Association Between Serum Magnesium Levels and Severity of Acute Exacerbations in COPD: A Cross-Sectional Study

Association Between Serum Magnesium Levels and Severity of Acute Exacerbations in COPD: A Cross-Sectional Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association Between Serum Magnesium Levels and Severity of Acute Exacerbations in COPD: A Cross-Sectional Study Ghazal Siroos Najafabadi, Forough Kalantari, Elham Kalantari This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8497073/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Magnesium plays an important role in respiratory physiology and has been proposed as a potential biomarker in chronic obstructive pulmonary disease (COPD). However, existing evidence regarding its association with the severity of acute exacerbations (AECOPD) remains inconsistent. This study aimed to evaluate whether serum magnesium levels are associated with clinical severity in hospitalized patients with AECOPD. Methods: In this cross-sectional study, 149 patients admitted with AECOPD in 2024 were classified into mild, moderate, or severe groups based on clinical, physiological, and inflammatory criteria. Serum magnesium levels, arterial pH, oxygen saturation, C-reactive protein (CRP), and other clinical variables were recorded at admission. Between-group differences were assessed using ANOVA and chi-square tests. Correlation analyses and an ordinal logistic regression model were applied to determine whether serum magnesium independently predicted exacerbation severity. Results: AECOPD severity was significantly associated with reduced oxygen saturation, lower arterial pH, higher CRP levels, and longer hospital stay (all P < 0.001). Mean serum magnesium levels did not differ significantly across severity groups (2.15 ± 0.21 mg/dL in mild, 2.07 ± 0.21 mg/dL in moderate, and 2.10 ± 0.29 mg/dL in severe; P = 0.357). Hypomagnesemia (Mg < 1.8 mg/dL) occurred in 7.4% of patients and showed no significant relationship with exacerbation severity (P = 0.873). Correlation analyses demonstrated no significant association between serum magnesium and oxygen saturation, CRP, or arterial pH. In ordinal logistic regression, serum magnesium was not an independent predictor of exacerbation severity (P = 0.960). Conclusion: Although physiological markers clearly differentiated AECOPD severity, total serum magnesium levels remained relatively stable across severity groups and did not independently predict exacerbation severity. These findings suggest that total serum magnesium is unlikely to serve as a reliable standalone biomarker for assessing AECOPD severity. Future studies incorporating ionized or intracellular magnesium measurements are warranted. Chronic Obstructive Pulmonary Disease Acute Exacerbation Magnesium Hypomagnesemia Biomarkers Inflammation Hospitalization Figures Figure 1 Figure 2 Introduction Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, exerting substantial pressure on healthcare systems ( 3 , 4 ). In 2019, it was responsible for 3.3 million deaths, ranking as the third leading cause of death globally by 2020 ( 3 , 4 ). The global burden of COPD continues to rise, driven by factors such as population aging, urbanization, industrial air pollution, and chronic exposure to indoor biomass smoke ( 5 , 15 ). Pathophysiologically, COPD is characterized by persistent airflow limitation due to chronic inflammation, resulting in irreversible narrowing of the airways. While bronchodilators and anti-inflammatory agents can alleviate symptoms, they do not halt disease progression. Acute exacerbations of COPD (AECOPD) represent a critical aspect of disease management. According to the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, AECOPDs are defined by acute worsening of respiratory symptoms—such as dyspnea, cough, and sputum production—and are often accompanied by systemic inflammation, tachypnea, and tachycardia ( 8 ). These episodes significantly contribute to reduced quality of life, increased hospitalizations, and elevated mortality ( 11 ). Risk factors for frequent exacerbations include older age, advanced disease stage, hypercapnia, and a prior history of exacerbations ( 9 , 10 ). Among the various factors implicated in COPD pathogenesis and prognosis, magnesium has garnered attention due to its role in bronchial smooth muscle relaxation, mast cell stabilization, mucociliary function, and anticholinergic activity ( 6 , 13 ). Several studies have reported an association between low serum magnesium levels and increased frequency or severity of AECOPD ( 1 , 2 , 10 , 12 ). Hypomagnesemia may be more prevalent among males, elderly patients, and those with severe COPD. However, the literature remains inconclusive, with some studies showing no significant difference in magnesium levels between COPD patients and healthy controls ( 7 , 10 ). Despite the clinical relevance of magnesium in respiratory physiology, no prior studies in Iran have examined the association between serum magnesium levels and AECOPD severity. Given the potential of magnesium as a predictive biomarker and the high burden of COPD in the Iranian population, we conducted this cross-sectional study to evaluate whether serum magnesium levels are associated with the severity of acute exacerbations in COPD patients. Method Study Design and Participants This analytical cross-sectional study was conducted on patients diagnosed with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) who were admitted to Al-Zahra Hospital in 2024. Inclusion criteria were: ( 1 ) diagnosis of COPD based on clinical history and GOLD 2024 criteria; ( 2 ) age over 40 years; and ( 3 ) clinical presentation of AECOPD defined as worsening of dyspnea, cough, or sputum production within the last 14 days. Patients were enrolled after obtaining written informed consent. Exclusion criteria included: history of thoracic surgery, use of medications known to affect serum magnesium levels (e.g., thiazide diuretics, digoxin), presence of pneumothorax, hemodynamic instability, recent stroke, chronic alcohol use, gastrointestinal disorders, and other respiratory diseases such as tuberculosis, bronchial asthma, lung cancer, sarcoidosis, pulmonary fibrosis, or prior lung resection. Additionally, patients with chronic kidney disease, uncontrolled type 2 diabetes mellitus, or congestive heart failure were excluded. The severity of AECOPD was categorized into three levels—mild, moderate, and severe—based on a combination of clinical signs and laboratory data, including dyspnea intensity, respiratory rate, heart rate, arterial pH, CRP levels, and oxygen saturation at admission. Mild exacerbations were defined by the absence of acidosis, a resting SpO₂ of ≥ 92%, CRP < 10 mg/L, and stable vital signs. Moderate exacerbations met at least three of the following: increased dyspnea, RR ≥ 24, HR ≥ 95, SpO₂ <92%, and CRP ≥ 10 mg/L. Severe exacerbations were defined by the presence of respiratory acidosis (pH 45 mmHg) in addition to other features of moderate severity. ( 2 ) A total of 149 patients meeting the eligibility criteria were selected through convenience sampling. Data Collection and Measurements After ethical approval was obtained from the Ethics Committee of Isfahan University of Medical Sciences, data collection was performed at the time of admission (IR.MUI.MED.REC.1403.217). Serum magnesium levels were measured using Serum magnesium levels were measured using the colorimetric method with Xylidyl Blue reagent. Additional clinical data including age, sex, smoking history (measured in pack-years), number of hospitalizations in the past year, oxygen saturation (SpO₂), pH, CRP levels, and length of hospital stay were extracted from patient records. Statistical Analysis Statistical analyses were performed using SPSS version 14 (IBM Corp., Armonk, NY, USA) and Python (statsmodels and SciPy packages). Continuous variables were summarized as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. The normality of continuous variables within AECOPD severity groups (mild, moderate, severe) was assessed using the Shapiro–Wilk test, and homogeneity of variances was examined with Levene’s test. Between-group comparisons were conducted using one-way analysis of variance (ANOVA) for normally distributed variables with approximately equal variances, and the chi-square test