, 95% CI: 3.3165 to 12.6843, p value:0.002). From 2021 to 2023, there was a significant decrease in AAMR to 3.6 (APC: -5.6450*, 95% CI: -9.3601 to -1.7776, p value:0.007). West group: AAMR was 3.68 in 1999 which decreased significantly to 2.43 in 2011 (APC: -3.7160*, 95% CI: -4.6994 to -2.7224, p value: <0.001). From 2011 to 2023, AAMR significantly increased to 2.93 (APC:2.3263*, 95% CI: 1.4319 to 3.2286, p value:<0.001). Overall, AAMR was highest in the South group and lowest in the West group. (See Fig. 6 , Supplementary Tables 3 and 4B) 7. AAMR Stratified by States : AAMR varied widely across states from 1999 to 2023 ranging from low of 0.48 in Maine (95% CI: 0.31 to 0.72) to a high of 7.86 in District of Colombia (95% CI:6.47 to 9.26). States in the top 95th percentile included District of Columbia (95% CI:6.47 to 9.26), Mississippi (95% CI:6.47 to 7.62), Oklahoma (95% CI: 5.58 to 6.5) which had approximately five to six times higher AAMRs than states that fell in the 5th percentile, such as Maine (95% CI: 0.31 to 0.72), Rhode Island (95% CI: 1.24 to 2.11), New Hampshire (95% CI: 1.33 to 2.13), and Arizona (95% CI: 1.54 to 1.89).(See Fig. 7 , Supplementary Tables 5 and 6) Discussions Our study highlights several significant findings regarding AAMR. Overall, there was a reduction in mortality due to sepsis and stroke, with most deaths occurring in medical facilities. Males and older adults emerged as the most vulnerable groups. Among racial demographics, the Black population was the most severely affected. Additionally, metropolitan areas exhibited higher AAMR compared to non-metropolitan areas; however, the impact of urbanization on mortality trends remained fluctuating at a similar rate. The South was particularly affected among census regions, and the District of Columbia showed a profound impact from stroke and sepsis. Males were having a higher ratio of mortality than their female counterparts. The fact that males less likely visit healthcare setup, seek health care advice, and follow up treatment is well established 14 . This can lead to more serious health problems with co-morbidities like diabetes, hypertension and stroke, deteriorating into sepsis 15 . Moreover, males are more likely to engage in IV drug abuse which can also lead to sepsis. In our study, we observed a significant rise in mortality trends for both males and females in 2018, coinciding with the onset of the COVID-19 pandemic. During the early phase of pandemic, death due to stroke increased 16 , with COVID-19 increasing the risk of stroke 17 . A meta-analysis indicated that sepsis developed in 52% of hospitalized patients with COVID-19 infection 18 . This trend must be closely observed to make an impactful healthcare policy to address this incidence. The old age group (75–84-year-old) was severely affected by stroke and sepsis. The mortality trend decreased till 2011, signifying the impact of advancements in health facilities and treatment options. However, this trend began to increase slightly until 2023. The underlying mechanism in this age group is atherosclerosis; without timely intervention, this condition can escalate, leading to the development of stroke and sepsis 15 . In contrast, the mortality trend for young adults in our study showed only insignificant fluctuations. This finding is inconsistent with the study by Morrissey et al., which indicated that the rise in mortality due to sepsis in young adults was linked to increased IV drug use 19 . Since the CDC database had no record of drug history, this relation was not analyzed in our study. Much of available data supports the fact that black communities lack proper health care access. Hence, racial disparities contribute to the deterioration of health outcomes. In our study, Black African population showed a reduced mortality trend till 2018, although the AAMR was higher than other racial groups. This trend then showed a spike starting in 2018. This finding aligns with previous research showing that 9.4% more deaths occurred in Black and 6.9% more in White after COVID-19 pandemic 20 . Also, the minority population experienced disproportionate increases in mortality during the early phase of the pandemic 16 . Therefore, regulatory bodies must consider these trends, and policies should be designed to be unbiased in order to reduce morbidity and mortality within the Black population. Metropolitan populations have access to more advanced technology in the health care setups than non-metropolitan groups. Hence, intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) reduce the severity of stroke and its complications 21 . In our study, both metropolitan and non-metropolitan showed a reduction in mortality (although AAMR became slightly higher for non-metropolitan after 2012). A peak developed for non-metropolitan in 2016, and trend then increased for both groups after 2019. This finding contrasts with the study of Song et.al., which reported a 27.96% increase in deaths in stroke units, likely due to delays in seeking healthcare intervention 22 . Hotz et.al reported a stable trend of AIS because of the combined effect of intervention (IVT and MT) which reduced mortality while increasing incidence of AIS among older adults which increased mortality 21 . In our analysis, the spike in 2019 aligns with the inflammatory effects of COVID-19, which can reduce oxygen delivery to tissues and activate the coagulation pathway 23 . Additionally, individuals from low socioeconomic backgrounds are less likely to receive adequate rehabilitation care compared to those from higher socioeconomic statuses 24 25 . Therefore, there must be equitable distribution of healthcare resources, ensuring that every individual, regardless of socioeconomic