---
title: "Serum Na–Cl Difference as a Noninvasive Screen for CO2 Retention in ALS"
id: "plos-one-2-serum-na-cl-value-from-routine-blood-tests-reflects-co-2-retention-in"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-2-serum-na-cl-value-from-routine-blood-tests-reflects-co-2-retention-in"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772"
published_at: "2026-09-18T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Serum Na–Cl Difference as a Noninvasive Screen for CO2 Retention in ALS
## Provenance & Clinical Metadata
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- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772)
- **Published At:** 2026-09-18T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS); early detection of CO2 retention is essential to time noninvasive positive pressure ventilation (NPPV). - Arterial blood gas (ABG) is the gold standard for detecting hypercapnia but is invasive and impractical for frequent outpatient monitoring. - Renal compensation for chronic CO2 retention increases bicarbonate (HCO3–) and promotes chloride excretion, raising the serum **Na–Cl value**, which can be calculated from routine serum chemistry. - This retrospective study analyzed 116 paired ABG and serum electrolyte samples from 88 ALS patients after excluding confounders (hypokalemia, supplemental oxygen, continuous daytime NPPV). - Na–Cl correlated strongly with HCO3– (r = 0.78, p < 0.001) and with PCO2 (r = 0.71, p < 0.001). - For detecting CO2 retention (PCO2 ≥ 45 mmHg), Na–Cl ≥ 37 mEq/L had sensitivity 85.11%, specificity 69.57%, NPV 87.27%, and AUC 0.842; Na–Cl ≥ 39 mEq/L increased specificity to 92.75% (sensitivity 46.81%). - Patients with %FVC < 50% had higher Na–Cl, PCO2, and HCO3–; Na–Cl correlated negatively with %FVC (r = −0.295, p = 0.0106) in 74 samples with concurrent %FVC. - Results were robust in sensitivity analysis using only the first sample per patient (n = 88): correlations and ROC performance were comparable or stronger. - Na–Cl is calculable from routine serum Na and Cl without additional cost or invasive sampling and appears independent of ALS onset type (spinal vs bulbar). - The authors propose a stepwise strategy: use Na–Cl ≥ 37 mEq/L as a screening threshold to prompt ABG, and Na–Cl ≥ 39 mEq/L when higher specificity is desired. - Details on long-term outcomes, prospective validation, and performance in other clinical settings were not reported in the source article.
## Clinical Analysis & Structured Key Points
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Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis * Isamu Yamakawa , Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft * E-mail: isamu136@belle.shiga-med.ac.jp Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0005-0968-5880 ](https://orcid.org/0009-0005-0968-5880 "ORCID Registry") ⨯ * Ryota Tamura, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Hiroyuki Yabata, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Takahito Tsukamoto, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Shuhei Kobashi, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Yoshitaka Tamaki, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Nobuhiro Ogawa, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Akihiro Kitamura, Roles Investigation Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan ⨯ * Makoto Urushitani Roles Investigation, Supervision, Writing – review & editing Affiliation Department of Neurology, Shiga University of Medical Science, Otsu, Shiga, Japan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-2773-9836 ](https://orcid.org/0000-0003-2773-9836 "ORCID Registry") ⨯ # Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis * Isamu Yamakawa, * Ryota Tamura, * Hiroyuki Yabata, * Takahito Tsukamoto, * Shuhei Kobashi, * Yoshitaka Tamaki, * Nobuhiro Ogawa, … * Akihiro Kitamura, * Makoto Urushitani ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: September 18, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0358772) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358772) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0358772) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0358772) * [Peer Review](https://journals.plos.org/plosone/article/peerReview?id=10.1371/journal.pone.0358772) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#abstract0) * [Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec006) * [Methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec007) * [Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec013) * [Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec014) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec015) * [Acknowledgments](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#ack) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0358772) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772) ## Abstract ### Background Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Early detection of CO2 retention is crucial for assessing respiratory failure severity and guiding noninvasive positive pressure ventilation (NPPV) management. However, arterial blood gas analysis is invasive and uncomfortable for routine monitoring. ### Objective We investigated whether the serum sodium-chloride difference (Na-Cl value), calculated from routine blood tests, could serve as a screening