for categorical variables. Hypomagnesemia was defined as serum magnesium < 1.8 mg/dL. The association between serum magnesium levels and AECOPD severity was first evaluated with ANOVA and then further explored using an ordinal logistic regression model, with AECOPD severity (mild, moderate, severe) as the ordinal dependent variable and serum magnesium, age, sex, smoking exposure (pack-years), and prior hospitalization as independent variables. Pearson correlation coefficients were calculated to assess linear relationships between serum magnesium and physiological or inflammatory markers (oxygen saturation, arterial pH, and CRP). A two-sided P-value < 0.05 was considered statistically significant. Results Patient Characteristics A total of 149 patients hospitalized with AECOPD were included in the analysis. Based on predefined clinical and biochemical criteria, 21 patients (14.1%) were classified as mild, 67 (45.0%) as moderate, and 61 (40.9%) as severe exacerbations. Baseline demographic and clinical characteristics across severity groups are summarized in Table 1. Table 1. Baseline demographic and clinical characteristics of patients with AECOPD stratified by exacerbation severity Characteristic Mild (n=21) Moderate (n=67) Severe (n=61) P-value Age (years), mean ± SD 62.33 ± 12.75 67.93 ± 10.41 66.38 ± 11.35 0.136 Male sex, n (%) 15 (71.4%) 53 (79.1%) 55 (90.2%) 0.090 Smoking status, n (%) 0.158 Smoker 12 (57.1%) 36 (53.7%) 43 (70.5%) Exposure only 2 (9.5%) 14 (20.9%) 10 (16.4%) Hospitalization in previous year, n (%) 7 (33.3%) 26 (38.8%) 18 (29.5%) 0.917 Length of stay (days), mean ± SD 3.52 ± 1.97 5.36 ± 2.65 5.79 ± 3.11 0.006 There were no statistically significant differences among the three groups regarding age, sex distribution, smoking status, or history of hospitalization within the previous year (P > 0.05 for all). However, length of hospital stay increased progressively with exacerbation severity (mild: 3.52 ± 1.97 days; moderate: 5.36 ± 2.65 days; severe: 5.79 ± 3.11 days; P = 0.006). Physiological and Inflammatory Parameters According to AECOPD Severity A clear gradient of physiological deterioration was observed with increasing exacerbation severity (Table 2). • Oxygen saturation declined significantly across severity levels (91.33 ± 2.80% in mild vs. 83.16 ± 6.90% in moderate vs. 77.13 ± 11.03% in severe; P < 0.001). • CRP levels were markedly higher in moderate and severe groups compared with mild (11.24 ± 5.41 mg/L vs. 41.06 ± 31.67 mg/L and 51.67 ± 40.22 mg/L, respectively; P < 0.001). • Arterial pH demonstrated a significant downward trend (mild: 7.36 ± 0.08; moderate: 7.34 ± 0.06; severe: 7.29 ± 0.04; P < 0.001). These findings confirm appropriate internal validity of the severity classification, showing physiologic consistency with established clinical expectations. Table 2. Comparison of clinical, physiological, inflammatory, and biochemical parameters according to AECOPD severity Variable Mild (n=21) Moderate (n=67) Severe (n=61) P-value O₂ saturation (%) 91.33 ± 2.80ᵃ 83.16 ± 6.90ᵇ 77.13 ± 11.03ᶜ <0.001 Serum magnesium (mg/dL) 2.15 ± 0.21ᵃ 2.07 ± 0.21ᵃ 2.10 ± 0.29ᵃ 0.357 CRP (mg/L) 11.24 ± 5.41ᵇ 41.06 ± 31.67ᵃ 51.67 ± 40.22ᵃ <0.001 Arterial pH 7.36 ± 0.08ᵃ 7.34 ± 0.06ᵃ 7.29 ± 0.04ᵇ <0.001 Note: Different superscript letters indicate significant pairwise differences in post-hoc comparisons. Serum Magnesium Levels and Prevalence of Hypomagnesemia Mean serum magnesium (Mg) concentrations were 2.15 ± 0.21 mg/dL in mild, 2.07 ± 0.21 mg/dL in moderate, and 2.10 ± 0.29 mg/dL in severe AECOPD groups. There was no significant difference in Mg levels across the three severity categories (P = 0.357), and post-hoc comparisons showed no meaningful pairwise differences (Table 2). Hypomagnesemia (Mg < 1.8 mg/dL) was detected in 11 patients (7.4%). Its distribution did not differ significantly across severity groups (mild: 4.8%; moderate: 7.5%; severe: 8.2%; P = 0.873) (Table 3). Table 3. Prevalence of hypomagnesemia and logistic regression assessing factors associated with hypomagnesemia A. Prevalence across severity levels Severity Normal Mg (n=138) Hypomagnesemia (n=11) P-value Mild 20 (14.5%) 1 (9.1%) Moderate 62 (44.9%) 5 (45.5%) Severe 56 (40.6%) 5 (45.5%) Total 138 (92.6%) 11 (7.4%) 0.873 B. Logistic regression model Predictor OR (95% CI) P-value Severity (per level increase) 1.32 (0.41–4.29) 0.671 Male sex — (no hypomagnesemia in females) — Age (per 1-year increase) 1.01 (0.96–1.07) 0.685 O₂ saturation 1.02 (0.95–1.10) 0.590 CRP 1.00 (0.98–1.02) 0.805 Arterial pH 0.01 (0–14.23) 0.155 Note: Model is underpowered due to low number of hypomagnesemia cases (n=11). Interpret with caution. The prevalence of hypomagnesemia was low across all severity categories (mild: 4.8%, moderate: 7.5%, severe: 8.2%), with no statistically significant differences between groups (P = 0.873). The distribution of hypomagnesemia according to AECOPD severity is presented in Figure 1. Correlation Between Magnesium and Clinical Markers No significant correlations were observed between serum Mg and physiological or inflammatory markers: • Mg vs. O₂ saturation: r = –0.06, P = 0.47 • Mg vs. CRP: r = –0.141, P = 0.086 • Mg vs. pH: r = –0.044, P = 0.598 Although a weak inverse trend was noted between Mg and CRP, this association did not reach statistical significance. No significant difference in smoking intensity (pack-years) was found between patients with normal serum magnesium levels and those with hypomagnesemia, in either active smokers or individuals with passive smoke exposure (P > 0.05). Detailed comparisons of pack-year distributions by magnesium status are shown in Figure 2. Ordinal Logistic Regression Analysis To determine whether serum Mg independently predicted exacerbation severity, an ordinal logistic regression model was constructed with severity (mild < moderate < severe) as the ordinal outcome and magnesium, age, sex, smoking exposure, and prior hospitalization as predictors. Serum Mg was not a significant predictor of exacerbation severity (coefficient = –0.036, P = 0.960). None of the demographic variables showed significant associations in the adjusted model. These findings indicate that serum magnesium is not an independent determinant of AECOPD severity. Discussion Acute exacerbations of COPD (AECOPD) remain a decisive driver of disease progression, healthcare utilization, and impaired quality of life ( 3 , 4 ). In this study, we characterized the clinical and biochemical features of 149 hospitalized patients and evaluated whether serum magnesium levels—a physiologically attractive but inconsistently studied biomarker—could meaningfully differentiate exacerbation severity. Our findings reaffirm several well-established pathophysiological trends while challenging the assumption that total serum magnesium provides clinically actionable prognostic information. Consistent with global evidence that exacerbations reflect episodes of intensified respiratory compromise ( 8 , 11 ), patients with more severe AECOPD in our cohort exhibited markedly lower oxygen saturation, more profound acidemia, higher CRP levels, and longer hospitalizations. These gradients mirror the underlying biological escalation that occurs during exacerbations, in which airflow obstruction, gas-exchange failure, and systemic inflammation converge to amplify physiological stress ( 9 , 10 ). The internal coherence of these parameters across severity groups also supports the robustness of the severity classification used in this study. Despite the biological plausibility of magnesium as a respiratory modulator—given its roles in bronchial smooth-muscle relaxation, calcium-channel regulation, mast-cell stabilization, and inhibition of cholinergic transmission ( 6 , 13 )—our results showed no significant differences in serum magnesium concentrations between severity groups. Only 7.4% of patients had hypomagnesemia. While a mild downward numerical trend was noted, the absence of statistical significance suggests that total serum magnesium alone is unlikely to be a major determinant of acute physiological deterioration. This finding aligns with earlier work indicating inconsistent or modest associations between serum magnesium levels and exacerbation risk ( 1 , 2 , 10 , 12 ). Importantly, serum magnesium represents less than 1% of total body magnesium stores ( 14 ). The