status, has the right to receive the best possible treatment. The South showed the highest disparity among census regions in our study. Several studies reported the same results where the Southeast stroke belt band had the highest mortality rates 22 . A significant 35.78% percent change (PC) in AAMR was noted from 2019 to 2021 for this region 19 . Additionally, the study by Ogundipe et.al also observed the highest disparity among American South 26 , while the Northeast had the second highest AAMR according to Morrissey et.al 19 . To address these issues, it is essential to conduct prospective studies that identify environmental risk factors contributing to these disparities, thereby informing strategies to reduce morbidity and mortality trends in the region. In our study, the District of Columbia, Mississippi, and Oklahoma exhibited the highest AAMR among census regions, while the Northeast also reported a high AAMR in the study by Morrissey et al 19 . Given that the Northeast has a high density of metropolitan areas, limited access to healthcare can contribute to elevated AAMR, similar to what is observed in the Appalachian states. Additionally, high mortality rates have been linked to low socioeconomic status in the U.S 27 28 . The COVID-19 pandemic has further burdened healthcare systems, exacerbating health outcomes, including those related to sepsis 29 . Therefore, public health facilitators must monitor trends in each region to identify causal factors, aiming to reduce the disease burden associated with sepsis and stroke. Conclusion There was a descending trend in AAMR of stroke and sepsis, attributed to timely diagnosis, prompt treatment, and advancements in technology and interventions. Each stratified group's trends showed peaks from 2019 to 2022, highlighting the close relationship between sepsis, stroke, and COVID-19 infection. Disparities persist among men, older adults, the Black population, residents of the South, non-metropolitan areas, and individuals from states such as the District of Columbia, Mississippi, and Oklahoma. Therefore, raising awareness about the severity of these diseases is crucial for reducing morbidity. Additionally, prospective studies will be essential for informing effective policy development. Limitations Our study reported several significant findings that can aid in effective policy-making. However, it also had several limitations. Being a cross-sectional study, it lacked information on demographics, education levels, and awareness, as well as co-morbidities that could predispose individuals to atherosclerosis and stroke, past surgical histories where sepsis could manifest as a post-operative complication, and lipid profiles. Data on these factors could further refine our findings. Therefore, prospective analyses are needed to observe trends and disparities, ultimately facilitating more effective policy development. Abbreviations CDC WONDER Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database AAMR Age adjusted mortality rates APC Annual Percentage change AAPC Average Annual Percentage Change Declarations Acknowledgements: Not applicable Funding: Self-funded Conflict of interest: None Author Contribution: EA: Conceptualization, data analysis, interpretation of results, methodology, visualization, preparation of supplementary file, and writing the original draft. MT: Writing the discussion, conclusion, and limitations; critical interpretation of findings; and review and editing of the manuscript. MS: Data extraction and abstract writing. MR: Visualization and preparation of the supplementary file. AA: Writing the introduction. AA: Writing the results section. AM: Reviewing the manuscript, checking grammar and spelling, and assisting with the publication process. References Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. 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Khanijahani A, Iezadi S, Gholipour K, Azami-Aghdash S, Naghibi D. A systematic review of racial/ethnic and socioeconomic disparities in COVID-19. Int J Equity Health. 2021;20:248. Mude W, Oguoma VM, Nyanhanda T, Mwanri L, Njue C. Racial disparities in COVID-19 pandemic cases, hospitalisations, and deaths: A systematic review and meta-analysis. J Glob Health. 2021;11:05015. Alcendor DJ. Racial Disparities-Associated COVID-19 Mortality among Minority Populations in the US. JCM. 2020;9:2442. Additional Declarations No competing interests reported. Supplementary Files Supplementarytables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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04:00:56","extension":"html","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96180,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/c2db42c2af65d2afa82799d1.html"},{"id":93453025,"identity":"09d1915b-3de4-44ca-928f-355ca182a5a7","added_by":"auto","created_at":"2025-10-14 04:00:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":15726,"visible":true,"origin":"","legend":"\u003cp\u003eAge-Adjusted Mortality Rates (AAMR) Stratified by Overall Mortality. This figure illustrates the AAMR stratified by overall mortality for sepsis and stroke from 1999 to 2023.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/df20528effb05e75a5525067.png"},{"id":93453996,"identity":"18a634a8-acac-4917-8906-de133ab9451b","added_by":"auto","created_at":"2025-10-14 04:16:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17254,"visible":true,"origin":"","legend":"\u003cp\u003eSex-Stratified Age-Adjusted Mortality Rates (AAMR). This figure presents the AAMR for sepsis and stroke, stratified by sex from 1999 to 2023. The data reveals significant differences in mortality trends between males and females.