marker for CO2 retention in ALS patients. ### Methods This retrospective study included 88 ALS patients with 116 paired samples of arterial blood gas and serum electrolyte data. We analyzed correlations between Na-Cl value and blood gas parameters (HCO3−, PCO2), performed receiver operating characteristic (ROC) analysis for detecting CO2 retention (PCO2 ≥ 45 mmHg), and examined relationships with respiratory function (%FVC). ### Results Na-Cl value showed strong correlation with HCO3− (r = 0.78, p 90%. This marker can be calculated from routine blood tests without additional cost, making it suitable for frequent monitoring and reducing the risk of missing intervention timing. ## Figures ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.t002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g003) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g002) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.t002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g003) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358772.g002) **Citation:** Yamakawa I, Tamura R, Yabata H, Tsukamoto T, Kobashi S, Tamaki Y, et al. (2026) Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis. PLoS One 21(9): e0358772. https://doi.org/10.1371/journal.pone.0358772 **Editor:** Tatsuo Shimosawa, International University of Health and Welfare, School of Medicine, JAPAN **Received:** January 16, 2026; **Accepted:** September 4, 2026; **Published:** September 18, 2026 **Copyright:** © 2026 Yamakawa et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All relevant data are within the manuscript and its [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#sec015) files. **Funding:** Intramural Research Grant from Shiga University of Medical Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** The authors have declared that no competing interests exist. ## Introduction Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS), occurring in nearly all patients during the natural course of disease progression. Progressive weakness of the diaphragm and intercostal muscles inevitably leads to restrictive ventilatory impairment, and the majority of patients develop chronic progressive CO2 retention [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref001)–[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref003)]. Critically, hypercapnia often develops insidiously before the emergence of overt respiratory symptoms, making early detection essential [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref004)]. Timely initiation of noninvasive positive pressure ventilation (NPPV) upon detection of respiratory insufficiency has been demonstrated to prolong survival and improve quality of life in ALS patients [[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref005)–[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref007)]. Arterial blood gas (ABG) analysis remains the gold standard for detecting CO2 retention and holds particular importance in ALS monitoring, as its results are not influenced by bulbar involvement and require no active patient collaboration [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref008)]. However, the procedure’s inherently invasive nature and associated patient discomfort severely limit its feasibility for frequent, routine assessment in outpatient clinical practice. While pulmonary function tests such as forced vital capacity and maximal inspiratory pressure are commonly used to monitor respiratory function and serve as reliable indicators of CO2 retention risk in patients without significant bulbar dysfunction, these parameters may show limited utility in predicting hypercapnia in patients with prominent bulbar symptoms who have difficulty forming a tight lip seal around the spirometry tube, thereby preventing accurate measurement [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref009),[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref010)]. Transcutaneous CO2 monitoring and overnight oximetry provide noninvasive alternatives but require specialized equipment and are not routinely available in all clinical settings [[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref011)]. Therefore, a simple, noninvasive, and readily accessible screening marker derived from routine laboratory tests would be of substantial clinical value. In chronic respiratory acidosis due to CO2 retention, compensatory metabolic alkalosis develops through renal mechanisms: the kidneys enhance bicarbonate (HCO3−) reabsorption while increasing chloride (Cl−) excretion to maintain acid-base homeostasis [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref012),[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref013)]. This physiological adaptation results in an elevated serum sodium-chloride difference (Na-Cl value), which can be readily calculated from routine serum chemistry panels. The Na-Cl value has theoretical advantages over isolated chloride measurements, as it accounts for variations in sodium levels and better reflects the degree of metabolic compensation [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref014),[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref015)]. Indeed, in patients with chronic obstructive pulmonary disease (COPD), Alfaro et al. demonstrated that chronic hypercapnia leads to an increase in the strong