vast majority resides intracellularly or in bone, making serum measurements a weak surrogate for physiologically relevant depletion. This discrepancy may help explain why several interventional and observational studies—despite demonstrating minor improvements in airflow metrics with intravenous magnesium sulfate ( 7 )—have not produced conclusive evidence supporting serum magnesium as a prognostic biomarker. In other words, the biological importance of magnesium in respiratory physiology does not necessarily translate into measurable differences in circulating levels during acute exacerbations. Smoking, indoor biomass exposure, and ambient air pollution are recognized contributors to COPD pathogenesis and systemic oxidative stress ( 5 , 15 ). However, our analysis found no association between smoking intensity and serum magnesium levels. This suggests that if micronutrient depletion occurs due to smoking-related oxidative stress, it may not be reflected in the extracellular magnesium pool. Similar null relationships have been reported in previous studies evaluating lifestyle and demographic predictors of hypomagnesemia among COPD patients ( 1 , 10 ). Interestingly, cumulative smoking exposure expressed as pack-years did not differ significantly across exacerbation severity categories in our cohort. Although tobacco smoke is the principal etiologic factor in the development of COPD, this finding suggests that lifetime smoking dose alone may not be a key determinant of acute exacerbation severity. In the acute setting, the clinical course of an exacerbation is more likely influenced by immediate and dynamic factors, including the nature and virulence of the triggering infection, the magnitude of airway and systemic inflammation, underlying comorbidities, and the patient’s physiological reserve. In line with this interpretation, data from large cohorts such as COPDGene have demonstrated that frailty is strongly associated with respiratory exacerbations and mortality, even after adjustment for pack-years and spirometric impairment, highlighting the role of global vulnerability rather than exposure metrics in isolation. From a methodological standpoint, pack-years may also represent an imperfect surrogate for smoking-related injury in this context, as it combines intensity and duration into a single measure and fails to capture structural lung damage or extra-pulmonary susceptibility. Consequently, future studies may benefit from incorporating alternative markers—such as smoking duration, imaging-based indices of emphysema and airway disease, diffusion capacity, or multidimensional frailty constructs. Taken together, our findings should not be interpreted as diminishing the importance of smoking cessation in long-term COPD management; rather, they underscore that acute exacerbation severity is a multifactorial phenomenon, in which current clinical status and triggering factors may obscure a direct signal from cumulative smoking exposure. The strength of our study lies in its structured, clinically relevant stratification of AECOPD severity using routinely available indices such as pH, SpO₂, CRP, and vital signs. These markers reliably captured the physiological trajectory of exacerbations, reinforcing their utility in comparative biomarker research. Nevertheless, our findings underscore that total serum magnesium—despite its theoretical appeal—does not behave as a dynamic marker of exacerbation severity. This study has limitations. Its cross-sectional design precludes causal inference. Measurements were limited to total serum magnesium rather than ionized or intracellular forms, which may have greater physiological relevance ( 13 , 14 ). Additionally, the single-center design and modest sample size may limit generalizability. Future multicenter, prospective studies employing ionized or intracellular magnesium assessments, coupled with longitudinal tracking of exacerbation outcomes, are essential to clarify whether magnesium status holds predictive or therapeutic value in COPD. In summary, while severe AECOPD in our cohort was characterized by expected clinical and biochemical deterioration, serum magnesium levels remained largely unchanged across severity groups. These findings suggest that total serum magnesium is not a reliable biomarker for assessing exacerbation severity, despite the well-established physiological role of magnesium in respiratory function. Further investigations leveraging more sensitive indices of magnesium status are warranted to determine whether this electrolyte holds deeper prognostic or mechanistic relevance in the COPD population. Conclusion In this cross-sectional study of 149 hospitalized patients with AECOPD, clinical severity—defined using objective physiological and biochemical criteria—was significantly associated with reduced oxygen saturation, lower arterial pH, elevated CRP levels, and longer hospital stay. Although serum magnesium levels showed a mild decreasing trend across severity groups, this difference was not statistically significant, and the prevalence of hypomagnesemia, defined as serum magnesium < 1.8 mg/dL, was 7.4%. These findings suggest that total serum magnesium alone may not serve as a reliable standalone biomarker for assessing AECOPD severity. Further studies using intracellular or ionized magnesium measurements and larger, multicenter cohorts are warranted to clarify its potential diagnostic and prognostic relevance. Abbreviations • AECOPD Acute Exacerbation of Chronic Obstructive Pulmonary Disease • ATS American Thoracic Society • CI Confidence Interval • COPD Chronic Obstructive Pulmonary Disease • CRP C–reactive Protein • ERS European Respiratory Society • FEV₁ Forced Expiratory Volume in 1 second • GOLD Global Initiative for Chronic Obstructive Lung Disease • HR Heart Rate • OR Odds Ratio • PaCO₂ Partial Pressure of Carbon Dioxide in Arterial Blood • pH Potential of Hydrogen (acidity/alkalinity measure in blood) • RR Respiratory Rate • SD Standard Deviation • SpO₂ Peripheral Capillary Oxygen Saturation • WHO World Health Organization Declarations Disclosure This manuscript has been previously uploaded as a preprint to Preprints with The Lancet: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5391657 . Declaration of interests The authors declare no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Role of the funding source There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Data sharing De-identified participant data, the study protocol, and statistical analysis plan will be made available from the corresponding author upon reasonable request, following publication. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (approval code: IR.MUI.MED.REC.1403.217). Written informed consent was obtained from all participants prior to enrolment. Author Contribution G.S: wrote the main manuscript textF.K: writing–review, and editingE.K: conceptualization, methodology, supervision, validation, writing–review, and editing Data Availability De-identified participant data, the study protocol, and statistical analysis plan will be made available from the corresponding author upon reasonable request, following publication. References Aziz HS, Blamoun AI, Shubair MK, Ismail MM, DeBari VA, Khan MA (2005) Serum magnesium levels and acute exacerbation of chronic obstructive pulmonary disease: a retrospective study. Annals Clin Lab Sci 35(4):423–427 Kshirsagar K, Patil VC (2021) Chronic obstructive pulmonary disease: Is serum magnesium level a risk factor for its acute exacerbation? Caspian J Intern Med 12(2):223 World Health Organization. Chronic obstructive pulmonary disease (COPD) fact sheet. World Health Organization.[Nov, 2017] (2017) http://www.who.int/en/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd ). 