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/1b4e862a5ab6fa34f5f11d94.png"},{"id":93453029,"identity":"bf8dfa35-3cc3-4a9f-8a08-a2da62363f58","added_by":"auto","created_at":"2025-10-14 04:00:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":27446,"visible":true,"origin":"","legend":"\u003cp\u003eAge Group Stratification of Age-Adjusted Mortality Rates (AAMR). This figure illustrates the AAMR for sepsis and stroke, stratified by age groups from 1999 to 2023. The analysis highlights the varying mortality trends across different age demographics.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/2c4da81e90c0938861143879.png"},{"id":93453759,"identity":"9f6da1ba-7d7b-43e2-9bfb-fa0c0a181bae","added_by":"auto","created_at":"2025-10-14 04:08:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40878,"visible":true,"origin":"","legend":"\u003cp\u003eRace Stratification of Age-Adjusted Mortality Rates (AAMR). This figure displays the AAMR for sepsis and stroke, stratified by race from 1999 to 2023.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/c199d2d30dc630427c1b45cc.png"},{"id":93453031,"identity":"ce8063b5-610c-405e-928f-98c9cc29e57b","added_by":"auto","created_at":"2025-10-14 04:00:55","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":28576,"visible":true,"origin":"","legend":"\u003cp\u003eUrbanization Stratification of Age-Adjusted Mortality Rates (AAMR). This figure depicts AAMR for sepsis and stroke, stratified by urbanization levels from 1999 to 2023. The analysis reveals notable differences in mortality patterns between urban and non-urban populations.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/e5120ee957483c2ad0228e97.png"},{"id":93453997,"identity":"d092d393-4142-47f9-b5e9-16ec6813a812","added_by":"auto","created_at":"2025-10-14 04:16:55","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":37048,"visible":true,"origin":"","legend":"\u003cp\u003eCensus Region Stratification of Age-Adjusted Mortality Rates (AAMR). This figure presents the AAMR for sepsis and stroke, stratified by census regions from 1999 to 2023.\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/60c5c636c25357208c797d08.png"},{"id":93453762,"identity":"950750ef-30ed-44ab-b78b-ea17fc42cb5e","added_by":"auto","created_at":"2025-10-14 04:08:55","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":185033,"visible":true,"origin":"","legend":"\u003cp\u003eAge-Adjusted Mortality Rates (AAMR) Stratified by states. This figure illustrates the AAMR for sepsis and stroke, stratified by states from 1999 to 2023. It highlights states that fall above the 95th percentile and below the 5th percentile in mortality rates, drawing attention to significant disparities and the need for targeted health policies.\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/e7fd10003af20d9a54565bf7.png"},{"id":103603513,"identity":"7854a3f0-394c-497e-b2d6-10b2d6077854","added_by":"auto","created_at":"2026-02-27 14:27:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1120456,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/4769583e-11ff-4df2-bdd6-dd28e227b661.pdf"},{"id":93453028,"identity":"be255613-627f-4544-8431-9c6092c5c042","added_by":"auto","created_at":"2025-10-14 04:00:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34007,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7771530/v1/9831e08bcf8dcb3d6dbf9ead.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends and Disparities in Sepsis and Acute Stroke-Related Mortality Rates among Adults in the United States (1999-2023): A CDC Wonder Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to the World Health Organization, a stroke is defined as 'rapidly developed clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than vascular origin\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Stroke is a severe debilitating disease leading to disability and death. It is the third leading cause of death and the fourth leading cause of DALYs (Disability-Adjusted Life-Years)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. In 2021, there were 7.25\u0026nbsp;million deaths due to stroke worldwide while in the United States in the year 2022, 1 of every 20 deaths was due to stroke\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThere have been many definitions of sepsis with the most widely used as \u0026lsquo;body's systemic inflammatory response syndrome (SIRS) to infection\u0026rsquo; but in 2016 a new definition was proposed as \u0026lsquo;dysregulated immune response to infection leading to organ dysfunction\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. There were 48.9\u0026nbsp;million cases of sepsis worldwide in 2017 with 11.0\u0026nbsp;million deaths directly related to sepsis\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It presents a major challenge for healthcare, as it is often underdiagnosed; in fact, 1 in 3 patients who die in hospitals had sepsis. Sepsis is not uncommon, affecting approximately 1.7\u0026nbsp;million U.S. adults each year\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSepsis, particularly when it progresses to septic shock, is a common cause of atrial fibrillation\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Atrial fibrillation, in turn, increases the risk of thromboembolic events, particularly cardioembolic stroke\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Consequently, sepsis\u0026mdash;due to various mechanisms such as circulatory collapse, coagulation disorders, and systemic inflammation\u0026mdash;can lead to stroke\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Similarly, patients admitted to the ICU for ischemic stroke have an increased risk of developing sepsis during their hospital stay\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In patients with hemorrhagic stroke, increased mortality and poorer medical outcomes within the first three months are linked to sepsis, making it one of the earliest medical complications following a stroke\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Given the strong association between sepsis and stroke, particularly during long duration of hospital admission, a thorough study related to the temporal trends of the aforementioned diseases is crucial.