Temporal Trends in Electrolyte and Acid-Base Imbalance Mortality in the U.S. (1999- 2020): A Longitudinal Analysis

Temporal Trends in Electrolyte and Acid-Base Imbalance Mortality in the U.S. (1999- 2020): A Longitudinal 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 Temporal Trends in Electrolyte and Acid-Base Imbalance Mortality in the U.S. (1999- 2020): A Longitudinal Analysis Zaima Afzaal, Asma Chaudhary, Inshal Uddin Khattak, Asad Khan, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6846811/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: Electrolyte and acid-base imbalance (EABI) has emerged as a critical contributor to rising mortality rates worldwide. This study aims to investigate the underexplored mortality trends associated with EABI in the United States from 1999 to 2020. Methods: Mortality data spanning 1999 to 2020 were retrieved from the CDC WONDER database, encompassing all age groups. Age-adjusted mortality rates (AAMRs) per 100,000 individuals were analyzed. Joinpoint regression modeling was employed to calculate annual percentage changes (APCs). AAMRs were further stratified by race, sex, age, U.S. census region, and urbanization status. Results: Between 1999 and 2020, a total of 580,238 deaths were attributed to EABI. AAMRs declined from 1999 to 2008 (APC: -2.73), followed by a gradual increase from 2008 to 2018 (APC: 4.44), and a pronounced rise between 2018 and 2020 (APC: 12.08). Males exhibited consistently higher AAMRs (8.58) compared to females (7.29). Among racial groups, Non-Hispanic Blacks had the highest AAMR (12.70), while Asians had the lowest (5.45). Regionally, the South reported the highest AAMR (8.70), followed by the Midwest (7.78), Northeast (7.35), and West (7.06). Non-metropolitan areas had notably higher AAMRs (9.73) than metropolitan counterparts (7.49). Conclusion: The upward trend in EABI-related mortality over the study period is alarming and underscores the need for urgent public health interventions. Enhanced health education and preventive strategies are essential to mitigate EABI risk and reduce associated mortality in the future. electrolytes mortality trends disparities Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. INTRODUCTION Electrolytes are essential for normal physiological function, and even minor deviations from their narrow range can be life-threatening [ 1 , 2 ]. Electrolyte imbalances are known to disrupt cardiac electrophysiology, increasing the risk of arrhythmias, and can exacerbate outcomes in critically ill patients [ 3 , 4 ]. Additionally, the burden of diseases such as diabetes mellitus, cancer, and the COVID-19 pandemic has further highlighted the lethal implications of acid-base disturbances [ 5 – 7 ]. Mortality patterns associated with electrolyte and acid-base imbalance (EABI) vary among patient populations, with critically ill children—often subjected to prolonged hospitalizations—being particularly vulnerable [ 8 ]. Despite its clinical importance, large-scale epidemiological data on long-term EABI mortality trends in the United States remain limited. To address this gap, our study analyzes over two decades of national mortality data (1999–2020) from the CDC WONDER database, offering a comprehensive assessment of population-level trends. 2. METHODS Study Setting and Population This study utilized de-identified death certificate data from the CDC WONDER database spanning 1999 to 2020 [ 9 ]. Electrolyte and acid-base imbalance (EABI)–related deaths were identified across all age groups using ICD-10 codes E87.0–E87.8. Relevant comorbid conditions included heart failure (HF) (I50), diabetes mellitus (DM) (E10–E14), sepsis (A41), and chronic kidney disease (CKD) (N18) as underlying causes. EABI-related deaths were defined as those listing EABI as either a contributing or underlying cause. Analyses were conducted both individually by variable and collectively to assess national trends. Data covered all 50 states and the District of Columbia, using the Multiple Cause-of-Death Public Use files. Institutional review board approval was not required, as the study employed publicly available, de-identified data and adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [ 10 ]. Data Abstraction We extracted data on population size, year, demographics, urban-rural classification, and geographic region. Demographic variables included sex, age, and race/ethnicity. Racial/ethnic categories were defined as Non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaskan Native, and NH Asian or Pacific Islander. Urban-rural classification followed the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. Geographic regions were categorized according to the U.S. Census Bureau’s definitions: Northeast, Midwest, South, and West [ 11 ]. Statistical Analysis We analyzed mortality trends related to electrolyte imbalance from 1999 to 2020, reporting crude and age-adjusted mortality rates (AAMRs) per 100,000 population with 95% confidence intervals (CIs), stratified by year, sex, race/ethnicity, region, and urban-rural status. Crude mortality rates were calculated by dividing total EABI-related deaths by the corresponding annual U.S. population. AAMRs were standardized to the 2000 U.S. population [ 12 ]. To assess annual trends, we used the Joinpoint Regression Program (version 5.3.0, National Cancer Institute) to calculate annual percent change (APC) with 95% CI, employing the Monte Carlo permutation test for model selection. Joinpoint regression applied log-linear models to detect significant temporal changes in AAMR. APCs were classified as increasing or decreasing when the slope significantly differed from zero using two-tailed t-tests, with statistical significance set at P < 0.05. 3. RESULTS A total of 580,238 EABI deaths occurred among groups of all ages between 1999 and 2020 (Supplemental table 1 , Central Illustration) . However, the place of death was known for 569,917 deaths only. Of these 76.46% were in medical facilities, 12.86% at nursing homes/long term care facilities, 9.25% at and 1.45% at hospices (Supplemental table 2) . Annual trends for electrolyte and acid-base imbalances-related AAMR The AAMR for EABI across all ages was 7.88 (95% CI: 7.78 to 7.99) in 1999 and peaked at 12.25 (95% CI: 12.14 to 12.36) in 2020. The lowest recorded AAMR was 6.21 (95% CI: 6.13 to 6.30) in 2007. Overall, the AAMR declined from 1999 to 2008 (APC: − 2.73; 95% CI: − 3.18 to − 2.27), followed by a rising trend from 2008 to 2018 (APC: 4.44; 95% CI: 4.00 to 4.89). A marked increase was observed from 2018 to 2020 (APC: 12.08; 95% CI: 7.93 to 16.38) ( Fig. 1 , Supplemental Tables 3 and 4) . Electrolyte and acid-base imbalances related AAMR stratified by Sex Men exhibited a higher overall AAMR of 8.58 (95% CI: 8.55 to 8.62) compared to females at 7.29 (95% CI: 7.27 to 7.32), with both sexes reaching peak AAMRs in 2020 (13.85 vs. 10.93, respectively). Among men, AAMR declined from 1999 to 2007 (APC: − 3.49; 95% CI: − 4.17 to − 2.79), then increased from 2007 to 2018 (APC: 4.16; 95% CI: 3.71 to 4.61), followed by a sharp rise between 2018 and 2020 (APC: 15.12; 95% CI: 10.35 to 20.09). For women, the AAMR decreased from 1999 to 2008 (APC: − 2.63; 95% CI: − 3.18 to − 2.08), then increased steadily from 2008 to 2018 (APC: 4.29; 95% CI: 3.77 to 4.80), with a more pronounced rise from 2018 to 2020 (APC: 10.58; 95% CI: 5.72 to 15.65). Overall, mortality rates initially declined until the late 2000s before rising steadily, with a notable surge in recent years, especially