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Agustí A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, Bourbeau J, Han MK, Martinez FJ, de Oca MM, Mortimer K (2022) Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. J Pan Afr Thorac Soc 4(2):58–80 Holtjer JC, Bloemsma LD, Beijers RJ, Cornelissen ME, Hilvering B, Houweling L, Vermeulen RC, Downward GS (2023) Maitland-Van der Zee AH. Identifying risk factors for COPD and adult-onset asthma: an umbrella review. Eur respiratory Rev. ;32(168) Bhatt SP, Khandelwal P, Nanda S, Stoltzfus JC, Fioravanti GT (2008) Serum magnesium is an independent predictor of frequent readmissions due to acute exacerbation of chronic obstructive pulmonary disease. Respir Med 102(7):999–1003 Halpin DM, Mahler DA (2024) Systematic review of the effects of patient errors using inhaled delivery systems on clinical outcomes in COPD. BMJ Open Respiratory Res. ;11(1) Kumar PN, Amirullah A, Kumar DR (2025) Association between serum magnesium levels and acute exacerbations in chronic obstructive pulmonary disease patients. Int J Med Health Dev 30(2):146–151 Fiorentini D, Cappadone C, Farruggia G, Prata C (2021) Magnesium: biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients 13(4):1136 Reddy ST, Soman SS, Yee J (2018) Magnesium balance and measurement. Advances in chronic kidney disease. 25(3):224–229 Duan RR, Hao K, Yang T (2020) Air pollution and chronic obstructive pulmonary disease. Chronic Dis translational Med 6(04):260–269 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Feb, 2026 Reviews received at journal 06 Feb, 2026 Reviewers agreed at journal 11 Jan, 2026 Reviews received at journal 07 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 07 Jan, 2026 Submission checks completed at journal 07 Jan, 2026 First submitted to journal 01 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8497073","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":571088224,"identity":"69bea4c9-68ec-46ad-ad30-df3c7cd39352","order_by":0,"name":"Ghazal Siroos Najafabadi","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ghazal","middleName":"Siroos","lastName":"Najafabadi","suffix":""},{"id":571088228,"identity":"66455ce6-539f-4e30-95ec-7503963d5777","order_by":1,"name":"Forough Kalantari","email":"","orcid":"","institution":"Iran University of Medical 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06:24:47","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75766,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8497073/v1/e933e92383f892f6c673cf9d.html"},{"id":100014523,"identity":"6d45dbb8-96c2-469a-bdfc-e72410c38689","added_by":"auto","created_at":"2026-01-12 06:24:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30604,"visible":true,"origin":"","legend":"\u003cp\u003ePercentage prevalence of hypomagnesemia according to AECOPD severity\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8497073/v1/0adc2443f964110d66f27b66.png"},{"id":100014517,"identity":"d3dcd18e-cb13-4120-b486-9f361e6c8590","added_by":"auto","created_at":"2026-01-12 06:24:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97803,"visible":true,"origin":"","legend":"\u003cp\u003eMean pack-years among active smokers and smoke-exposed patients stratified by magnesium status (normal vs. hypomagnesemia). Error bars represent standard deviations. No statistically significant differences were observed between groups (P \u0026gt; 0.05).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8497073/v1/78ca9b8e53d64afe070c3236.png"},{"id":100361647,"identity":"9b701279-3f9b-4032-92c3-52dd51ac0d74","added_by":"auto","created_at":"2026-01-16 07:45:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1007817,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8497073/v1/ecbde4c8-ee24-418d-8427-d0589109e2af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAssociation Between Serum Magnesium Levels and Severity of Acute Exacerbations in COPD: A Cross-Sectional Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, exerting substantial pressure on healthcare systems (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In 2019, it was responsible for 3.3\u0026nbsp;million deaths, ranking as the third leading cause of death globally by 2020 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The global burden of COPD continues to rise, driven by factors such as population aging, urbanization, industrial air pollution, and chronic exposure to indoor biomass smoke (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Pathophysiologically, COPD is characterized by persistent airflow limitation due to chronic inflammation, resulting in irreversible narrowing of the airways. While bronchodilators and anti-inflammatory agents can alleviate symptoms, they do not halt disease progression.\u003c/p\u003e \u003cp\u003eAcute exacerbations of COPD (AECOPD) represent a critical aspect of disease management. According to the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, AECOPDs are defined by acute worsening of respiratory symptoms\u0026mdash;such as dyspnea, cough, and sputum production\u0026mdash;and are often accompanied by systemic inflammation, tachypnea, and tachycardia (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). These episodes significantly contribute to reduced quality of life, increased hospitalizations, and elevated mortality (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Risk factors for frequent exacerbations include older age, advanced disease stage, hypercapnia, and a prior history of exacerbations (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong the various factors implicated in COPD pathogenesis and prognosis, magnesium has garnered attention due to its role in bronchial smooth muscle relaxation, mast cell stabilization, mucociliary function, and anticholinergic activity (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Several studies have reported an association between low serum magnesium levels and increased frequency or severity of AECOPD (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Hypomagnesemia may be more prevalent among males, elderly patients, and those with severe COPD. However, the literature remains inconclusive, with some studies showing no significant difference in magnesium levels between COPD patients and healthy controls (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the clinical relevance of magnesium in respiratory physiology, no prior studies in Iran have examined the association between serum magnesium levels and AECOPD severity. Given the potential of magnesium as a predictive biomarker and the high burden of COPD in the Iranian population, we conducted this cross-sectional study to evaluate whether serum magnesium levels are associated with the severity of acute exacerbations in COPD patients.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis analytical cross-sectional study was conducted on patients diagnosed with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) who were admitted to Al-Zahra Hospital in 2024. Inclusion criteria were: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) diagnosis of COPD based on clinical history and GOLD 2024 criteria; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) age over 40 years; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) clinical presentation of AECOPD defined as worsening of dyspnea, cough, or sputum production within the last 14 days. Patients were enrolled after obtaining written informed consent.\u003c/p\u003e \u003cp\u003eExclusion criteria included: history of thoracic surgery, use of medications known to affect serum magnesium levels (e.g., thiazide diuretics, digoxin), presence of pneumothorax, hemodynamic instability, recent stroke, chronic alcohol use, gastrointestinal disorders, and other respiratory diseases such as tuberculosis, bronchial asthma, lung cancer, sarcoidosis, pulmonary fibrosis, or prior lung resection. Additionally, patients with chronic kidney disease, uncontrolled type 2 diabetes mellitus, or congestive heart failure were excluded.\u003c/p\u003e \u003cp\u003eThe severity of AECOPD was categorized into three levels\u0026mdash;mild, moderate, and severe\u0026mdash;based on a combination of clinical signs and laboratory data, including dyspnea intensity, respiratory rate, heart rate, arterial pH, CRP levels, and oxygen saturation at admission. Mild exacerbations were defined by the absence of acidosis, a resting SpO₂ of \u0026ge;\u0026thinsp;92%, CRP\u0026thinsp;\u0026lt;\u0026thinsp;10 mg/L, and stable vital signs. Moderate exacerbations met at least three of the following: increased dyspnea, RR\u0026thinsp;\u0026ge;\u0026thinsp;24, HR\u0026thinsp;\u0026ge;\u0026thinsp;95, SpO₂ \u0026lt;92%, and CRP\u0026thinsp;\u0026ge;\u0026thinsp;10 mg/L. Severe exacerbations were defined by the presence of respiratory acidosis (pH\u0026thinsp;\u0026lt;\u0026thinsp;7.35 and PaCO₂ \u0026gt;45 mmHg) in addition to other features of moderate severity. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA total of 149 patients meeting the eligibility criteria were selected through convenience sampling.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection and Measurements\u003c/h3\u003e\n\u003cp\u003e After ethical approval was obtained from the Ethics Committee of Isfahan University of Medical Sciences, data collection was performed at the time of admission (IR.MUI.MED.REC.1403.217). Serum magnesium levels were measured using Serum magnesium levels were measured using the colorimetric method with Xylidyl Blue reagent. Additional clinical data including age, sex, smoking history (measured in pack-years), number of hospitalizations in the past year, oxygen saturation (SpO₂), pH, CRP levels, and length of hospital stay were extracted from patient records.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS version 14 (IBM Corp., Armonk, NY, USA) and Python (statsmodels and SciPy packages). Continuous variables were summarized as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and categorical variables as frequencies and percentages. The normality of continuous variables within AECOPD severity groups (mild, moderate, severe) was assessed using the Shapiro\u0026ndash;Wilk test, and homogeneity of variances was examined with Levene\u0026rsquo;s test. Between-group comparisons were conducted using one-way analysis of variance (ANOVA) for normally distributed variables with approximately equal variances, and the chi-square test for categorical variables.\u003c/p\u003e \u003cp\u003eHypomagnesemia was defined as serum magnesium\u0026thinsp;\u0026lt;\u0026thinsp;1.8 mg/dL. The association between serum magnesium levels and AECOPD severity was first evaluated with ANOVA and then further explored using an ordinal logistic regression model, with AECOPD severity (mild, moderate, severe) as the ordinal dependent variable and serum magnesium, age, sex, smoking exposure (pack-years), and prior hospitalization as independent variables. Pearson correlation coefficients were calculated to assess linear relationships between serum magnesium and physiological or inflammatory markers (oxygen saturation, arterial pH, and CRP). A two-sided P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 149 patients hospitalized with AECOPD were included in the analysis. Based on predefined clinical and biochemical criteria, 21 patients (14.1%) were classified as mild, 67 (45.0%) as moderate, and 61 (40.9%) as severe exacerbations. Baseline demographic and clinical characteristics across severity groups are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline demographic and clinical characteristics of patients with AECOPD stratified by exacerbation severity\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMild (n=21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate (n=67)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere (n=61)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years), mean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62.33 \u0026plusmn; 12.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e67.93 \u0026plusmn; 10.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66.38 \u0026plusmn; 11.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale sex, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15 (71.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e53 (79.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e55 (90.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking status, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026emsp;Smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e36 (53.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e43 (70.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026emsp;Exposure only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14 (20.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (16.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHospitalization in previous year, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26 (38.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18 (29.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.917\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLength of stay (days), mean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.52 \u0026plusmn; 1.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.36 \u0026plusmn; 2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.79 \u0026plusmn; 3.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;There were no statistically significant differences among the three groups regarding age, sex distribution, smoking status, or history of hospitalization within the previous year (P \u0026gt; 0.05 for all). However, length of hospital stay increased progressively with exacerbation severity (mild: 3.52 \u0026plusmn; 1.97 days; moderate: 5.36 \u0026plusmn; 2.65 days; severe: 5.79 \u0026plusmn; 3.11 days; P = 0.006).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePhysiological and Inflammatory Parameters According to AECOPD Severity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA clear gradient of physiological deterioration was observed with increasing exacerbation severity (Table 2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Oxygen saturation declined significantly across severity levels (91.33 \u0026plusmn; 2.80% in mild vs. 83.16 \u0026plusmn; 6.90% in moderate vs. 77.13 \u0026plusmn; 11.03% in severe; P \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;CRP levels were markedly higher in moderate and severe groups compared with mild (11.24 \u0026plusmn; 5.41 mg/L vs. 41.06 \u0026plusmn; 31.67 mg/L and 51.67 \u0026plusmn; 40.22 mg/L, respectively; P \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Arterial pH demonstrated a significant downward trend (mild: 7.36 \u0026plusmn; 0.08; moderate: 7.34 \u0026plusmn; 0.06; severe: 7.29 \u0026plusmn; 0.04; P \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eThese findings confirm appropriate internal validity of the severity classification, showing physiologic consistency with established clinical expectations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Comparison of clinical, physiological, inflammatory, and biochemical parameters according to AECOPD severity\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"612\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMild (n=21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eModerate (n=67)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere (n=61)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eO₂ saturation (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e91.33 \u0026plusmn; 2.80ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e83.16 \u0026plusmn; 6.90ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e77.13 \u0026plusmn; 11.03ᶜ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum magnesium (mg/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.15 \u0026plusmn; 0.21ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.07 \u0026plusmn; 0.21ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.10 \u0026plusmn; 0.29ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRP (mg/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11.24 \u0026plusmn; 5.41ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e41.06 \u0026plusmn; 31.67ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e51.67 \u0026plusmn; 40.22ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eArterial pH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.36 \u0026plusmn; 0.08ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.34 \u0026plusmn; 0.06ᵃ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.29 \u0026plusmn; 0.04ᵇ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Different superscript letters indicate significant pairwise differences in post-hoc comparisons.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eSerum Magnesium Levels and Prevalence of Hypomagnesemia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean serum magnesium (Mg) concentrations were 2.15 \u0026plusmn; 0.21 mg/dL in mild, 2.07 \u0026plusmn; 0.21 mg/dL in moderate, and 2.10 \u0026plusmn; 0.29 mg/dL in severe AECOPD groups.\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in Mg levels across the three severity categories (P = 0.357), and post-hoc comparisons showed no meaningful pairwise differences (Table 2).