# Accuracy of Measured Venous Bicarbonate to Detect Nocturnal Hypoventilation in Neuromuscular Adults

Marjolaine Georges, Claudio Rabec, Marie Labruyère, Yoann Chiche, Serge L.

Aho, Agnès Jacquin-Piques, Déborah Schenesse, Pierre Mouillot, Philippe

Bonniaud

► To cite this version:

Marjolaine Georges, Claudio Rabec, Marie Labruyère, Yoann Chiche, Serge L. Aho, et al. *Accuracy of Measured Venous Bicarbonate to Detect Nocturnal Hypoventilation in Neuromuscular Adults*. *Archivos de Bronconeumología*, 2025, 10.1016/j.arbres.2025.07.006. [hal-05201922](https://hal.inrae.fr/hal-05201922v1)

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Scientific Letter

Accuracy of Measured Venous Bicarbonate to
Detect Nocturnal Hypoventilation in
Neuromuscular Adults

To the Editor,

In neuromuscular diseases (NMD), respiratory failure due to progressive diaphragmatic weakness is a leading cause of morbidity and mortality [1]. Nocturnal hypoventilation often precedes daytime respiratory failure, making early detection crucial. Non-invasive ventilation (NIV) is the gold standard treatment, improving symptoms, quality of life, and survival [2]. Early initiation of NIV, as soon as nocturnal hypoventilation is identified, may prevent acute hypercapnic episodes [3].

Although partial arterial pressure of carbon dioxide (PaCO₂) >45 mmHg in arterial blood gases (ABG) is the current gold standard to define hypoventilation, ABG provide only a momentary snapshot and may not reflect nocturnal PaCO₂ trends. Nocturnal pulse oximetry (NPO) is easy to use but may underestimate hypoventilation [4]. Transcutaneous CO₂ monitoring (TcPCO₂) is more accurate for detecting nocturnal hypercapnia [5] but remains underused due to cost, limited availability, technical failure, and interpretation variability.

Recent data suggest that a measured venous total CO₂ concentration (MVtCO₂) >27 mmol/L could serve as a surrogate marker of nocturnal hypoventilation in NMD [6]. Since nocturnal hypercapnia may cause residual metabolic alkalosis during the day, elevated MVtCO₂ may help detect early ventilatory failure in NMD.

This monocentric retrospective study aimed to evaluate the predictive value of MVtCO₂ for identifying nocturnal or diurnal hypoventilation and determining the need for NIV in a cohort of NMD patients with suspected diaphragmatic weakness.

Adult NMD patients referred for elective transcutaneous oxicapnography between January 2016 and May 2019 due to suspected respiratory involvement were included. This suspicion was based on symptoms suggestive of hypoventilation (daytime sleepiness, poor sleep quality, morning headache), or diaphragmatic dysfunction (dyspnoea, orthopnoea, paradoxical breathing, use of accessory neck muscles), or abnormal pulmonary function tests, including vital capacity <80% of predicted value, maximal inspiratory pressure <60% of predicted value, or a >15% decrease in supine vital capacity [7,8]. Oxicapnography was recorded on average for 8 h using a SenTec 92 device (Therwil, Switzerland). The combined Severinghaus-type TcPCO₂ electrode and SpO₂ sensor was calibrated according to the manufacturer's instructions before and after each measurement to adjust for calibration drift. The sensor was applied to the patient's earlobe at the usual bedtime and left for a mean recording time of 8 h. Recording was performed at home

or during an in-hospital sleep study. Stored data were analysed with a dedicated software (V Stats, Therwil, Switzerland). TcPCO₂ trends were visually inspected by the same investigator (YC) to exclude any artefacts (absurd values or drift).

Oxicapnography was not performed in NMD patients (i) on oxygen therapy, (ii) pregnant, (iii) who had experienced a respiratory exacerbation within the previous two months, or (iv) with moderate-to-severe sleep apnea confirmed by poly(somno)graphy. ABG were taken at rest in room air. A venous blood sample was collected in the afternoon (4–6 h before oxicapnography's beginning) to measure MVtCO₂. According to the results of this exhaustive assessment, NIV was initiated according to current guidelines [2,9,10]. Our study was approved by the French Respiratory Society's ethics board (CEPRO 2020-009), and all participants provided written informed consent.