among men ( Fig. 1 , Supplemental Tables 3 and 4) . Electrolyte and acid-base imbalances related AAMR stratified by race Racial stratification revealed the highest AAMRs among Non-Hispanic (NH) Black/African Americans at 12.7 (95% CI: 12.61 to 12.79), followed by NH American Indian/Alaska Natives at 11.71 (95% CI: 11.36 to 12.06), NH Whites at 7.41 (95% CI: 7.39 to 7.43), Hispanic/Latinos at 7.22 (95% CI: 7.15 to 7.30), and NH Asian/Pacific Islanders at 5.45 (95% CI: 5.37 to 5.54). Among NH Black/African Americans, AAMRs declined from 1999 to 2008 (APC: − 4.02; 95% CI: − 4.60 to − 3.42) before steadily rising until 2018 (APC: 3.59; 95% CI: 3.02 to 4.15), followed by a sharp increase from 2018 to 2020 (APC: 15.52; 95% CI: 10.38 to 20.89). Hispanic/Latino and NH White populations showed declines from 1999 to 2007 (Hispanic: APC: − 3.46; 95% CI: − 4.63 to − 2.27; NH White: APC: − 3.07; 95% CI: − 3.83 to − 2.30), then increases until 2018 (Hispanic: APC: 3.98; 95% CI: 3.31 to 4.63; NH White: APC: 4.20; 95% CI: 3.66 to 4.73), followed by steep rises through 2020 (Hispanic: APC: 25.70; 95% CI: 19.14 to 32.60; NH White: APC: 11.31; 95% CI: 5.73 to 17.16). NH American Indian/Alaska Natives experienced a steady increase from 1999 to 2018 (APC: 2.79; 95% CI: 1.95 to 3.62), with a marked rise from 2018 to 2020 (APC: 21.45; 95% CI: 2.58 to 43.78). NH Asian/Pacific Islanders saw a decline from 1999 to 2004 (APC: − 5.63; 95% CI: − 10.67 to − 0.30), followed by a stable period until 2015, then a rapid increase through 2020 (APC: 9.19; 95% CI: 6.03 to 12.43) ( Fig. 2 , Supplemental Tables 4 and 5) . Electrolyte and acid-base imbalances related AAMR stratified by Census Region The study identified notable regional disparities in AAMRs, with the highest overall AAMR observed in the South (8.70; 95% CI: 8.67 to 8.74), followed by the Midwest (7.78; 95% CI: 7.73 to 7.82), Northeast (7.35; 95% CI: 7.30 to 7.39), and West (7.06; 95% CI: 7.01 to 7.10). From 1999 until the late 2000s, AAMRs declined across all regions: Northeast (until 2008, APC: − 3.20; 95% CI: − 3.94 to − 2.44), Midwest (until 2009, APC: − 2.91; 95% CI: − 3.67 to − 2.14), South (until 2007, APC: − 2.66; 95% CI: − 3.39 to − 1.92), and West (until 2010, APC: − 1.90; 95% CI: − 2.89 to − 0.90). Subsequently, AAMRs increased in all regions through 2020 (Central Illustration, Supplemental Table 6) . Electrolyte and acid-base imbalances related AAMR stratified by geographic regions Throughout the study period, non-metropolitan areas consistently exhibited higher EABI-related AAMRs than metropolitan areas (9.73; 95% CI: 9.67–9.78 vs. 7.49; 95% CI: 7.47–7.51). AAMRs in large central metropolitan and non-core non-metropolitan areas declined from 1999 to 2009 (APC: − 3.35; 95% CI: − 4.48 to − 2.21 and − 1.87; 95% CI: − 3.09 to − 0.63, respectively), followed by a steady increase through 2020 (APC: 5.32; 95% CI: 4.41 to 6.24 and 5.66; 95% CI: 4.68 to 6.65). Similarly, AAMRs in large fringe, medium metro, and micropolitan non-metro areas declined from 1999 to 2008 (APC range: − 2.07 to − 2.90), rose steadily through 2018 (APC range: 3.92 to 4.72), and then sharply increased through 2020 (APC range: 11.97 to 15.67). Small metropolitan areas also showed a decline from 1999 to 2008 (APC: − 1.68; 95% CI: − 3.18 to − 0.17), followed by a rise through 2020 (APC: 5.52; 95% CI: 4.68 to 6.37) ( Fig. 3 , Supplemental table 4, Supplemental table 7) . Electrolyte and acid-base imbalances related AAMR stratified by Sub-categories AAMRs were also analyzed across EABI subcategories. The highest overall AAMR was observed for acidosis (2.88; 95% CI: 2.87 to 2.89), followed by hyperkalemia (1.80; 95% CI: 1.79 to 1.81), other electrolyte/fluid disorders not elsewhere classified (1.05; 95% CI: 1.05 to 1.06), hypo-osmolality and hyponatremia (0.91; 95% CI: 0.90 to 0.92), hyperosmolality and hypernatremia (0.84; 95% CI: 0.83 to 0.85), hypokalemia (0.38; 95% CI: 0.38 to 0.39), fluid overload (0.35; 95% CI: 0.35 to 0.36), and alkalosis (0.02; 95% CI: 0.02 to 0.02) ( Fig. 4 , Supplemental table 8) . Electrolyte and acid-base imbalances related AAMR stratified by Underlying cause of deaths The overall AAMRs for EABI varied across different comorbid conditions as the underlying cause of death. Individuals with HF had the lowest AAMR (0.13; 95% CI: 0.12 to 0.13) while the highest AAMR was observed in individuals with sepsis (0.3; 95% CI: 0.3 to 0.31). The overall AAMR for CKD patients and diabetic patients was very similar (0.28; 95% CI: 0.27 to 0.28 and 0.28; 95% CI: 0.28 to 0.29 respectively). These findings highlight the variation in mortality risk associated with electrolyte imbalance across different conditions (Central Illustration, Supplemental table 9) . Central Illustration Trends in Demographics and Disparities in Electrolyte Imbalances-Related Mortality in the United States, 1999 to 2020 (AAMR = age-adjusted mortality rate) Electrolyte and acid-base imbalances related Crude Mortality Rates stratified by Ten Year Age Group Among EABI-related deaths, 1.77% occurred in individuals ≤ 24 years, 11.4% in those aged 25–54, and 86.82% in those > 54 years. The highest number of deaths was observed in the ≥ 55 age group (n = 503,751; 86.82%), while the lowest was in children aged 1–14 years (n = 1,919; 0.33%). The highest crude mortality rate (CMR) was recorded in the ≥ 85 age group (139.49 per 100,000; 95% CI: 138.82–140.16) whilst lowest CMR was observed in ≤ 24 age group (0.45; 95% CI: 0.44–0.46) (Supplemental Table 10) . 4. DISCUSSION This study offers a comprehensive evaluation of EABI-related mortality in the U.S. from 1999 to 2020 using CDC WONDER data. The overall AAMR rose from 7.88 in 1999 to 12.25 in 2020. Geographically, mortality was highest in the Southern region and non-metropolitan areas. Demographically, older adults, males, and NH Black/African American populations experienced the highest AAMRs. Among EABI subtypes, acidosis had the highest AAMR, while alkalosis had the lowest. Furthermore, sepsis emerged as the most common underlying cause of EABI related death while HF was the least common. The annual AAMRs displayed a biphasic trend—initially declining until 2008, followed by a sustained rise, and finally a sharp increase from 2018 to 2020. This trend was observed in both men and women, though men experienced a more pronounced increase in recent years. The recent surge in mortality may, in part, reflect the impact of the COVID-19 pandemic, which is known to exacerbate electrolyte imbalances in critically ill patients through mechanisms such as renal dysfunction, fluid shifts, and the use of diuretics and corticosteroids [ 13 ]. With advances in the management of acute and chronic conditions, life expectancy has increased, leading to greater susceptibility to chronic diseases, including EABI [ 14 ]. Our analysis confirms that advancing age is significantly associated with increased AAMR which is consistent with prior studies [ 15 , 16 ]. Unlike other conditions where mortality has either stabilized or declined, EABI-related mortality has risen, particularly in the last decade and among adults aged > 25 years. This increase is likely multifactorial. Potential contributors include systemic healthcare limitations such as the Hospital Readmissions Reduction Program, polypharmacy, underdiagnosis or misdiagnosis of EABI and greater travel burdens in rural areas. Polypharmacy, in particular, has been linked to adverse drug reactions, medication non-adherence, functional decline, geriatric