\u003c/p\u003e\n\u003cp\u003eHypomagnesemia (Mg \u0026lt; 1.8 mg/dL) was detected in 11 patients (7.4%). Its distribution did not differ significantly across severity groups (mild: 4.8%; moderate: 7.5%; severe: 8.2%; P = 0.873) (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Prevalence of hypomagnesemia and logistic regression assessing factors associated with hypomagnesemia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.\u0026nbsp; \u0026nbsp; \u0026nbsp;Prevalence across severity levels\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal Mg (n=138)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypomagnesemia (n=11)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20 (14.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e62 (44.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56 (40.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e138 (92.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.873\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;B. \u0026nbsp; \u0026nbsp; Logistic regression model\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePredictor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSeverity (per level increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.32 (0.41\u0026ndash;4.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.671\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026mdash; (no hypomagnesemia in females)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge (per 1-year increase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.01 (0.96\u0026ndash;1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eO₂ saturation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.02 (0.95\u0026ndash;1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.590\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.00 (0.98\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.805\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eArterial pH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.01 (0\u0026ndash;14.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Model is underpowered due to low number of hypomagnesemia cases (n=11). Interpret with caution.\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eThe prevalence of hypomagnesemia was low across all severity categories (mild: 4.8%, moderate: 7.5%, severe: 8.2%), with no statistically significant differences between groups (P = 0.873). The distribution of hypomagnesemia according to AECOPD severity is presented in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation Between Magnesium and Clinical Markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant correlations were observed between serum Mg and physiological or inflammatory markers:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mg vs. O₂ saturation: r = \u0026ndash;0.06, P = 0.47\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mg vs. CRP: r = \u0026ndash;0.141, P = 0.086\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026bull;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mg vs. pH: r = \u0026ndash;0.044, P = 0.598\u003c/p\u003e\n\u003cp\u003eAlthough a weak inverse trend was noted between Mg and CRP, this association did not reach statistical significance.\u003c/p\u003e\n\u003cp\u003eNo significant difference in smoking intensity (pack-years) was found between patients with normal serum magnesium levels and those with hypomagnesemia, in either active smokers or individuals with passive smoke exposure (P \u0026gt; 0.05). Detailed comparisons of pack-year distributions by magnesium status are shown in Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOrdinal Logistic Regression Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine whether serum Mg independently predicted exacerbation severity, an ordinal logistic regression model was constructed with severity (mild \u0026lt; moderate \u0026lt; severe) as the ordinal outcome and magnesium, age, sex, smoking exposure, and prior hospitalization as predictors.\u003c/p\u003e\n\u003cp\u003eSerum Mg was not a significant predictor of exacerbation severity (coefficient = \u0026ndash;0.036, P = 0.960).\u003c/p\u003e\n\u003cp\u003eNone of the demographic variables showed significant associations in the adjusted model.\u003c/p\u003e\n\u003cp\u003eThese findings indicate that serum magnesium is not an independent determinant of AECOPD severity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAcute exacerbations of COPD (AECOPD) remain a decisive driver of disease progression, healthcare utilization, and impaired quality of life (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In this study, we characterized the clinical and biochemical features of 149 hospitalized patients and evaluated whether serum magnesium levels\u0026mdash;a physiologically attractive but inconsistently studied biomarker\u0026mdash;could meaningfully differentiate exacerbation severity. Our findings reaffirm several well-established pathophysiological trends while challenging the assumption that total serum magnesium provides clinically actionable prognostic information.\u003c/p\u003e \u003cp\u003eConsistent with global evidence that exacerbations reflect episodes of intensified respiratory compromise (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), patients with more severe AECOPD in our cohort exhibited markedly lower oxygen saturation, more profound acidemia, higher CRP levels, and longer hospitalizations. These gradients mirror the underlying biological escalation that occurs during exacerbations, in which airflow obstruction, gas-exchange failure, and systemic inflammation converge to amplify physiological stress (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The internal coherence of these parameters across severity groups also supports the robustness of the severity classification used in this study.\u003c/p\u003e \u003cp\u003eDespite the biological plausibility of magnesium as a respiratory modulator\u0026mdash;given its roles in bronchial smooth-muscle relaxation, calcium-channel regulation, mast-cell stabilization, and inhibition of cholinergic transmission (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u0026mdash;our results showed no significant differences in serum magnesium concentrations between severity groups. Only 7.4% of patients had hypomagnesemia. While a mild downward numerical trend was noted, the absence of statistical significance suggests that total serum magnesium alone is unlikely to be a major determinant of acute physiological deterioration. This finding aligns with earlier work indicating inconsistent or modest associations between serum magnesium levels and exacerbation risk (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImportantly, serum magnesium represents less than 1% of total body magnesium stores (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The vast majority resides intracellularly or in bone, making serum measurements a weak surrogate for physiologically relevant depletion. This discrepancy may help explain why several interventional and observational studies\u0026mdash;despite demonstrating minor improvements in airflow metrics with intravenous magnesium sulfate (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u0026mdash;have not produced conclusive evidence supporting serum magnesium as a prognostic biomarker. In other words, the biological importance of magnesium in respiratory physiology does not necessarily translate into measurable differences in circulating levels during acute exacerbations.\u003c/p\u003e \u003cp\u003eSmoking, indoor biomass exposure, and ambient air pollution are recognized contributors to COPD pathogenesis and systemic oxidative stress (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, our analysis found no association between smoking intensity and serum magnesium levels. This suggests that if micronutrient depletion occurs due to smoking-related oxidative stress, it may not be reflected in the extracellular magnesium pool. Similar null relationships have been reported in previous studies evaluating lifestyle and demographic predictors of hypomagnesemia among COPD patients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInterestingly, cumulative smoking exposure expressed as pack-years did not differ significantly across exacerbation severity categories in our cohort. Although tobacco smoke is the principal etiologic factor in the development of COPD, this finding suggests that lifetime smoking dose alone may not be a key determinant of acute exacerbation severity. In the acute setting, the clinical course of an exacerbation is more likely influenced by immediate and dynamic factors, including the nature and virulence of the triggering infection, the magnitude of airway and systemic inflammation, underlying comorbidities, and the patient\u0026rsquo;s physiological reserve.