Diurnal hypoventilation was defined by PaCO₂ >45 mmHg. Nocturnal hypoventilation was assessed using three established TcPCO₂-based criteria: (i) definition 1: mean TcPCO₂ >50 mmHg [11,12], (ii) definition 2: peak TcPCO₂ ≥49 mmHg [3], and (iii) definition 3: TcPCO₂ >55 mmHg for ≥10 min or increase in TcCO₂ ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 min [13].

Continuous variables are reported as medians with interquartile ranges (IQR) and compared using the Student t-test or Wilcoxon-Mann-Whitney test. Categorical variables were expressed as numbers (%) and compared using the Chi-squared or Fisher's exact test. A p-value <0.05 was considered statistically significant. Diagnostic performance was assessed through sensitivity, specificity, predictive values, and likelihood ratios. We used Youden's J statistic (sensitivity + specificity - 1) [14] to identify the optimal diagnostic threshold, as it is unaffected by disease prevalence, a key consideration in our tertiary single-centre study. This index balances sensitivity and specificity, enabling us to choose a cut-point that maximizes sensitivity and negative predictive value. Prioritizing these metrics helps minimize false negatives (i.e., NMD patients with nocturnal hypoventilation with an unidentified need for NIV) and ensures early detection of NMD patients with nocturnal hypoventilation who may otherwise experience delayed NIV initiation or worsening respiratory function, posing a serious health risk. Fagan's nomogram was applied to estimate post-test probabilities [15]. Predictive performance of MVtCO₂ was evaluated using the area under the receiver operating characteristic curve (AUC-ROC) [16], with 95% confidence intervals (CI) derived by bootstrap. All analyses were conducted using R version 4.3.1.

Sixty-two patients (35 men, 58.5 [44.7–67] years old, 22.4 [20.2–28.3] kg/m²) met inclusion criteria and 12 additional recordings were excluded due to technical issues. The most common NMD were amyotrophic lateral sclerosis (ALS) (47%), unilateral
<table><caption>**Table 1**
Diagnostic performance of MVtCO₂ = 27 mmol/L for neuromuscular patients' screening.</caption><thead><tr><th></th><th>Sensitivity</th><th>Specificity</th><th>Positive predictive value</th><th>Negative predictive value</th><th>Positive likelihood ratio</th><th>Negative likelihood ratio</th></tr></thead><tbody><tr><td><strong>Nocturnal hypoventilation</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Definition 1</td><td>0.86 [0.67–0.99]</td><td>0.78 [0.66–0.90]</td><td>0.55 [0.34–0.70]</td><td>0.95 [0.88–0.99]</td><td>3.94 [2.19–7.10]</td><td>0.18 [0.05–0.67]</td></tr><tr><td>Definition 2</td><td>0.56 [0.39–0.73]</td><td>0.86 [0.73–0.99]</td><td>0.82 [0.66–0.98]</td><td>0.63 [0.78–0.79]</td><td>3.94 [1.51–10.26]</td><td>0.51 [0.34–0.78]</td></tr><tr><td>Definition 3</td><td>0.71 [0.52–0.91]</td><td>0.82 [0.70–0.94]</td><td>0.68 [0.49–0.88]</td><td>0.84 [0.73–0.96]</td><td>3.98 [1.93–8.20]</td><td>0.35 [0.17–0.70]</td></tr><tr><td><strong>Diurnal hypoventilation</strong></td><td>0.79 [0.57–0.99]</td><td>0.76 [0.64–0.88]</td><td>0.50 [0.29–0.71]</td><td>0.92 [0.84–0.99]</td><td>3.29 [1.83–5.89]</td><td>0.28 [0.10–0.78]</td></tr><tr><td><strong>NIV initiation</strong></td><td>0.53 [0.37–0.68]</td><td>0.95 [0.85–0.99]</td><td>0.96 [0.87–0.99]</td><td>0.50 [0.34–0.66]</td><td>10.5 [1.5–72.5]</td><td>0.50 [0.36–0.70]</td></tr></tbody></table>

Abbreviation. NIV: non-invasive ventilation.