\u003c/p\u003e\u003cp\u003eWith stroke and sepsis being one of the leading causes of mortality in both the developed and developing countries, urgent attention to determine their correlation is imperative.\u003c/p\u003e\u003cp\u003eWhile many previous studies have conceptualized these two conditions in relation to the cardiovascular system, none have yet analyzed their mortality trends. Similarly, although stroke has been studied within the domain of cardiovascular diseases, our study focuses specifically on the relationship between acute events of stroke and sepsis. The following CDC analysis aims to bridge this gap in the literature.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eCenters for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database (CDC WONDER) was used in this retrospective study to determine deaths occurring in the USA due to sepsis and acute stroke\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Data was extracted from the Multiple Cause of Death (final) database for the years 1999\u0026ndash;2023. The International Classification of Diseases (ICD), 10th Revision (ICD-10), codes A-40, A-41 were used for septicemia while codes I-60, I-61, I-62, I-63, and I-64 were used for acute stroke events. Codes I-65 through I-69 were excluded as they represent long-term complications of stroke, allowing us to focus solely on acute events. Data was extracted for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;15, as data for those under 15 was deemed unreliable.\u003c/p\u003e\u003cp\u003eData were analyzed for overall mortality and further stratified by gender, race, urbanization, states, and census regions. Races were categorized into Hispanic and non-Hispanic, which included Americans, Whites, Blacks, and Asians. We studied mortality for the age range of 15 to 85+, as data for patients under 15 was not available on CDC WONDER. Ages were grouped in 20-year increments: young adults (15\u0026ndash;34), early middle-aged adults (35\u0026ndash;54), middle-aged adults (55\u0026ndash;64), and older adults (75\u0026ndash;85+). Census regions were divided into Northeast, Midwest, West, and South, as defined by the Census Bureau.\u003c/p\u003e\u003cp\u003eOverall mortality was studied by extracting the number of deaths per year and Age adjusted mortality rates (AAMR) was calculated using the 2000 United States standard population. The Joinpoint Regression Program (version 4.9.0.0) from National Cancer Institute was used for data analysis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Annual Percentage change (APC), Average Annual Percentage Change (AAPC) and 95% Confidence Interval for AAMRs were calculated. For determining segment joints by connecting join points, the Monte Carlo Permutation test was employed. Changes in APCs and slopes were assessed on the basis of difference from zero by 2-tailed t-test. Statistical significance was determined using asterisks and was set as p\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 1999\u0026ndash;2023, sepsis and stroke accounted for \u003cb\u003e209,719\u003c/b\u003e deaths in the U.S., with \u003cb\u003e102,682\u003c/b\u003e in males and \u003cb\u003e107,117\u003c/b\u003e in females. (See Supplementary Table\u0026nbsp;1,2)\u003c/p\u003e\u003cp\u003eThe majority of deaths occurred in medical facilities (\u003cb\u003e77.8%\u003c/b\u003e) followed by nursing homes (\u003cb\u003e12.17%\u003c/b\u003e), hospice facilities (\u003cb\u003e4.34%\u003c/b\u003e) and decedent\u0026rsquo;s homes (\u003cb\u003e4.12%\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003e1. Annual trends for Sepsis and Stroke related AAMR\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe AAMR for sepsis and stroke related deaths was \u003cb\u003e4.59\u003c/b\u003e in 1999 and \u003cb\u003e3.04\u003c/b\u003e in 2023. (APC: -1.6674*, 95% CI: -2.3496 to -0.9804, p value:\u0026lt;0.001). Overall AAMR was \u003cb\u003e3.17\u003c/b\u003e (APC: -1.6676*, 95% CI: -2.3496 to -0.9804, p-value:\u0026lt;0.001). (See Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplementary Tables\u0026nbsp;3 and 4A)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2. AAMR stratified by Gender\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eMales have higher AAMRs than females throughout the study period. Overall AAMR for males is \u003cb\u003e3.09\u003c/b\u003e (APC: -1.5726*, 95% CI: -2.4700 to -0.6668, p value: \u0026lt;0.001) and for females is \u003cb\u003e2.74\u003c/b\u003e (APC: -1.6356*, 95% CI: -2.0903 to -0.1787, p value: \u0026lt;0.001).\u003c/p\u003e\u003cp\u003eIn 1999, the AAMR for females was \u003cb\u003e4.09\u003c/b\u003e which significantly decreased in 2012 to \u003cb\u003e2.26\u003c/b\u003e (APC: -4.8158*, 95% CI: -5.3817 to -4.2464, p value: \u0026lt;0.001). This was followed by an increase till 2023, where the AAMR rose to \u003cb\u003e2.62\u003c/b\u003e (APC:2.2601*, 95%CI: 1.4322 to 3.0948, p value: \u0026lt;0.001).