\u003c/p\u003e \u003cp\u003eIn line with this interpretation, data from large cohorts such as COPDGene have demonstrated that frailty is strongly associated with respiratory exacerbations and mortality, even after adjustment for pack-years and spirometric impairment, highlighting the role of global vulnerability rather than exposure metrics in isolation. From a methodological standpoint, pack-years may also represent an imperfect surrogate for smoking-related injury in this context, as it combines intensity and duration into a single measure and fails to capture structural lung damage or extra-pulmonary susceptibility. Consequently, future studies may benefit from incorporating alternative markers\u0026mdash;such as smoking duration, imaging-based indices of emphysema and airway disease, diffusion capacity, or multidimensional frailty constructs. Taken together, our findings should not be interpreted as diminishing the importance of smoking cessation in long-term COPD management; rather, they underscore that acute exacerbation severity is a multifactorial phenomenon, in which current clinical status and triggering factors may obscure a direct signal from cumulative smoking exposure.\u003c/p\u003e \u003cp\u003eThe strength of our study lies in its structured, clinically relevant stratification of AECOPD severity using routinely available indices such as pH, SpO₂, CRP, and vital signs. These markers reliably captured the physiological trajectory of exacerbations, reinforcing their utility in comparative biomarker research. Nevertheless, our findings underscore that total serum magnesium\u0026mdash;despite its theoretical appeal\u0026mdash;does not behave as a dynamic marker of exacerbation severity.\u003c/p\u003e \u003cp\u003eThis study has limitations. Its cross-sectional design precludes causal inference. Measurements were limited to total serum magnesium rather than ionized or intracellular forms, which may have greater physiological relevance (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Additionally, the single-center design and modest sample size may limit generalizability. Future multicenter, prospective studies employing ionized or intracellular magnesium assessments, coupled with longitudinal tracking of exacerbation outcomes, are essential to clarify whether magnesium status holds predictive or therapeutic value in COPD.\u003c/p\u003e \u003cp\u003eIn summary, while severe AECOPD in our cohort was characterized by expected clinical and biochemical deterioration, serum magnesium levels remained largely unchanged across severity groups. These findings suggest that total serum magnesium is not a reliable biomarker for assessing exacerbation severity, despite the well-established physiological role of magnesium in respiratory function. Further investigations leveraging more sensitive indices of magnesium status are warranted to determine whether this electrolyte holds deeper prognostic or mechanistic relevance in the COPD population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this cross-sectional study of 149 hospitalized patients with AECOPD, clinical severity\u0026mdash;defined using objective physiological and biochemical criteria\u0026mdash;was significantly associated with reduced oxygen saturation, lower arterial pH, elevated CRP levels, and longer hospital stay. Although serum magnesium levels showed a mild decreasing trend across severity groups, this difference was not statistically significant, and the prevalence of hypomagnesemia, defined as serum magnesium\u0026thinsp;\u0026lt;\u0026thinsp;1.8 mg/dL, was 7.4%. These findings suggest that total serum magnesium alone may not serve as a reliable standalone biomarker for assessing AECOPD severity. Further studies using intracellular or ionized magnesium measurements and larger, multicenter cohorts are warranted to clarify its potential diagnostic and prognostic relevance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; AECOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAcute Exacerbation of Chronic Obstructive Pulmonary Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; ATS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Thoracic Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; CI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; COPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic Obstructive Pulmonary Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; CRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC\u0026ndash;reactive Protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; ERS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Respiratory Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; FEV₁\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eForced Expiratory Volume in 1 second\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; GOLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlobal Initiative for Chronic Obstructive Lung Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; HR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHeart Rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; OR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; PaCO₂\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial Pressure of Carbon Dioxide in Arterial Blood\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; pH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePotential of Hydrogen (acidity/alkalinity measure in blood)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; RR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRespiratory Rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; SD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; SpO₂\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeripheral Capillary Oxygen Saturation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; WHO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDisclosure\u003c/h2\u003e \u003cp\u003eThis manuscript has been previously uploaded as a preprint to Preprints with The Lancet: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://papers.ssrn.com/sol3/papers.cfm?abstract_id=5391657\u003c/span\u003e\u003cspan address=\"https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5391657\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDeclaration of interests\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e \u003cp\u003eRole of the funding source\u003c/p\u003e \u003cp\u003eThere was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.\u003c/p\u003e \u003cp\u003eData sharing\u003c/p\u003e \u003cp\u003eDe-identified participant data, the study protocol, and statistical analysis plan will be made available from the corresponding author upon reasonable request, following publication.\u003c/p\u003e \u003cp\u003eEthics approval and consent to participate:\u003c/p\u003e \u003cp\u003e This study was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (approval code: IR.MUI.MED.REC.1403.217). Written informed consent was obtained from all participants prior to enrolment.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eG.S: wrote the main manuscript textF.K: writing\u0026ndash;review, and editingE.K: conceptualization, methodology, supervision, validation, writing\u0026ndash;review, and editing\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eDe-identified participant data, the study protocol, and statistical analysis plan will be made available from the corresponding author upon reasonable request, following publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAziz HS, Blamoun AI, Shubair MK, Ismail MM, DeBari VA, Khan MA (2005) Serum magnesium levels and acute exacerbation of chronic obstructive pulmonary disease: a retrospective study. Annals Clin Lab Sci 35(4):423\u0026ndash;427\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKshirsagar K, Patil VC (2021) Chronic obstructive pulmonary disease: Is serum magnesium level a risk factor for its acute exacerbation? Caspian J Intern Med 12(2):223\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Chronic obstructive pulmonary disease (COPD) fact sheet. World Health Organization.