This retrospective analysis assessed whether the serum Na–Cl value, calculated from routine electrolyte testing, can screen for chronic CO2 retention in patients with amyotrophic lateral sclerosis (ALS). The study used paired arterial blood gas (ABG) and serum electrolyte results collected during outpatient care and proposes clinically applicable cutoff values to guide confirmatory ABG testing.
Respiratory failure is the principal cause of death in ALS. Progressive respiratory muscle weakness leads to restrictive ventilatory impairment and often to chronic CO2 retention. Hypercapnia can develop gradually and precede clinical symptoms, so timely detection is important to guide initiation of noninvasive positive pressure ventilation (NPPV), which may prolong survival and improve quality of life.
ABG analysis remains the reference standard for detecting elevated PCO2, but its invasiveness and patient discomfort limit frequent use. Alternative noninvasive monitoring methods exist but have equipment and availability constraints. Physiologically, chronic respiratory acidosis triggers renal metabolic compensation: increased bicarbonate (HCO3–) reabsorption and increased chloride excretion. This shifts the serum electrolyte balance and increases the Na–Cl value, a parameter that is readily derived from standard serum chemistry panels and may reflect the degree of metabolic compensation for hypercapnia.
This single-center retrospective observational study included ALS patients seen between July 1, 2016, and October 31, 2025. From an initial cohort of 107 patients with 165 paired ABG and serum electrolyte samples, the analysis excluded samples from patients with hypokalemia (serum potassium < 3.5 mEq/L), those using supplemental oxygen at sampling, and those on continuous daytime NPPV. After exclusion, 88 patients contributing 116 paired samples comprised the primary dataset. Among these, 74 samples had concurrent %FVC measurements.
Arterial blood gas analysis measured pH, PCO2, PO2, HCO3–, and base excess. Serum electrolytes—sodium (Na), chloride (Cl), and potassium (K)—were measured using automated analyzers. The Na–Cl value was calculated as serum Na minus serum Cl. Respiratory function was assessed as percent predicted forced vital capacity (%FVC).
Continuous data were summarized as mean ± standard deviation or median (range). Correlations used Spearman or Pearson coefficients as appropriate. Group comparisons used the Mann–Whitney U test. Receiver operating characteristic (ROC) analysis evaluated Na–Cl performance for detecting CO2 retention, defined as PCO2 ≥ 45 mmHg based on guideline thresholds that inform NPPV consideration. Multiple Na–Cl cutoffs (37–40 mEq/L) were examined to balance sensitivity and specificity. A sensitivity analysis used only the first sample from each patient (n = 88) to test robustness. Statistical significance was set at p < 0.05.
Across 116 samples, Na–Cl correlated strongly with HCO3– (r = 0.78, p < 0.001) and with PCO2 (r = 0.71, p < 0.001). Scatter-plot regression demonstrated consistent positive relationships, supporting the physiological expectation that renal compensation for chronic hypercapnia increases bicarbonate and alters chloride, thereby increasing Na–Cl.
For detecting CO2 retention (PCO2 ≥ 45 mmHg), ROC analysis identified an optimal screening cutoff of Na–Cl ≥ 37 mEq/L by Youden’s index. At this threshold, sensitivity was 85.11%, specificity 69.57%, positive predictive value (PPV) 65.57%, negative predictive value (NPV) 87.27%, and area under the curve (AUC) 0.842. A higher cutoff, Na–Cl ≥ 39 mEq/L, prioritized specificity (92.75%) while reducing sensitivity (46.81%), yielding PPV 81.47% and NPV 71.91%.
The authors propose a stepwise clinical approach: use Na–Cl ≥ 37 mEq/L as a screening threshold to prompt confirmatory ABG, and consider Na–Cl ≥ 39 mEq/L when high specificity is required to reduce false positives.
Among 74 samples with concurrent %FVC, there were significant negative correlations between %FVC and PCO2 (r = −0.403, p = 0.0004), HCO3– (r = −0.362, p = 0.0015), and Na–Cl (r = −0.295, p = 0.0106). Patients with %FVC < 50% had significantly higher Na–Cl, PCO2, and HCO3– compared with those with %FVC ≥ 50% (all p < 0.05). These results suggest Na–Cl may reflect declining respiratory function and complement spirometric monitoring.
Na–Cl values did not differ between spinal-onset and bulbar-onset samples, indicating the marker reflects respiratory status independently of ALS onset site.
Analyses restricted to the first sample from each patient (n = 88) produced comparable or stronger correlations: Na–Cl vs HCO3– r = 0.802 and Na–Cl vs PCO2 r = 0.736. ROC performance improved slightly (AUC 0.868); Na–Cl ≥ 37 mEq/L showed sensitivity 88.2%, specificity 68.5%, NPV 90.2%, and Na–Cl ≥ 39 mEq/L showed specificity 94.4% with sensitivity 52.9%. These findings indicate repeated measures did not bias the overall conclusions.
Because serum Na and Cl are routinely measured in standard chemistry panels in many clinical settings, the Na–Cl value can be calculated without additional tests or cost and permits frequent, noninvasive screening for CO2 retention. The proposed practical thresholds are:
This approach may reduce missed opportunities to detect insidious hypercapnia, support timely initiation of NPPV, and be applicable regardless of ALS onset type.
This is a retrospective, single-center study. The source reports patient selection, exclusions, correlation and ROC results, and a sensitivity analysis, but does not provide prospective outcome data, external validation, or long-term follow-up on whether using Na–Cl–guided screening alters clinical outcomes. Information on performance in populations beyond the study sample or in other laboratory assay contexts was not reported. Further prospective validation is warranted before broad clinical adoption.