syndromes, and increased mortality [ 17 – 19 ]. Our findings also reveal significant variation across EABI subtypes, with acidosis showing the highest AAMR and alkalosis the lowest. Lactic acidosis, a common finding in critically ill patients, is strongly associated with increased mortality [ 20 ]. Among electrolyte disorders, hyponatremia is the most frequently observed imbalance, affecting up to 30% of hospitalized patients in its mild form (serum sodium: 130–135 mEq/L) [ 21 ]. Hyponatremia is particularly associated with increased in-hospital mortality in older adults [ 22 , 23 ], yet remains underdiagnosed. Notably, only 53.2% of hospitalized patients show any improvement in sodium levels, and approximately 25% fail to achieve levels ≥ 130 mEq/L [ 24 ]. Hypernatremia increases mortality risk sevenfold [ 25 ], while hyponatremia doubles the risk compared to normonatremic peers [ 26 ], underscoring the prognostic importance of sodium imbalances, irrespective of direction. Additionally, dyskalemia in patients with HF and DM is associated with increased mortality, as it predisposes to life threatening arrhythmias, flaccid paralysis, respiratory failure, tetany, and rhabdomyolysis [ 27 , 28 ]. Poorer outcomes among NH Black individuals likely stem from multiple factors, including social determinants of health such as geographic location, socioeconomic status, and healthcare access [ 29 ]. State-level disparities in service accessibility and affordability may further exacerbate these outcomes [ 30 ]. Broader systemic issues including uneven healthcare policy implementation and access to care also play a significant role [ 31 ]. Although limited access to endocrinology services affects all groups, its impact is particularly pronounced among racial and ethnic populations that face a higher burden of endocrine disorders [ 32 ]. Significant geographical disparities were evident, with the Southern region and non-metropolitan areas having the highest AAMRs. This disparity may be linked to limited access to healthcare services, fewer specialists, and socioeconomic challenges faced by rural populations. One concerning factor is the ongoing decline in primary care providers in nonmetropolitan areas, which may have contributed to worse health outcomes for patients with electrolyte imbalances. A 2012 report showed that nearly 99% of urban adults had access to at least one endocrinologist, compared to much lower access in rural areas [ 5 ]. Rural regions also lack the infrastructure for managing complex conditions like electrolyte imbalances, which require timely nephrology and critical care [ 33 ]. Mortality rates from EABI in older adults with comorbidities such as CKD [ 34 ], DM [ 35 ], HF [ 36 ], and sepsis [ 37 ] have risen, likely due to improved detection, clinical awareness, and changes in ICD-10 coding [ 37 ]. Electrolyte disturbances such as hyperkalemia, hyponatremia, metabolic acidosis, and fluid overload are common in these patients and contribute to poor outcomes [ 38 , 39 ]. CKD patients, especially those in marginalized communities also face challenges in accessing care and adhering to treatment [ 40 ]. Addressing these disparities is critical to improving care for high-risk groups. Reducing EABI-related mortality requires better preventive care, increased access to specialists in underserved areas, and culturally tailored interventions. Telemedicine and care coordination can improve chronic disease management in rural settings. Medication safety is key—long-term proton pump inhibitors (PPIs) use has been linked to kidney damage and electrolyte imbalances [ 41 ]. Raising awareness among healthcare providers about the risks associated with prolonged PPI use and optimizing medication regimens could contribute to better patient outcomes. Studies on electrolyte and acid-base disorders in emergency critical care settings have emphasized the importance of early detection and intervention, which could inform future public health strategies [ 41 ]. Additionally, research into the long-term effects of post-hospitalization electrolyte disturbances on mortality rates could enhance clinical and public health interventions. 5. LIMITATIONS Several limitations should be noted in this study. Using death certificate data carries risks of coding errors and misclassification, potentially underrepresenting electrolyte imbalances as a cause of death. Changes in coding practices over time may have influenced the observed trends. This analysis lacks individual-level data on socioeconomic status, healthcare utilization, and specific comorbidities that could affect mortality. Data after 2020 were not included. Furthermore, the database does not contain clinical variables such as vital signs, labs, ventilator settings, genetic data, or medical therapy details. The code E87.4 (Mixed disorder of acid-base balance) was unreliable due to unavailable AAMRs. Individuals with this diagnosis may benefit from targeted risk factor optimization to reduce adverse outcomes. Further research is needed to explore how social determinants, age at diagnosis, symptom onset, and comorbidities influence demographic disparities in EABI mortality. For sepsis, only ICD code A41 (other septicemia) was used, as A40 (streptococcal septicemia) data were unreliable in multiple years. 6. CONCLUSION The initial decline from 1999 to 2008 in our results was followed by an upward trend with a steeper increase from 2018 to 2020 in the AAMR for the mortality trends related to EABI. The NH African Americans, men, the south region of the United States and nonmetropolitan areas observed the highest AAMRs across all age groups. Understanding these trends is essential for designing healthcare services that cater to this expanding population. Future research should explore these factors in greater detail and assess the impact of healthcare policies and the COVID-19 pandemic on electrolyte-related mortality. Abbreviations AAMR Age-Adjusted Mortality Rate AAPC Average Annual Percentage Change APC Annual percentage changes CDC Centers for Disease Control and Prevention CDC WONDER Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research CI Confidence Interval CKD Chronic Kidney Disease DM Diabetes Mellitus EABI Electrolyte and Acid Base Imbalance HF Heart Failure ICD International Classification of Diseases IRB Institutional Review Board NH non-Hispanic STROBE Strengthening the Reporting of Observational Studies in Epidemiology Declarations Funding Declaration : No funding Author Contribution Zaima Afzaal (Analyzed, wrote the first draft of the manuscript and reviewed)Asma Chaudhary (Analyzed and wrote the first draft of the manuscript)Inshal Uddin Khattak (Analyzed and wrote the first draft of the manuscript)Asad Khan4, Anas M Din Bashir (Analyzed and wrote the first draft of the manuscript)Hameer Ali6, Amnah Khan (Analyzed and wrote the first draft of the manuscript)Aizaz Anwar Khalid (Analyzed and wrote the first draft of the manuscript)Wania Khan (Analyzed and wrote the first draft of the manuscript)Touqeer Rehman (Analyzed and wrote the first draft of the manuscript)Maryam Atif (Analyzed and wrote the first draft of the manuscript)Areen Zia (Analyzed and wrote the first draft of the manuscript)Mazia Mahnoor (Analyzed and wrote the first draft of the manuscript)Saad Ahmed Waqas (Reviewed the final manuscript)Saba Aliha (Analyzed, wrote the first draft of the manuscript, and conceptualized)Raheel Ahmed (Supervisor) References Hamm LL, Nakhoul N, Hering-Smith KS. 