\u003c/p\u003e\u003cp\u003eSimilarly, AAMR for males in 1999 was \u003cb\u003e5.35\u003c/b\u003e, followed by a decrease till 2010 to \u003cb\u003e3.03\u003c/b\u003e (APC: -5.2821*, 95%CI: -5.7256 to -4.8366, p value: \u0026lt;0.001). There was a slight increase in AAMR in 2018 to \u003cb\u003e3.14\u003c/b\u003e (APC:1.1228*, 95% CI: 0.1842 to 2.0702, p value:0.223). Then from 2018 to 2021, there was a significant increase in AAMR, rising to \u003cb\u003e3.99\u003c/b\u003e (APC:7.2909*, 95%CI: 0.6889 to 14.3249, p value:0.032). However, from 2021 to 2023, AAMR declined to \u003cb\u003e3.6\u003c/b\u003e (APC: -4.1087, 95%CI: -9.4902 to 1.5927, p value: 0.141). (See Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Supplementary Tables\u0026nbsp;3 and 4A)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3. AAMR stratified by Age Group\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eYoung adults showed no significant trends during this period. In 1999, AAMR was \u003cb\u003e0.05\u003c/b\u003e, which slightly increased to \u003cb\u003e0.1\u003c/b\u003e by 2023 (APC:2.8605*, 95%CI: 1.3515 to 4.3920, p value: \u0026lt;0.001).\u003c/p\u003e\u003cp\u003eEarly middle-aged adults showed an AAMR of \u003cb\u003e0.62\u003c/b\u003e in 1999, which decreased to 0.53 in 2007(APC: -2.2084*, 95% CI: -3.9919 to -0.3918, p value:0.020). From 2007 to 2018, the AAMR slightly increased to \u003cb\u003e0.67\u003c/b\u003e (APC:1.9163, 95% CI: 0.5135 to 3.3386, p value:0.010). Then, from 2018 to 2021, there was a significant increase in AAMR to \u003cb\u003e1.1\u003c/b\u003e (APC:15.9190* 95% CI: 0.2593 to 34.0248, p value:0.046). However, from 2021 to 2023, the AAMR declined to \u003cb\u003e0.86\u003c/b\u003e (APC: -8.9247, 95% CI: -19.5842 to 3.1479, p value:0.129).\u003c/p\u003e\u003cp\u003eFor middle aged adults, AAMR was \u003cb\u003e6.69\u003c/b\u003e in 1999, decreasing significantly to \u003cb\u003e4.18\u003c/b\u003e in 2011 (APC: -4.3403*, 95% CI: -4.6446 to -4.0351, p value:\u0026lt;0.001). There was an increase in AAMR to \u003cb\u003e4.68\u003c/b\u003e in 2018. (APC: 2.1144* 95% CI:1.2581 to 2.9779, p value:\u0026lt;0.001). The AAMR rapidly increased to \u003cb\u003e6.18\u003c/b\u003e in 2021 (APC:9.9832*, 95% CI: 5.1883 to 14.9966, p value: \u0026lt;0.001). From 2021 to 2023, the AAMR declined to \u003cb\u003e5.58\u003c/b\u003e (APC: -3.9285*, 95% CI: -7.5857 to -0.126, p value:0.043).\u003c/p\u003e\u003cp\u003eFor older adults, the AAMR was \u003cb\u003e39.52\u003c/b\u003e in 1999, decreasing to \u003cb\u003e20.28\u003c/b\u003e in 2011 (APC: -5.6543, 95% CI: -6.12702 to -5.1793, p value:\u0026lt;0.001). From 2011 to 2023, there was a slight increase in AAMR to \u003cb\u003e20.7\u003c/b\u003e (APC:0.7526, 95% CI: 0.2182 to 1.2899, p value:0.008). (See Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Supplementary Tables\u0026nbsp;3 and 4C)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e4. AAMR stratified by Race/Ethnicity\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eIn 1999, AAMR for \u003cb\u003eBlacks\u003c/b\u003e was \u003cb\u003e12.45\u003c/b\u003e, which decreased significantly to \u003cb\u003e5.69\u003c/b\u003e in 2012 (APC: -5.9457* 95% CI: -6.3451 to -5.5446, p value:\u0026lt;0.001). From 2012 to 2018, there was an insignificant decrease in AAMR to \u003cb\u003e5.52\u003c/b\u003e (APC: -1.1179, 95% CI: -3.0317 to 0.8336, p value:0.2376). AAMR increased significantly to \u003cb\u003e6.98\u003c/b\u003e from 2018 to 2021 (APC:8.2091*, 95% CI: 0.00292 to 17.089, p value:0.049). From 2021 to 2023, AAMR declined to \u003cb\u003e6.54\u003c/b\u003e (APC: -1.6847 95%CI: -8.556 to 5.7034, p value:0.622).\u003c/p\u003e\u003cp\u003e\u003cb\u003eAmericans\u003c/b\u003e showed no trends during the study period. AAMR was \u003cb\u003e4.84\u003c/b\u003e in 1999, slightly decreasing to \u003cb\u003e3.99\u003c/b\u003e by 2023 (APC:0.7316, 95% CI: \u0026minus;\u0026thinsp;0.1141 to 1.5844, p value:0.086).\u003c/p\u003e\u003cp\u003eFor \u003cb\u003eAsians\u003c/b\u003e, the AAMR was \u003cb\u003e4.95\u003c/b\u003e in 1999, decreasing to \u003cb\u003e2.47\u003c/b\u003e in 2018 (APC: -3.5685*, 95%CI: -4.1268 to -3.0069, p value: \u0026lt;0.001). From 2018 to 2021 AAMR increased to \u003cb\u003e3.25\u003c/b\u003e (APC:11.5800, 95% CI: -4.5320 to 30.4112, p value:0.156). It then decreased to \u003cb\u003e2.47\u003c/b\u003e from 2021 to 2023 (APC: -12.1307, 95% CI: -24.337 to 2.4450, p value: 0.085).\u003c/p\u003e\u003cp\u003eIn 1999, \u003cb\u003eWhites\u003c/b\u003e had AAMR of \u003cb\u003e3.78\u003c/b\u003e, which decreased significantly to \u003cb\u003e2.18\u003c/b\u003e in 2011 (APC: -4.9076*, 95% CI: -5.4618 to -4.3501, p value:\u0026lt;0.001). From 2011 to 2023, there was a significant increase in AAMR to \u003cb\u003e2.61\u003c/b\u003e (APC:2.5091*, 95%CI: 1.9168 to 3.1049, p value:\u0026lt;0.001).\u003c/p\u003e\u003cp\u003eFor \u003cb\u003eHispanics\u003c/b\u003e, AAMR was 4.77 in 1999, which decreased significantly to \u003cb\u003e2.82\u003c/b\u003e in 2012 (APC: -4.4631*, 95% CI: -5.6284 to -3.2833, p value:\u0026lt;0.001). There was a significant rise in AAMR to \u003cb\u003e3.07\u003c/b\u003e from 2012 to 2023 (APC: 1.4856*, 95%CI: -0.2615 to 2.7246, p value:0.019). (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, supplementary table 3 and 4A)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e5. AAMR stratified by Urbanization\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eFor \u003cb\u003eNon-Metropolitan areas\u003c/b\u003e, AAMR was \u003cb\u003e4.46\u003c/b\u003e in 1999, decreasing to \u003cb\u003e2.67\u003c/b\u003e in 2011 (APC: -4.2115, 95% CI: -4.7853 to -3.6342, p value:\u0026lt;0.001). From 2011 to 2020, AAMR significantly increased to \u003cb\u003e3.38\u003c/b\u003e (APC:2.7304, 95%CI:1.7349 to 3.7356, p value:\u0026lt;0.001).\u003c/p\u003e\u003cp\u003eAAMR was \u003cb\u003e4.62\u003c/b\u003e for \u003cb\u003eMetropolitan areas\u003c/b\u003e in 1999, significantly decreasing to \u003cb\u003e2.47\u003c/b\u003e in 2012 (APC: -4.7981*, 95% CI: -5.2617 to -4.3322, p value:\u0026lt;0.001). Subsequently, AAMR increased significantly to \u003cb\u003e3\u003c/b\u003e from 2012 to 2020 (APC:2.0261*, 95% CI:1.0841 to 2.9769, p value:0.0002).