Criteria for nocturnal hypoventilation are:

- Definition 1: mean TcPCO₂ >50 mmHg

- Definition 2: peak TcPCO₂ ≥49 mmHg

- Definition 3: TcPCO₂ >55 mmHg for ≥10 min or increase in TcCO₂ ≥10 mmHg (in comparison to an awake supine value) to a value exceeding 50 mmHg for ≥10 min

Diurnal hypoventilation is defined by PaCO₂ >45 mmHg.

Data are presented as medians [first-third quartile].

diaphragmatic palsy (19%) and myotonic dystrophy type 1 (8%) with restrictive pattern (median FVC: 71 [48–82]% of predicted value) and diaphragmatic weakness (SNIP: 39 [30.5–48.7]% of predicted value) (see supplemental data for detailed population characteristics). Overall, 68% of patients (n = 42) initiated non-invasive ventilation (NIV). These patients had significantly higher PaCO₂ (40.1 [37.9–43.5] vs. 43.9 [39.5–49.3] mmHg) and nocturnal peak TcPCO₂ levels (49.9 [46.4–52.4] vs. 54.9 [47.9–61.1] mmHg), as well as elevated MVtCO₂ (25 [24.7–27.2] vs. 28 [26–30] mmol/L), all *p* < 0.01. Prevalence of hypoventilation varied depending on the definition used: for nocturnal hypoventilation, 22% with definition 1, 52% with definition 2, 34% with definition 3 and 22% for diurnal hypoventilation.

Table 1 shows performance metrics for MVtCO₂. The optimal threshold identified for predicting NIV need were 27 mmol/L. Post-test probabilities derived from Fagan's nomogram indicated a 92% likelihood of requiring NIV when MVtCO₂ exceeded 27 mmol/L. Conversely, values below this threshold were associated with only a 33% probability of NIV need.

MVtCO₂ demonstrated strong predictive performance for diurnal (AUC 0.876 [95% CI: 0.783–0.968]) and nocturnal hypoventila-

tion (definition 1: AUC 0.852 [95% CI: 0.723–0.980]; definition 2: AUC 0.786 [95% CI: 0.675–0.898]; definition 3: AUC 0.835 [95% CI: 0.783–0.968]) and NIV initiation (AUC 0.781 [95% CI: 0.669–0.893]) (see supplemental material for figure).

Our findings support the use of MVtCO₂ as a practical screening biomarker for hypoventilation in NMD patients. A threshold of >27 mmol/L was significantly associated with both nocturnal and diurnal hypoventilation and the need for NIV. MVtCO₂ offers key advantages: it is non-invasive, more accessible, especially in low-income countries, and feasible even in severely disabled NMD patients. Venous sampling can also be performed at home, improving its potential as a widespread screening tool.

This threshold aligns with values proposed for OHS [8,17]. Due to the slower renal elimination of bicarbonate compared to CO₂ clearance by the lungs, MVtCO₂ serve as a surrogate marker of nocturnal CO₂ retention. Residual daytime metabolic alkalosis indicates prior nocturnal hypoventilation [8]. Early identification and management of hypoventilation is crucial to prevent acute hypercapnic failure, particularly in patients with Duchenne muscular dystrophy, myotonic dystrophy type 1, and ALS [3,17,18]. Nonetheless, interpretation of elevated MVtCO₂ must consider potential confounders.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Algorithm including measured venous total carbon dioxide concentration (MVtCO₂) to screen respiratory involvement in neuromuscular patients. Abbreviations: MVtCO₂: measured venous total carbon dioxide concentration; NIV: non-invasive ventilation; PFT: pulmonary function test. Rythm for respiratory monitoring depends on the aetiology of NMD.</figcaption></figure>
Several medications (e.g., antihypertensives, antidiabetics, proton pump inhibitors) may alter acid-base balance [19,20]. Only four patients were on such medications (3 for Duchenne cardiomyopathy), suggesting limited interference in our cohort. Most included patients, even ALS patients, were relatively young and had fewer comorbidities. Methodological issues also exist as CO₂ dissolved in serum is volatile, leading to artificially low MVtCO₂ values [21]. These potential discrepancies must be acknowledged when using bicarbonate thresholds.