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Uro 2023;3:271–81. https://doi.org/10.3390/uro3040027. Chin MH. New Horizons-Addressing Healthcare Disparities in Endocrine Disease: Bias, Science, and Patient Care. J Clin Endocrinol Metab 2021;106:e4887–902. https://doi.org/10.1210/clinem/dgab229. Lu H, Holt JB, Cheng YJ, Zhang X, Onufrak S, Croft JB. Population-based geographic access to endocrinologists in the United States, 2012. BMC Health Serv Res 2015;15:541. https://doi.org/10.1186/s12913-015-1185-5. Murphy D, McCulloch CE, Lin F, Banerjee T, Bragg-Gresham JL, Eberhardt MS, et al. Trends in Prevalence of Chronic Kidney Disease in the United States. Ann Intern Med 2016;165:473–81. https://doi.org/10.7326/M16-0273. Waqas SA, Aamir J, Dani SS, Abramov D, Virani SS, Minhas AMK. CDC WONDER: Trends in diabetes mellitus mortality in the United States from 1968 to 2021. Diabetes Res Clin Pract 2025;221:112012. https://doi.org/10.1016/j.diabres.2025.112012. Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, Khan SS, Pandey A, et al. Trends in Heart Failure-Related Mortality Among Older Adults in the United States From 1999-2019. JACC Heart Fail 2022;10:851–9. https://doi.org/10.1016/j.jchf.2022.06.012. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA 2017;318:1241–9. https://doi.org/10.1001/jama.2017.13836. Mayne KJ, Shemilt R, Keane DF, Lees JS, Mark PB, Herrington WG. Bioimpedance Indices of Fluid Overload and Cardiorenal Outcomes in Heart Failure and Chronic Kidney Disease: a Systematic Review. J Card Fail 2022;28:1628–41. https://doi.org/10.1016/j.cardfail.2022.08.005. Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J 1994;128:564–74. https://doi.org/10.1016/0002-8703(94)90633-5. La Porta E, Lanino L, Calatroni M, Caramella E, Avella A, Quinn C, et al. Volume Balance in Chronic Kidney Disease: Evaluation Methodologies and Innovation Opportunities. Kidney Blood Press Res 2021;46:396–410. https://doi.org/10.1159/000515172. Edinoff AN, Wu NW, Parker K, Dudossat E, Linquest L, Flanagan CJ, et al. Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review. Adv Ther 2023;40:2693–709. https://doi.org/10.1007/s12325-023-02476-3. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.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. 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2","display":"","copyAsset":false,"role":"figure","size":123723,"visible":true,"origin":"","legend":"\u003cp\u003eElectrolyte \u0026amp; Acid-Base Imbalance AAMRs per 100,000 Stratified by Race in the United States, 1999–2020\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/71a33aaceb34e4c2bbe7e758.png"},{"id":85773312,"identity":"9591a328-7431-4bf1-afb0-38cdddd5587c","added_by":"auto","created_at":"2025-07-01 13:53:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":87415,"visible":true,"origin":"","legend":"\u003cp\u003eElectrolyte \u0026amp; Acid-Base Imbalance AAMRs per 100,000 stratified by Metropolitan and Non-Metropolitan in the United States, 1999–2020\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/238a1cb21c7722233fa8b6ae.png"},{"id":85773272,"identity":"0019bdab-aa8b-45b5-8ee5-8963238a4038","added_by":"auto","created_at":"2025-07-01 13:53:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":367651,"visible":true,"origin":"","legend":"\u003cp\u003eElectrolyte \u0026amp; Acid-Base Imbalance AAMRs per 100,000 Stratified by Sub-Categories, 1999–2020\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/dbea978de1e918ed5290a5fa.png"},{"id":85773269,"identity":"fdecf7f2-77d3-4170-b04c-fa453c9e1454","added_by":"auto","created_at":"2025-07-01 13:53:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":506485,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Results section.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/cb55bd882acec096de0a1629.png"},{"id":86596455,"identity":"01e7ff55-504c-4777-a727-60d2af0cdc8c","added_by":"auto","created_at":"2025-07-13 10:16:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1989064,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/753f024c-9bd4-4566-8249-e579808bb2d5.pdf"},{"id":85773271,"identity":"158f6cdf-acd5-40a6-9a25-de05d01ab984","added_by":"auto","created_at":"2025-07-01 13:53:45","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":32291,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6846811/v1/a37e5d3a74bfbc7e5d81e4a7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Temporal Trends in Electrolyte and Acid-Base Imbalance Mortality in the U.S. (1999- 2020): A Longitudinal Analysis","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eElectrolytes are essential for normal physiological function, and even minor deviations from their narrow range can be life-threatening [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Electrolyte imbalances are known to disrupt cardiac electrophysiology, increasing the risk of arrhythmias, and can exacerbate outcomes in critically ill patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, the burden of diseases such as diabetes mellitus, cancer, and the COVID-19 pandemic has further highlighted the lethal implications of acid-base disturbances [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Mortality patterns associated with electrolyte and acid-base imbalance (EABI) vary among patient populations, with critically ill children\u0026mdash;often subjected to prolonged hospitalizations\u0026mdash;being particularly vulnerable [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite its clinical importance, large-scale epidemiological data on long-term EABI mortality trends in the United States remain limited. To address this gap, our study analyzes over two decades of national mortality data (1999\u0026ndash;2020) from the CDC WONDER database, offering a comprehensive assessment of population-level trends.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003e \u003cb\u003eStudy Setting and Population\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis study utilized de-identified death certificate data from the CDC WONDER database spanning 1999 to 2020 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Electrolyte and acid-base imbalance (EABI)\u0026ndash;related deaths were identified across all age groups using ICD-10 codes E87.0\u0026ndash;E87.8. Relevant comorbid conditions included heart failure (HF) (I50), diabetes mellitus (DM) (E10\u0026ndash;E14), sepsis (A41), and chronic kidney disease (CKD) (N18) as underlying causes. EABI-related deaths were defined as those listing EABI as either a contributing or underlying cause. Analyses were conducted both individually by variable and collectively to assess national trends. Data covered all 50 states and the District of Columbia, using the Multiple Cause-of-Death Public Use files. Institutional review board approval was not required, as the study employed publicly available, de-identified data and adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eData Abstraction\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe extracted data on population size, year, demographics, urban-rural classification, and geographic region. Demographic variables included sex, age, and race/ethnicity. Racial/ethnic categories were defined as Non-Hispanic (NH) White, NH Black or African American, Hispanic or Latino, NH American Indian or Alaskan Native, and NH Asian or Pacific Islander. Urban-rural classification followed the 2013 National Center for Health Statistics Urban-Rural Classification Scheme. Geographic regions were categorized according to the U.S. Census