ion difference (the difference between strong cations [Na + , K + , Ca2+] and strong anions [Cl−, lactate]). This increase in the strong ion difference is primarily due to a decrease in plasma chloride concentration and reflects metabolic compensation for respiratory acidosis [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref016)]. Although previous studies have reported associations between serum chloride levels and both survival and timing of NPPV initiation in ALS patients [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref017)], the specific utility of the Na-Cl value as a quantitative screening marker for CO2 retention has not been systematically evaluated. The objectives of this study were: (i) to investigate the correlation between serum Na-Cl value and PaCO2 in ALS patients; (ii) to establish clinically applicable cutoff values for screening CO2 retention; and (iii) to examine the relationship between Na-Cl value and respiratory function parameters (%FVC) to evaluate its complementary role in respiratory monitoring. We hypothesized that the Na-Cl value would serve as a useful surrogate marker for CO2 retention and could facilitate earlier detection of hypercapnia in routine clinical practice. ## Methods ### Study design and patients This retrospective observational study included patients with ALS who visited the Department of Neurology at Shiga University of Medical Science between July 1, 2016, and October 31, 2025. A total of 107 patients with ALS who underwent both arterial blood gas analysis and routine blood chemistry examination were enrolled in this study, yielding 165 paired samples of blood gas and serum electrolyte data. ### Exclusion criteria To minimize confounding factors that could affect acid-base balance, we excluded patients with the following conditions: (1) Hypokalemia (serum potassium <3.5 mEq/L), which can induce metabolic alkalosis [[18](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref018)]; (2) use of supplemental oxygen at the time of blood sampling; and (3) continuous use of non-invasive positive pressure ventilation (NPPV) throughout the day. Initially, 107 patients with 165 blood samples were identified. After applying the exclusion criteria, 88 patients with 116 samples remained for analysis. Among these 116 samples, 74 had concurrent measurements of %FVC, allowing for analysis of the relationships between respiratory function and blood gas parameters (Na-Cl, HCO3−, and PCO2). ### Laboratory measurements Arterial blood gas analysis was performed to determine pH, PCO2, partial pressure of oxygen (PO2), HCO3−, and base excess. Serum electrolytes including sodium (Na), chloride (Cl), and potassium (K) were measured using standard automated analyzers. The Na-Cl value was calculated by subtracting the chloride concentration from the sodium concentration. Respiratory function was assessed by measuring forced vital capacity (FVC) and expressing it as percent predicted forced vital capacity (%FVC). ### Statistical analysis Continuous variables are presented as mean ± standard deviation or median (range) as appropriate. Categorical variables are expressed as numbers and percentages. Spearman’s correlation coefficients were used to assess relationships between Na-Cl and blood gas parameters (HCO3−, PCO2) as well as respiratory function (%FVC). Comparisons between two groups (CO2 retention defined as PCO2 ≥ 45 mmHg vs. PCO2 < 45 mmHg; respiratory dysfunction as %FVC < 50% vs. %FVC ≥ 50%) were performed using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic performance of Na-Cl for detecting CO2 retention. The area under the curve (AUC), optimal cutoff value (determined by Youden’s index), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Multiple cutoff values (37, 38, 39, and 40 mEq/L) were examined to assess the sensitivity-specificity trade-off. Because multiple samples were obtained from some patients, we performed a sensitivity analysis using only the first sample from each patient (n = 88) to confirm that the results were not influenced by repeated measurements from the same patient. All statistical analyses were performed with EZR (Jichi Medical University, Tochigi, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics [[19](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone.0358772.ref019)]. Statistical significance was set at p < 0.05 (two-tailed). ### Standard protocol approvals, registrations, and patient consents This retrospective study was approved by the Ethics Committee of Shiga University of Medical Science (approval number: R2025-092, approved on November 28, 2025). Medical records and laboratory data were accessed for research purposes from December 28, 2025. During data collection, the authors had access to information that could identify individual participants. Written informed consent was waived by the ethics committee due to the retrospective nature of the study, and an opt-out approach was used to ensure participants’ rights to refuse participation. ## Results A total of 88 ALS patients were enrolled in this study, yielding 116 serum samples for analysis. Detailed patient characteristics are presented in [Table 1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358772#pone-0358772-t001). [![thumbnail](https://journals.pl
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