The main limitation of our retrospective and monocentric study was the modest sample size, although reflective of the rarity of NMD. Our cohort was drawn from a tertiary center, with possible referral of more severe respiratory involvement explaining the fact that two-thirds of our patients required NIV. However, it is the same proportion that is observed in the studies by Orlikowski et al. [22] and Ward et al. [3] where respectively 42 and 90% of NMD patients with a peak $TcPCO_2 \ge 49$ mmHg require NIV after 2 years of follow-up. This limits the generalizability of predictive values, which are prevalence-dependent [23]. For this reason, we emphasized likelihood ratios, which are more robust [24].

Moreover, because no consensus exists on the ideal strategy for defining nocturnal hypoventilation, we employed various recommended definitions to allow comparison with prior studies [3,12,13,21]. Transcutaneous capnography is increasingly regarded as the gold standard to assess nocturnal hypoventilation. However, despite recent technical improvements, $TcPCO_2$ accuracy remains strongly dependent of appropriate handling and knowledge of the equipment and procedure and $TcPCO_2$ interpretation mostly relies on expert opinions. Few data in NMD comparing $TcPCO_2$ ability to predict relevant clinical outcomes suggest that the cut-off value (peak $TcPCO_2 \ge 49$ mmHg) should be preferred. This reinforces the need for alternatives easier to interpret.

In conclusion, $MVtCO_2 > 27$ mmol/L is a low-cost, accessible and easy marker that may help identify NMD patients at risk for hypoventilation and guide early NIV initiation. It could be incorporated into clinical screening algorithm (Fig. 1), but prospective multicentric validation is essential.

### CRediT authorship contribution statement

Data acquisition: YC, MG, CR, PM, DSC

Data analysis: YC, MG, CR, SA, ML

Manuscript drafting: MG, CR

Manuscript revision, editing and approval: all authors

### Declaration of generative AI and AI-assisted technologies in the writing process

None declared.

### Funding

None declared.

### Conflict of interest

MG declares personal fees from ResMed for participating to advisory board and from Asten Santé, Elivie SAS and Oxylis for speaking, lecture fees and travel reimbursement, all outside of this work.

CR declares personal fees from ResMed and Philips for participating to advisory board and from Asten Santé, Elivie SAS, ASDIA, Oxylis and ANTADIR for speaking, lecture fees and travel reimbursement, all outside of this work.

Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgement

The authors wish to thank Suzanne Rankin from the Dijon University Hospital for proofreading the manuscript and making the necessary corrections.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found in the online version available at https://doi.org/10.1016/j.arbres.2025.07.006.

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Marjolaine Georges<sup>a,*</sup>, Claudio Rabec<sup>b</sup>, Marie Labruyère<sup>c</sup>, Yoann Chiche<sup>d</sup>, Serge L. Aho<sup>e</sup>, Agnès Jacquin-Piques<sup>f</sup>, Déborah Schenesse<sup>b</sup>, Pierre Mouillot<sup>b</sup>, Philippe Bonniaud<sup>g</sup>

<sup>a</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Institut Universitaire du Poumon, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, L'institut Agro UMR CNRS 6265 INRAE 1324, Dijon, France

<sup>b</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Institut Universitaire du Poumon, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Dijon, France

<sup>c</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Service de Médecine Intensive et Réanimation, Dijon, France

<sup>d</sup> CH Mâcon, Service de Pneumologie, Mâcon

<sup>e</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Service d'Epidémiologie et d'Hygiène Hospitalières, Dijon, France

<sup>f</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Service de Neurologie – Neurophysiologie clinique, Centre de Compétence Maladies Rares – Maladies Neuromusculaires, L'institut Agro UMR CNRS 6265 INRAE 1324, Dijon, France

<sup>g</sup> Université Bourgogne Europe, CHU Dijon Bourgogne, Institut Universitaire du Poumon, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Inserm 1231 CTM, Dijon, France

<footnote>*Corresponding author.</footnote>

<footnote>E-mail address: marjolaine.georges@chu-dijon.fr (M. Georges).</footnote>