Bureau\u0026rsquo;s definitions: Northeast, Midwest, South, and West [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analysis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe analyzed mortality trends related to electrolyte imbalance from 1999 to 2020, reporting crude and age-adjusted mortality rates (AAMRs) per 100,000 population with 95% confidence intervals (CIs), stratified by year, sex, race/ethnicity, region, and urban-rural status. Crude mortality rates were calculated by dividing total EABI-related deaths by the corresponding annual U.S. population. AAMRs were standardized to the 2000 U.S. population [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. To assess annual trends, we used the Joinpoint Regression Program (version 5.3.0, National Cancer Institute) to calculate annual percent change (APC) with 95% CI, employing the Monte Carlo permutation test for model selection. Joinpoint regression applied log-linear models to detect significant temporal changes in AAMR. APCs were classified as increasing or decreasing when the slope significantly differed from zero using two-tailed t-tests, with statistical significance set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eA total of 580,238 EABI deaths occurred among groups of all ages between 1999 and 2020 \u003cb\u003e(Supplemental table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Central Illustration)\u003c/b\u003e. However, the place of death was known for 569,917 deaths only. Of these 76.46% were in medical facilities, 12.86% at nursing homes/long term care facilities, 9.25% at and 1.45% at hospices \u003cb\u003e(Supplemental table 2)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAnnual trends for electrolyte and acid-base imbalances-related AAMR\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe AAMR for EABI across all ages was 7.88 (95% CI: 7.78 to 7.99) in 1999 and peaked at 12.25 (95% CI: 12.14 to 12.36) in 2020. The lowest recorded AAMR was 6.21 (95% CI: 6.13 to 6.30) in 2007. Overall, the AAMR declined from 1999 to 2008 (APC: \u0026minus;\u0026thinsp;2.73; 95% CI: \u0026minus;\u0026thinsp;3.18 to \u0026minus;\u0026thinsp;2.27), followed by a rising trend from 2008 to 2018 (APC: 4.44; 95% CI: 4.00 to 4.89). A marked increase was observed from 2018 to 2020 (APC: 12.08; 95% CI: 7.93 to 16.38) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Tables\u0026nbsp;3 and 4)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by Sex\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMen exhibited a higher overall AAMR of 8.58 (95% CI: 8.55 to 8.62) compared to females at 7.29 (95% CI: 7.27 to 7.32), with both sexes reaching peak AAMRs in 2020 (13.85 vs. 10.93, respectively). Among men, AAMR declined from 1999 to 2007 (APC: \u0026minus;\u0026thinsp;3.49; 95% CI: \u0026minus;\u0026thinsp;4.17 to \u0026minus;\u0026thinsp;2.79), then increased from 2007 to 2018 (APC: 4.16; 95% CI: 3.71 to 4.61), followed by a sharp rise between 2018 and 2020 (APC: 15.12; 95% CI: 10.35 to 20.09). For women, the AAMR decreased from 1999 to 2008 (APC: \u0026minus;\u0026thinsp;2.63; 95% CI: \u0026minus;\u0026thinsp;3.18 to \u0026minus;\u0026thinsp;2.08), then increased steadily from 2008 to 2018 (APC: 4.29; 95% CI: 3.77 to 4.80), with a more pronounced rise from 2018 to 2020 (APC: 10.58; 95% CI: 5.72 to 15.65). Overall, mortality rates initially declined until the late 2000s before rising steadily, with a notable surge in recent years, especially among men \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Tables\u0026nbsp;3 and 4)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by race\u003c/b\u003e \u003c/p\u003e \u003cp\u003eRacial stratification revealed the highest AAMRs among Non-Hispanic (NH) Black/African Americans at 12.7 (95% CI: 12.61 to 12.79), followed by NH American Indian/Alaska Natives at 11.71 (95% CI: 11.36 to 12.06), NH Whites at 7.41 (95% CI: 7.39 to 7.43), Hispanic/Latinos at 7.22 (95% CI: 7.15 to 7.30), and NH Asian/Pacific Islanders at 5.45 (95% CI: 5.37 to 5.54). Among NH Black/African Americans, AAMRs declined from 1999 to 2008 (APC: \u0026minus;\u0026thinsp;4.02; 95% CI: \u0026minus;\u0026thinsp;4.60 to \u0026minus;\u0026thinsp;3.42) before steadily rising until 2018 (APC: 3.59; 95% CI: 3.02 to 4.15), followed by a sharp increase from 2018 to 2020 (APC: 15.52; 95% CI: 10.38 to 20.89). Hispanic/Latino and NH White populations showed declines from 1999 to 2007 (Hispanic: APC: \u0026minus;\u0026thinsp;3.46; 95% CI: \u0026minus;\u0026thinsp;4.63 to \u0026minus;\u0026thinsp;2.27; NH White: APC: \u0026minus;\u0026thinsp;3.07; 95% CI: \u0026minus;\u0026thinsp;3.83 to \u0026minus;\u0026thinsp;2.30), then increases until 2018 (Hispanic: APC: 3.98; 95% CI: 3.31 to 4.63; NH White: APC: 4.20; 95% CI: 3.66 to 4.73), followed by steep rises through 2020 (Hispanic: APC: 25.70; 95% CI: 19.14 to 32.60; NH White: APC: 11.31; 95% CI: 5.73 to 17.16). NH American Indian/Alaska Natives experienced a steady increase from 1999 to 2018 (APC: 2.79; 95% CI: 1.95 to 3.62), with a marked rise from 2018 to 2020 (APC: 21.45; 95% CI: 2.58 to 43.78). NH Asian/Pacific Islanders saw a decline from 1999 to 2004 (APC: \u0026minus;\u0026thinsp;5.63; 95% CI: \u0026minus;\u0026thinsp;10.67 to \u0026minus;\u0026thinsp;0.30), followed by a stable period until 2015, then a rapid increase through 2020 (APC: 9.19; 95% CI: 6.03 to 12.43) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplemental Tables\u0026nbsp;4 and 5)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by Census Region\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe study identified notable regional disparities in AAMRs, with the highest overall AAMR observed in the South (8.70; 95% CI: 8.67 to 8.74), followed by the Midwest (7.78; 95% CI: 7.73 to 7.82), Northeast (7.35; 95% CI: 7.30 to 7.39), and West (7.06; 95% CI: 7.01 to 7.10). From 1999 until the late 2000s, AAMRs declined across all regions: Northeast (until 2008, APC: \u0026minus;\u0026thinsp;3.20; 95% CI: \u0026minus;\u0026thinsp;3.94 to \u0026minus;\u0026thinsp;2.44), Midwest (until 2009, APC: \u0026minus;\u0026thinsp;2.91; 95% CI: \u0026minus;\u0026thinsp;3.67 to \u0026minus;\u0026thinsp;2.14), South (until 2007, APC: \u0026minus;\u0026thinsp;2.66; 95% CI: \u0026minus;\u0026thinsp;3.39 to \u0026minus;\u0026thinsp;1.92), and West (until 2010, APC: \u0026minus;\u0026thinsp;1.90; 95% CI: \u0026minus;\u0026thinsp;2.89 to \u0026minus;\u0026thinsp;0.90). Subsequently, AAMRs increased in all regions through 2020 \u003cb\u003e(Central Illustration, Supplemental Table\u0026nbsp;6)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by geographic regions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThroughout the study period, non-metropolitan areas consistently exhibited higher EABI-related AAMRs than metropolitan areas (9.73; 95% CI: 9.67\u0026ndash;9.78 vs. 7.49; 95% CI: 7.47\u0026ndash;7.51). AAMRs in large central metropolitan and non-core non-metropolitan areas declined from 1999 to 2009 (APC: \u0026minus;\u0026thinsp;3.35; 95% CI: \u0026minus;\u0026thinsp;4.48 to \u0026minus;\u0026thinsp;2.21 and \u0026minus;\u0026thinsp;1.87; 95% CI: \u0026minus;\u0026thinsp;3.09 to \u0026minus;\u0026thinsp;0.63, respectively), followed by a steady increase through 2020 (APC: 5.32; 95% CI: 4.41 to 6.24 and 5.66; 95% CI: 4.68 to 6.65). Similarly, AAMRs in large fringe, medium metro, and micropolitan non-metro areas declined from 1999 to 2008 (APC range: \u0026minus;\u0026thinsp;2.07 to \u0026minus;\u0026thinsp;2.90), rose steadily