[Nov, 2017] (2017) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.who.int/en/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd\u003c/span\u003e\u003cspan address=\"http://www.who.int/en/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Dec 21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMomtazmanesh S, Moghaddam SS, Ghamari SH, Rad EM, Rezaei N, Shobeiri P, Aali A, Abbasi-Kangevari M, Abbasi-Kangevari Z, Abdelmasseh M, Abdoun M Global burden of chronic respiratory diseases and risk factors, 1990\u0026ndash;2019: an update from the Global Burden of Disease Study 2019. EClinicalMedicine. 2023 Apr 27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Yan F, Jiang L, Zhen W, Li X, Wang H (2025) Epidemiological trends and risk factors of chronic obstructive pulmonary disease in young individuals based on the 2021 global burden of disease data (1990\u0026ndash;2021). BMC Pulm Med 25(1):174\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFawcett WJ, Haxby EJ, Male DA (1999) Magnesium: physiology and pharmacology. Br J Anaesth 83(2):302\u0026ndash;320\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi H, Aye SZ, Naing C Magnesium sulfate for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Reviews. 2022(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgust\u0026iacute; A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, Bourbeau J, Han MK, Martinez FJ, de Oca MM, Mortimer K (2022) Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. J Pan Afr Thorac Soc 4(2):58\u0026ndash;80\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoltjer JC, Bloemsma LD, Beijers RJ, Cornelissen ME, Hilvering B, Houweling L, Vermeulen RC, Downward GS (2023) Maitland-Van der Zee AH. Identifying risk factors for COPD and adult-onset asthma: an umbrella review. Eur respiratory Rev. ;32(168)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhatt SP, Khandelwal P, Nanda S, Stoltzfus JC, Fioravanti GT (2008) Serum magnesium is an independent predictor of frequent readmissions due to acute exacerbation of chronic obstructive pulmonary disease. Respir Med 102(7):999\u0026ndash;1003\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalpin DM, Mahler DA (2024) Systematic review of the effects of patient errors using inhaled delivery systems on clinical outcomes in COPD. BMJ Open Respiratory Res. ;11(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar PN, Amirullah A, Kumar DR (2025) Association between serum magnesium levels and acute exacerbations in chronic obstructive pulmonary disease patients. Int J Med Health Dev 30(2):146\u0026ndash;151\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiorentini D, Cappadone C, Farruggia G, Prata C (2021) Magnesium: biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients 13(4):1136\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReddy ST, Soman SS, Yee J (2018) Magnesium balance and measurement. Advances in chronic kidney disease. 25(3):224\u0026ndash;229\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuan RR, Hao K, Yang T (2020) Air pollution and chronic obstructive pulmonary disease. Chronic Dis translational Med 6(04):260\u0026ndash;269\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-bronchology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Bronchology](https://ejb.springeropen.com/)","snPcode":"43168","submissionUrl":"https://submission.nature.com/new-submission/43168/3","title":"The Egyptian Journal of Bronchology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Chronic Obstructive Pulmonary Disease, Acute Exacerbation, Magnesium, Hypomagnesemia, Biomarkers, Inflammation, Hospitalization","lastPublishedDoi":"10.21203/rs.3.rs-8497073/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8497073/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eMagnesium plays an important role in respiratory physiology and has been proposed as a potential biomarker in chronic obstructive pulmonary disease (COPD). However, existing evidence regarding its association with the severity of acute exacerbations (AECOPD) remains inconsistent. This study aimed to evaluate whether serum magnesium levels are associated with clinical severity in hospitalized patients with AECOPD.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eIn this cross-sectional study, 149 patients admitted with AECOPD in 2024 were classified into mild, moderate, or severe groups based on clinical, physiological, and inflammatory criteria. Serum magnesium levels, arterial pH, oxygen saturation, C-reactive protein (CRP), and other clinical variables were recorded at admission. Between-group differences were assessed using ANOVA and chi-square tests. Correlation analyses and an ordinal logistic regression model were applied to determine whether serum magnesium independently predicted exacerbation severity.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eAECOPD severity was significantly associated with reduced oxygen saturation, lower arterial pH, higher CRP levels, and longer hospital stay (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Mean serum magnesium levels did not differ significantly across severity groups (2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21 mg/dL in mild, 2.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21 mg/dL in moderate, and 2.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29 mg/dL in severe; P\u0026thinsp;=\u0026thinsp;0.357). Hypomagnesemia (Mg\u0026thinsp;\u0026lt;\u0026thinsp;1.8 mg/dL) occurred in 7.4% of patients and showed no significant relationship with exacerbation severity (P\u0026thinsp;=\u0026thinsp;0.873). Correlation analyses demonstrated no significant association between serum magnesium and oxygen saturation, CRP, or arterial pH. In ordinal logistic regression, serum magnesium was not an independent predictor of exacerbation severity (P\u0026thinsp;=\u0026thinsp;0.960).\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eAlthough physiological markers clearly differentiated AECOPD severity, total serum magnesium levels remained relatively stable across severity groups and did not independently predict exacerbation severity. These findings suggest that total serum magnesium is unlikely to serve as a reliable standalone biomarker for assessing AECOPD severity. Future studies incorporating ionized or intracellular magnesium measurements are warranted.\u003c/p\u003e","manuscriptTitle":"Association Between Serum Magnesium Levels and Severity of Acute Exacerbations in COPD: A Cross-Sectional Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:23:22","doi":"10.21203/rs.3.rs-8497073/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-06T21:31:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-06T21:30:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"248413666998198052503387053678981267882","date":"2026-01-11T20:17:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-07T21:15:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148172645014231324325483128173936419422","date":"2026-01-07T19:39:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T19:18:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-07T05:57:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-07T05:05:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Egyptian Journal of Bronchology","date":"2026-01-01T20:43:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-bronchology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Bronchology](https://ejb.springeropen.com/)","snPcode":"43168","submissionUrl":"https://submission.nature.com/new-submission/43168/3","title":"The Egyptian Journal of Bronchology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8cb686cc-b22e-49c0-8e15-d8cb79403597","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-23T23:23:43+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 06:23:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8497073","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8497073","identity":"rs-8497073","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}