\u003c/p\u003e\u003cp\u003eFrom 1999 to 2012, AAMR was higher in Metropolitan areas; however, it became lower than that of Non-Metropolitan areas from 2012 to 2020. (See Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, supplementary table 3 and 4C)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e6. AAMR Trends by Census Region (1999\u0026ndash;2023)\u003c/b\u003e:\u003c/p\u003e\n\u003ch3\u003eNortheast group:\u003c/h3\u003e\n\u003cp\u003eAAMR was \u003cb\u003e4.27\u003c/b\u003e in 1999, decreasing to \u003cb\u003e2.36\u003c/b\u003e in 2010 (APC: -5.4752*, 95% CI: -6.1273 to -4.8186, p value:\u0026lt;0.001). From 2010 to 2019, there was a slight decline in AAMR to \u003cb\u003e2.3\u003c/b\u003e (APC: -0.2498, 95% CI: -1.4752 to 0.9908, p value:0.674). AAMR increased significantly to \u003cb\u003e2.59\u003c/b\u003e from 2019 to 2023 (APC:3.6208*, 95% CI: 0.0208 to 7.3503, p value:0.048).\u003c/p\u003e\n\u003ch3\u003eMidwest group:\u003c/h3\u003e\n\u003cp\u003eIn 1999, AAMR was \u003cb\u003e4.18\u003c/b\u003e which decreased significantly to \u003cb\u003e2.09\u003c/b\u003e in 2012 (APC: -4.6761*, 95% CI: -5.3290 to -4.0186, p value:\u0026lt;0.001). From 2012 to 2023, AAMR was significantly increased to \u003cb\u003e2.56\u003c/b\u003e (APC:2.2527*, 95%CI: 1.3102 to 3.2039, p value:\u0026lt;0.001).\u003c/p\u003e\n\u003ch3\u003eSouth group:\u003c/h3\u003e\n\u003cp\u003eAAMR was 5.6 in 1999, significantly decreasing to \u003cb\u003e3.01\u003c/b\u003e in 2011 (APC: -5.4517*, 95% CI: -5.7132 to -5.1895, p value:\u0026lt;0.001). From 2011 to 2018, AAMR significantly increased to \u003cb\u003e3.35\u003c/b\u003e (APC:1.6417*, 95% CI: 0.8778 to 2.4114, p value:0.0003). AAMR further increased to \u003cb\u003e4.18\u003c/b\u003e from 2018 to 2021 (APC: 7.8988*, 95% CI: 3.3165 to 12.6843, p value:0.002). From 2021 to 2023, there was a significant decrease in AAMR to \u003cb\u003e3.6\u003c/b\u003e (APC: -5.6450*, 95% CI: -9.3601 to -1.7776, p value:0.007).\u003c/p\u003e\n\u003ch3\u003eWest group:\u003c/h3\u003e\n\u003cp\u003eAAMR was \u003cb\u003e3.68\u003c/b\u003e in 1999 which decreased significantly to \u003cb\u003e2.43\u003c/b\u003e in 2011 (APC: -3.7160*, 95% CI: -4.6994 to -2.7224, p value: \u0026lt;0.001). From 2011 to 2023, AAMR significantly increased to \u003cb\u003e2.93\u003c/b\u003e (APC:2.3263*, 95% CI: 1.4319 to 3.2286, p value:\u0026lt;0.001).\u003c/p\u003e\u003cp\u003eOverall, AAMR was highest in the South group and lowest in the West group. (See Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, Supplementary Tables\u0026nbsp;3 and 4B)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e7. AAMR Stratified by States\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAAMR varied widely across states from 1999 to 2023 ranging from low of 0.48 in \u003cb\u003eMaine\u003c/b\u003e (95% CI: 0.31 to 0.72) to a high of 7.86 in \u003cb\u003eDistrict of Colombia\u003c/b\u003e (95% CI:6.47 to 9.26).\u003c/p\u003e\u003cp\u003eStates in the top 95th percentile included District of Columbia (95% CI:6.47 to 9.26), Mississippi (95% CI:6.47 to 7.62), Oklahoma (95% CI: 5.58 to 6.5) which had approximately five to six times higher AAMRs than states that fell in the 5th percentile, such as Maine (95% CI: 0.31 to 0.72), Rhode Island (95% CI: 1.24 to 2.11), New Hampshire (95% CI: 1.33 to 2.13), and Arizona (95% CI: 1.54 to 1.89).(See Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, Supplementary Tables\u0026nbsp;5 and 6)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eOur study highlights several significant findings regarding AAMR. Overall, there was a reduction in mortality due to sepsis and stroke, with most deaths occurring in medical facilities. Males and older adults emerged as the most vulnerable groups. Among racial demographics, the Black population was the most severely affected.\u003c/p\u003e\u003cp\u003eAdditionally, metropolitan areas exhibited higher AAMR compared to non-metropolitan areas; however, the impact of urbanization on mortality trends remained fluctuating at a similar rate. The South was particularly affected among census regions, and the District of Columbia showed a profound impact from stroke and sepsis.\u003c/p\u003e\u003cp\u003eMales were having a higher ratio of mortality than their female counterparts. The fact that males less likely visit healthcare setup, seek health care advice, and follow up treatment is well established\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. This can lead to more serious health problems with co-morbidities like diabetes, hypertension and stroke, deteriorating into sepsis\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Moreover, males are more likely to engage in IV drug abuse which can also lead to sepsis. In our study, we observed a significant rise in mortality trends for both males and females in 2018, coinciding with the onset of the COVID-19 pandemic. During the early phase of pandemic, death due to stroke increased\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, with COVID-19 increasing the risk of stroke\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. A meta-analysis indicated that sepsis developed in 52% of hospitalized patients with COVID-19 infection\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. This trend must be closely observed to make an impactful healthcare policy to address this incidence.