through 2018 (APC range: 3.92 to 4.72), and then sharply increased through 2020 (APC range: 11.97 to 15.67). Small metropolitan areas also showed a decline from 1999 to 2008 (APC: \u0026minus;\u0026thinsp;1.68; 95% CI: \u0026minus;\u0026thinsp;3.18 to \u0026minus;\u0026thinsp;0.17), followed by a rise through 2020 (APC: 5.52; 95% CI: 4.68 to 6.37) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eSupplemental table 4, Supplemental table 7)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by Sub-categories\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAAMRs were also analyzed across EABI subcategories. The highest overall AAMR was observed for acidosis (2.88; 95% CI: 2.87 to 2.89), followed by hyperkalemia (1.80; 95% CI: 1.79 to 1.81), other electrolyte/fluid disorders not elsewhere classified (1.05; 95% CI: 1.05 to 1.06), hypo-osmolality and hyponatremia (0.91; 95% CI: 0.90 to 0.92), hyperosmolality and hypernatremia (0.84; 95% CI: 0.83 to 0.85), hypokalemia (0.38; 95% CI: 0.38 to 0.39), fluid overload (0.35; 95% CI: 0.35 to 0.36), and alkalosis (0.02; 95% CI: 0.02 to 0.02) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cb\u003eSupplemental table 8)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related AAMR stratified by Underlying cause of deaths\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe overall AAMRs for EABI varied across different comorbid conditions as the underlying cause of death. Individuals with HF had the lowest AAMR (0.13; 95% CI: 0.12 to 0.13) while the highest AAMR was observed in individuals with sepsis (0.3; 95% CI: 0.3 to 0.31). The overall AAMR for CKD patients and diabetic patients was very similar (0.28; 95% CI: 0.27 to 0.28 and 0.28; 95% CI: 0.28 to 0.29 respectively). These findings highlight the variation in mortality risk associated with electrolyte imbalance across different conditions \u003cb\u003e(Central Illustration, Supplemental table 9)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCentral Illustration\u003c/strong\u003e \u003cp\u003eTrends in Demographics and Disparities in Electrolyte Imbalances-Related Mortality in the United States, 1999 to 2020 (AAMR\u0026thinsp;=\u0026thinsp;age-adjusted mortality rate)\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eElectrolyte and acid-base imbalances related Crude Mortality Rates stratified by Ten Year Age Group\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAmong EABI-related deaths, 1.77% occurred in individuals\u0026thinsp;\u0026le;\u0026thinsp;24 years, 11.4% in those aged 25\u0026ndash;54, and 86.82% in those\u0026thinsp;\u0026gt;\u0026thinsp;54 years. The highest number of deaths was observed in the \u0026ge;\u0026thinsp;55 age group (n\u0026thinsp;=\u0026thinsp;503,751; 86.82%), while the lowest was in children aged 1\u0026ndash;14 years (n\u0026thinsp;=\u0026thinsp;1,919; 0.33%). The highest crude mortality rate (CMR) was recorded in the \u0026ge;\u0026thinsp;85 age group (139.49 per 100,000; 95% CI: 138.82\u0026ndash;140.16) whilst lowest CMR was observed in \u0026le;\u0026thinsp;24 age group (0.45; 95% CI: 0.44\u0026ndash;0.46) \u003cb\u003e(Supplemental Table\u0026nbsp;10)\u003c/b\u003e.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThis study offers a comprehensive evaluation of EABI-related mortality in the U.S. from 1999 to 2020 using CDC WONDER data. The overall AAMR rose from 7.88 in 1999 to 12.25 in 2020. Geographically, mortality was highest in the Southern region and non-metropolitan areas. Demographically, older adults, males, and NH Black/African American populations experienced the highest AAMRs. Among EABI subtypes, acidosis had the highest AAMR, while alkalosis had the lowest. Furthermore, sepsis emerged as the most common underlying cause of EABI related death while HF was the least common.\u003c/p\u003e \u003cp\u003eThe annual AAMRs displayed a biphasic trend\u0026mdash;initially declining until 2008, followed by a sustained rise, and finally a sharp increase from 2018 to 2020. This trend was observed in both men and women, though men experienced a more pronounced increase in recent years. The recent surge in mortality may, in part, reflect the impact of the COVID-19 pandemic, which is known to exacerbate electrolyte imbalances in critically ill patients through mechanisms such as renal dysfunction, fluid shifts, and the use of diuretics and corticosteroids [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith advances in the management of acute and chronic conditions, life expectancy has increased, leading to greater susceptibility to chronic diseases, including EABI [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Our analysis confirms that advancing age is significantly associated with increased AAMR which is consistent with prior studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Unlike other conditions where mortality has either stabilized or declined, EABI-related mortality has risen, particularly in the last decade and among adults aged\u0026thinsp;\u0026gt;\u0026thinsp;25 years. This increase is likely multifactorial. Potential contributors include systemic healthcare limitations such as the Hospital Readmissions Reduction Program, polypharmacy, underdiagnosis or misdiagnosis of EABI and greater travel burdens in rural areas. Polypharmacy, in particular, has been linked to adverse drug reactions, medication non-adherence, functional decline, geriatric syndromes, and increased mortality [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur findings also reveal significant variation across EABI subtypes, with acidosis showing the highest AAMR and alkalosis the lowest. Lactic acidosis, a common finding in critically ill patients, is strongly associated with increased mortality [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Among electrolyte disorders, hyponatremia is the most frequently observed imbalance, affecting up to 30% of hospitalized patients in its mild form (serum sodium: 130\u0026ndash;135 mEq/L) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Hyponatremia is particularly associated with increased in-hospital mortality in older adults [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], yet remains underdiagnosed. Notably, only 53.2% of hospitalized patients show any improvement in sodium levels, and approximately 25% fail to achieve levels\u0026thinsp;\u0026ge;\u0026thinsp;130 mEq/L [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Hypernatremia increases mortality risk sevenfold [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], while hyponatremia doubles the risk compared to normonatremic peers [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], underscoring the prognostic importance of sodium imbalances, irrespective of direction. Additionally, dyskalemia in patients with HF and DM is associated with increased mortality, as it predisposes to life threatening arrhythmias, flaccid paralysis, respiratory failure, tetany, and rhabdomyolysis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePoorer outcomes among NH Black individuals likely stem from multiple factors, including social determinants of health such as geographic location, socioeconomic status, and healthcare access [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. State-level disparities in service accessibility and affordability may further exacerbate these outcomes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Broader systemic issues including uneven healthcare policy implementation and access to care also play a significant role [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Although limited access to endocrinology services affects all groups, its impact is particularly pronounced among racial and ethnic populations that face a higher burden of endocrine disorders [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSignificant geographical disparities were evident, with the Southern region and non-metropolitan areas having the highest AAMRs. This disparity may be linked to limited access to healthcare services, fewer specialists, and socioeconomic challenges faced by rural populations. One concerning factor is the ongoing decline in primary care providers in nonmetropolitan areas, which may have contributed to worse health outcomes for patients with electrolyte imbalances. A 2012 report showed that nearly 99% of urban adults had access to at least one endocrinologist, compared to much lower access in rural areas [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Rural regions also lack the infrastructure for managing complex conditions like electrolyte imbalances, which require timely nephrology and critical care [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMortality rates from EABI in older adults with comorbidities such as CKD [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], DM [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], HF [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and sepsis [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] have risen, likely due to improved detection, clinical awareness, and changes in ICD-10 coding [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Electrolyte disturbances such as hyperkalemia, hyponatremia, metabolic acidosis, and fluid overload are common in these patients and contribute to poor outcomes [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. CKD patients, especially those in marginalized communities also face challenges in accessing care and adhering to treatment [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAddressing these disparities is critical to improving care for high-risk groups. Reducing EABI-related mortality requires better preventive care, increased access to specialists in underserved areas, and culturally tailored interventions. Telemedicine and care coordination can improve chronic disease management in rural settings. Medication safety is key\u0026mdash;long-term proton pump inhibitors (PPIs) use has been linked to kidney damage and electrolyte imbalances [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Raising awareness among healthcare providers about the risks associated with prolonged PPI use and optimizing medication regimens could contribute to better patient outcomes. Studies on electrolyte and acid-base disorders in emergency critical care settings have emphasized the importance of early detection and intervention, which could inform future public health strategies [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Additionally, research into the long-term effects of post-hospitalization electrolyte disturbances on mortality rates could enhance clinical and public health interventions.\u003c/p\u003e"},{"header":"5. LIMITATIONS","content":"\u003cp\u003eSeveral limitations should be noted in this study. Using death certificate data carries risks of coding errors and misclassification, potentially underrepresenting electrolyte imbalances as a cause of death. Changes in coding practices over time may have influenced the observed trends. This analysis lacks individual-level data on socioeconomic status, healthcare utilization, and specific comorbidities that could affect mortality. Data after 2020 were not included. Furthermore, the database does not contain clinical variables such as vital signs, labs, ventilator settings, genetic data, or medical therapy details. The code E87.4 (Mixed disorder of acid-base balance) was unreliable due to unavailable AAMRs. Individuals with this diagnosis may benefit from targeted risk factor optimization to reduce adverse outcomes. Further research is needed to explore how social determinants, age at diagnosis, symptom onset, and comorbidities influence demographic disparities in EABI mortality. For sepsis, only ICD code A41 (other septicemia) was used, as A40 (streptococcal septicemia) data were unreliable in multiple years.\u003c/p\u003e"},{"header":"6. CONCLUSION","content":"\u003cp\u003eThe initial decline from 1999 to 2008 in our results was followed by an upward trend with a steeper increase from 2018 to 2020 in the AAMR for the mortality trends related to EABI. The NH African Americans, men, the south region of the United States and nonmetropolitan areas observed the highest AAMRs across all age groups. Understanding these trends is essential for designing healthcare services that cater to this expanding population. Future research should explore these factors in greater detail and assess the impact of healthcare policies and the COVID-19 pandemic on electrolyte-related mortality.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eAAMR\u003c/strong\u003e Age-Adjusted Mortality Rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAAPC\u003c/strong\u003e Average Annual Percentage Change\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAPC\u003c/strong\u003e Annual percentage changes\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCDC\u003c/strong\u003e Centers for Disease Control and Prevention\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCDC WONDER\u003c/strong\u003e Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u0026nbsp;\u003c/strong\u003eConfidence Interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCKD\u003c/strong\u003e Chronic Kidney Disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e Diabetes Mellitus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEABI\u003c/strong\u003e Electrolyte and Acid Base Imbalance\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHF\u003c/strong\u003e Heart Failure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eICD\u0026nbsp;\u003c/strong\u003eInternational Classification of Diseases\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIRB\u003c/strong\u003e Institutional Review Board\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNH\u003c/strong\u003e non-Hispanic\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTROBE\u0026nbsp;\u003c/strong\u003eStrengthening the Reporting of Observational Studies in Epidemiology\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding \u003cstrong\u003eDeclaration\u003c/strong\u003e:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eZaima Afzaal (Analyzed, wrote the first draft of the manuscript and reviewed)Asma Chaudhary (Analyzed and wrote the first draft of the manuscript)Inshal Uddin Khattak (Analyzed and wrote the first draft of the manuscript)Asad Khan4, Anas M Din Bashir (Analyzed and wrote the first draft of the manuscript)Hameer Ali6, Amnah Khan (Analyzed and wrote the first draft of the manuscript)Aizaz Anwar Khalid (Analyzed and wrote the first draft of the manuscript)Wania Khan (Analyzed and wrote the first draft of the manuscript)Touqeer Rehman (Analyzed and wrote the first draft of the manuscript)Maryam Atif (Analyzed and wrote the first draft of the manuscript)Areen Zia (Analyzed and wrote the first draft of the manuscript)Mazia Mahnoor (Analyzed and wrote the first draft of the manuscript)Saad Ahmed Waqas (Reviewed the final manuscript)Saba Aliha (Analyzed, wrote the first draft of the manuscript, and conceptualized)Raheel Ahmed (Supervisor)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHamm LL, Nakhoul N, Hering-Smith KS. 