\u003c/p\u003e\u003cp\u003eThe old age group (75\u0026ndash;84-year-old) was severely affected by stroke and sepsis. The mortality trend decreased till 2011, signifying the impact of advancements in health facilities and treatment options. However, this trend began to increase slightly until 2023. The underlying mechanism in this age group is atherosclerosis; without timely intervention, this condition can escalate, leading to the development of stroke and sepsis\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn contrast, the mortality trend for young adults in our study showed only insignificant fluctuations. This finding is inconsistent with the study by Morrissey et al., which indicated that the rise in mortality due to sepsis in young adults was linked to increased IV drug use\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Since the CDC database had no record of drug history, this relation was not analyzed in our study.\u003c/p\u003e\u003cp\u003eMuch of available data supports the fact that black communities lack proper health care access. Hence, racial disparities contribute to the deterioration of health outcomes. In our study, Black African population showed a reduced mortality trend till 2018, although the AAMR was higher than other racial groups. This trend then showed a spike starting in 2018. This finding aligns with previous research showing that 9.4% more deaths occurred in Black and 6.9% more in White after COVID-19 pandemic\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Also, the minority population experienced disproportionate increases in mortality during the early phase of the pandemic\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Therefore, regulatory bodies must consider these trends, and policies should be designed to be unbiased in order to reduce morbidity and mortality within the Black population.\u003c/p\u003e\u003cp\u003eMetropolitan populations have access to more advanced technology in the health care setups than non-metropolitan groups. Hence, intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) reduce the severity of stroke and its complications\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In our study, both metropolitan and non-metropolitan showed a reduction in mortality (although AAMR became slightly higher for non-metropolitan after 2012). A peak developed for non-metropolitan in 2016, and trend then increased for both groups after 2019. This finding contrasts with the study of Song et.al., which reported a 27.96% increase in deaths in stroke units, likely due to delays in seeking healthcare intervention\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Hotz et.al reported a stable trend of AIS because of the combined effect of intervention (IVT and MT) which reduced mortality while increasing incidence of AIS among older adults which increased mortality\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In our analysis, the spike in 2019 aligns with the inflammatory effects of COVID-19, which can reduce oxygen delivery to tissues and activate the coagulation pathway\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Additionally, individuals from low socioeconomic backgrounds are less likely to receive adequate rehabilitation care compared to those from higher socioeconomic statuses\u003csup\u003e24 25\u003c/sup\u003e. Therefore, there must be equitable distribution of healthcare resources, ensuring that every individual, regardless of socioeconomic status, has the right to receive the best possible treatment.\u003c/p\u003e\u003cp\u003eThe South showed the highest disparity among census regions in our study. Several studies reported the same results where the Southeast stroke belt band had the highest mortality rates \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. A significant 35.78% percent change (PC) in AAMR was noted from 2019 to 2021 for this region\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Additionally, the study by Ogundipe et.al also observed the highest disparity among American South\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, while the Northeast had the second highest AAMR according to Morrissey et.al\u003csup\u003e19\u003c/sup\u003e. To address these issues, it is essential to conduct prospective studies that identify environmental risk factors contributing to these disparities, thereby informing strategies to reduce morbidity and mortality trends in the region.\u003c/p\u003e\u003cp\u003eIn our study, the District of Columbia, Mississippi, and Oklahoma exhibited the highest AAMR among census regions, while the Northeast also reported a high AAMR in the study by Morrissey et al\u003csup\u003e19\u003c/sup\u003e. Given that the Northeast has a high density of metropolitan areas, limited access to healthcare can contribute to elevated AAMR, similar to what is observed in the Appalachian states. Additionally, high mortality rates have been linked to low socioeconomic status in the U.S\u003csup\u003e27 28\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe COVID-19 pandemic has further burdened healthcare systems, exacerbating health outcomes, including those related to sepsis\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Therefore, public health facilitators must monitor trends in each region to identify causal factors, aiming to reduce the disease burden associated with sepsis and stroke.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThere was a descending trend in AAMR of stroke and sepsis, attributed to timely diagnosis, prompt treatment, and advancements in technology and interventions. Each stratified group's trends showed peaks from 2019 to 2022, highlighting the close relationship between sepsis, stroke, and COVID-19 infection. Disparities persist among men, older adults, the Black population, residents of the South, non-metropolitan areas, and individuals from states such as the District of Columbia, Mississippi, and Oklahoma. Therefore, raising awareness about the severity of these diseases is crucial for reducing morbidity. Additionally, prospective studies will be essential for informing effective policy development.