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Am J Geriatr Pharmacother 2007;5:345\u0026ndash;51. https://doi.org/10.1016/j.amjopharm.2007.12.002.\u003c/li\u003e\n\u003cli\u003eLeelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: A systematic review and meta-analysis. J Am Pharm Assoc (2003) 2017;57:729-738.e10. https://doi.org/10.1016/j.japh.2017.06.002.\u003c/li\u003e\n\u003cli\u003eVillar J, Short JH, Lighthall G. Lactate Predicts Both Short- and Long-Term Mortality in Patients With and Without Sepsis. Infect Dis (Auckl) 2019;12:1178633719862776. https://doi.org/10.1177/1178633719862776.\u003c/li\u003e\n\u003cli\u003eUpadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006;119:S30-35. https://doi.org/10.1016/j.amjmed.2006.05.005.\u003c/li\u003e\n\u003cli\u003eHawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta 2003;337:169\u0026ndash;72. https://doi.org/10.1016/j.cccn.2003.08.001.\u003c/li\u003e\n\u003cli\u003eNaaseh A, Tohmasi S, Stoll C, Luo C, Yaeger LH, Hoofnagle MH, et al. Association of hyponatremia with outcomes after geriatric trauma: a systematic review and meta-analysis. Trauma Surg Acute Care Open 2025;10:e001562. https://doi.org/10.1136/tsaco-2024-001562.\u003c/li\u003e\n\u003cli\u003eCorona G, Giuliani C, Verbalis JG, Forti G, Maggi M, Peri A. Hyponatremia Improvement Is Associated with a Reduced Risk of Mortality: Evidence from a Meta-Analysis. PLOS ONE 2015;10:e0124105. https://doi.org/10.1371/journal.pone.0124105.\u003c/li\u003e\n\u003cli\u003eSnyder NA, Feigal DW, Arieff AI. Hypernatremia in elderly patients. A heterogeneous, morbid, and iatrogenic entity. Ann Intern Med 1987;107:309\u0026ndash;19. https://doi.org/10.7326/0003-4819-107-2-309.\u003c/li\u003e\n\u003cli\u003eTerzian C, Frye EB, Piotrowski ZH. Admission hyponatremia in the elderly: factors influencing prognosis. J Gen Intern Med 1994;9:89\u0026ndash;91. https://doi.org/10.1007/BF02600208.\u003c/li\u003e\n\u003cli\u003eLuo J, Brunelli SM, Jensen DE, Yang A. Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function. Clin J Am Soc Nephrol 2016;11:90\u0026ndash;100. https://doi.org/10.2215/CJN.01730215.\u003c/li\u003e\n\u003cli\u003eReid A, Jones G, Isles C. Hypokalaemia: common things occur commonly \u0026ndash; a retrospective survey. JRSM Short Rep 2012;3:80. https://doi.org/10.1258/shorts.2012.011179.\u003c/li\u003e\n\u003cli\u003ePeterson K, Anderson J, Boundy E, Ferguson L, McCleery E, Waldrip K. Mortality Disparities in Racial/Ethnic Minority Groups in the Veterans Health Administration: An Evidence Review and Map. Am J Public Health 2018;108:e1\u0026ndash;11. https://doi.org/10.2105/AJPH.2017.304246.\u003c/li\u003e\n\u003cli\u003eKhan SU, Kalra A, Kapadia SR, Khan MU, Zia Khan M, Khan MS, et al. Demographic, Regional, and State-Level Trends of Mortality in Patients With Aortic Stenosis in United States, 2008 to 2018. J Am Heart Assoc 2020;9:e017433. https://doi.org/10.1161/JAHA.120.017433.\u003c/li\u003e\n\u003cli\u003eSalichs O, Doddi S, Hibshman T, Hersi J, Sindhwani P. Understanding Renal Failure Mortality Trends and Determinants in the US (1999\u0026ndash;2020): Impacts of the Affordable Care Act, Advancements, Disparities, and Challenges. Uro 2023;3:271\u0026ndash;81. https://doi.org/10.3390/uro3040027.\u003c/li\u003e\n\u003cli\u003eChin MH. New Horizons-Addressing Healthcare Disparities in Endocrine Disease: Bias, Science, and Patient Care. 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Trends in Heart Failure-Related Mortality Among Older Adults in the United States From 1999-2019. JACC Heart Fail 2022;10:851\u0026ndash;9. https://doi.org/10.1016/j.jchf.2022.06.012.\u003c/li\u003e\n\u003cli\u003eRhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA 2017;318:1241\u0026ndash;9. https://doi.org/10.1001/jama.2017.13836.\u003c/li\u003e\n\u003cli\u003eMayne KJ, Shemilt R, Keane DF, Lees JS, Mark PB, Herrington WG. Bioimpedance Indices of Fluid Overload and Cardiorenal Outcomes in Heart Failure and Chronic Kidney Disease: a Systematic Review. J Card Fail 2022;28:1628\u0026ndash;41. https://doi.org/10.1016/j.cardfail.2022.08.005.\u003c/li\u003e\n\u003cli\u003eLeier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J 1994;128:564\u0026ndash;74. https://doi.org/10.1016/0002-8703(94)90633-5.\u003c/li\u003e\n\u003cli\u003eLa Porta E, Lanino L, Calatroni M, Caramella E, Avella A, Quinn C, et al. Volume Balance in Chronic Kidney Disease: Evaluation Methodologies and Innovation Opportunities. Kidney Blood Press Res 2021;46:396\u0026ndash;410. https://doi.org/10.1159/000515172.\u003c/li\u003e\n\u003cli\u003eEdinoff AN, Wu NW, Parker K, Dudossat E, Linquest L, Flanagan CJ, et al. Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review. Adv Ther 2023;40:2693\u0026ndash;709. https://doi.org/10.1007/s12325-023-02476-3.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"electrolytes, mortality, trends, disparities","lastPublishedDoi":"10.21203/rs.3.rs-6846811/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6846811/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eElectrolyte and acid-base imbalance (EABI) has emerged as a critical contributor to rising mortality rates worldwide. This study aims to investigate the underexplored mortality trends associated with EABI in the United States from 1999 to 2020.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eMortality data spanning 1999 to 2020 were retrieved from the CDC WONDER database, encompassing all age groups. Age-adjusted mortality rates (AAMRs) per 100,000 individuals were analyzed. Joinpoint regression modeling was employed to calculate annual percentage changes (APCs). AAMRs were further stratified by race, sex, age, U.S. census region, and urbanization status.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eBetween 1999 and 2020, a total of 580,238 deaths were attributed to EABI. AAMRs declined from 1999 to 2008 (APC: -2.73), followed by a gradual increase from 2008 to 2018 (APC: 4.44), and a pronounced rise between 2018 and 2020 (APC: 12.08). Males exhibited consistently higher AAMRs (8.58) compared to females (7.29). Among racial groups, Non-Hispanic Blacks had the highest AAMR (12.70), while Asians had the lowest (5.45). Regionally, the South reported the highest AAMR (8.70), followed by the Midwest (7.78), Northeast (7.35), and West (7.06). Non-metropolitan areas had notably higher AAMRs (9.73) than metropolitan counterparts (7.49).\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThe upward trend in EABI-related mortality over the study period is alarming and underscores the need for urgent public health interventions. Enhanced health education and preventive strategies are essential to mitigate EABI risk and reduce associated mortality in the future.\u003c/p\u003e","manuscriptTitle":"Temporal Trends in Electrolyte and Acid-Base Imbalance Mortality in the U.S. (1999- 2020): A Longitudinal Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 13:53:25","doi":"10.21203/rs.3.rs-6846811/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":"d8742dc3-3783-49c9-84f8-b1fca18cc65d","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-13T10:08:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-01 13:53:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6846811","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6846811","identity":"rs-6846811","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}