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eOur study reported several significant findings that can aid in effective policy-making. However, it also had several limitations. Being a cross-sectional study, it lacked information on demographics, education levels, and awareness, as well as co-morbidities that could predispose individuals to atherosclerosis and stroke, past surgical histories where sepsis could manifest as a post-operative complication, and lipid profiles. Data on these factors could further refine our findings. Therefore, prospective analyses are needed to observe trends and disparities, ultimately facilitating more effective policy development.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDC WONDER\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCenters for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAge adjusted mortality rates\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnnual Percentage change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAAPC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAverage Annual Percentage Change\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eSelf-funded\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEA: Conceptualization, data analysis, interpretation of results, methodology, visualization, preparation of supplementary file, and writing the original draft.\u003c/p\u003e\n\u003cp\u003eMT: Writing the discussion, conclusion, and limitations; critical interpretation of findings; and review and editing of the manuscript.\u003c/p\u003e\n\u003cp\u003eMS: Data extraction and abstract writing.\u003c/p\u003e\n\u003cp\u003eMR: Visualization and preparation of the supplementary file.\u003c/p\u003e\n\u003cp\u003eAA: Writing the introduction.\u003c/p\u003e\n\u003cp\u003eAA: Writing the results section.\u003c/p\u003e\n\u003cp\u003eAM: Reviewing the manuscript, checking grammar and spelling, and assisting with the publication process.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. 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A systematic review of racial/ethnic and socioeconomic disparities in COVID-19. Int J Equity Health. 2021;20:248.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMude W, Oguoma VM, Nyanhanda T, Mwanri L, Njue C. Racial disparities in COVID-19 pandemic cases, hospitalisations, and deaths: A systematic review and meta-analysis. J Glob Health. 2021;11:05015.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlcendor DJ. Racial Disparities-Associated COVID-19 Mortality among Minority Populations in the US. JCM. 2020;9:2442.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Stroke, Mortality rates, disparity, CDC WONDER, Age-adjusted mortality","lastPublishedDoi":"10.21203/rs.3.rs-7771530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7771530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eSepsis and stroke are the leading causes of death in the United States with stroke accounting for 1 out of every 20 deaths each year. Sepsis increases the risk of stroke by causing hypercoagulable state, triggering inflammation, endothelial dysfunction and disseminated intravascular coagulation (DIC) resulting in microthrombi formation, hypoperfusion of the brain leading to stroke. This study aims at analyzing the trends and disparity in sepsis and stroke related mortality rates in the United States from 1999\u0026ndash;2023.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective study uses CDC WONDER database from 1999\u0026ndash;2023 for Sepsis and Stroke to analyze mortality trends using CDC-10 code (A40-41) for sepsis and (160\u0026ndash;164) for stroke. Age adjusted mortality rates (AAMR) per 100,000 were obtained and analyzed for overall mortality, gender, age, race and ethnicity, states, urbanization and census region. Join point analysis regression analyzed AAMR and annual percent change (APC).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom 1999\u0026ndash;2023 sepsis and stroke accounted for 209,719 deaths in the United States. Majority of deaths occurred in medical facilities (77.8%) with AAMR of 4.59 in 1999 followed by decrease to 3.04 in 2023. Higher AAMR's are observed in Males, Older age groups, Blacks, Hispanics and Non-metropolitan areas. States in the top 95th percentile included District of Columbia, Mississippi and Oklahoma which had five to six times higher AAMR's than states in 5th percentile. Peaks in mortality trends of demographic factors were observed, coinciding with Covid-19 pandemic.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eDisparity among Males, Old age, Black, Non-metropolitan, South and several states in mortality highlights the need for future studies to identify risk factors. Timely diagnosis, prompt treatment, effective use of technology and telemedicine can reduce morbidity and mortality.\u003c/p\u003e","manuscriptTitle":"Trends and Disparities in Sepsis and Acute Stroke-Related Mortality Rates among Adults in the United States (1999-2023): A CDC Wonder Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-14 04:00:50","doi":"10.21203/rs.3.rs-7771530/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ddf5546-2042-4272-bad1-44774149a689","owner":[],"postedDate":"October 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-27T14:26:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-14 04:00:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7771530","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7771530","identity":"rs-7771530","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}