Next Article in Journal
The Relationship between the Burden of Acromegaly, Associated Comorbidities, Complications and Disease Status
Next Article in Special Issue
Intravenous Diuresis in Severe Precapillary Pulmonary-Hypertension-Related Right Heart Failure: Effects on Renal Function and Blood Pressure
Previous Article in Journal
Current and Emerging Markers and Tools Used in the Diagnosis and Management of Chronic Kidney Disease–Mineral and Bone Disorder in Non-Dialysis Adult Patients
Previous Article in Special Issue
Determinants of Severe Nocturnal Hypoxemia in Adults with Chronic Thromboembolic Pulmonary Hypertension and Sleep-Related Breathing Disorders
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Significance of Hypocapnia in the Risk Assessment of Patients with Pulmonary Hypertension

Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
Author to whom correspondence should be addressed.
J. Clin. Med. 2023, 12(19), 6307;
Submission received: 29 August 2023 / Revised: 21 September 2023 / Accepted: 29 September 2023 / Published: 30 September 2023
(This article belongs to the Special Issue Pulmonary Hypertension: Updates in Diagnosis and Management)


Blood gas analysis is part of the diagnostic work−up for pulmonary hypertension (PH). Although some studies have found that the partial pressure of carbon dioxide (PaCO2) is an independent marker of mortality in individuals with pulmonary arterial hypertension (PH Group 1), there is a lack of data regarding the significance of PaCO2 in individuals with different types of PH based on the new 2022 definitions. Therefore, this study analyzed data from 157 individuals who were undergoing PH work−up, including right heart catheterization, using PH definitions from the 2022 European Society of Cardiology/European Respiratory Society guidelines. At diagnosis, N−terminal pro−B−type natriuretic peptide (NT−pro−BNP) levels were significantly higher, but the time−course of NT−pro−BNP levels during treatment was significantly more favorable in individuals with pulmonary arterial hypertension (PH Group 1) who did versus did not have hypocapnia (p = 0.026 and p = 0.017, respectively). These differences based on the presence of hypocapnia were not seen in individuals with PH Groups 2, 3, or 4. In conclusion, using the new definition of PH, hypocapnia may correlate with worse risk stratification at diagnosis in individuals with pulmonary arterial hypertension. However, hypocapnic individuals with pulmonary arterial hypertension may benefit more from disease−specific therapy than those without hypocapnia.

1. Introduction

Pulmonary hypertension (PH) is a complex and serious disease that is commonly seen by physicians across a range of specialties [1]. Furthermore, PH is a global health topic of considerable importance, and current estimates suggest that the worldwide prevalence of pulmonary hypertension is about 1%, with the rate increasing to 10% in people aged > 65 years [2]. Data show higher rates of PH as age increases, and highlight the relevance of an aging population [3]. PH was initially defined as a resting mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg, measured using right heart catheterization in the supine position [4]. Currently, PH is classified into five different groups based on presentation and underlying etiology [5]:
  • PH Group 1—Pulmonary arterial hypertension (PAH);
  • PH Group 2—Pulmonary hypertension associated with left heart disease (PH−LHD);
  • PH Group 3—Pulmonary hypertension associated with lung diseases and/or hypoxia; pulmonary hypertension associated with chronic lung disease (PH−CLD);
  • PH Group 4—Chronic thromboembolic pulmonary hypertension (CTEPH);
  • PH Group 5—Pulmonary hypertension with unclear and/or multifactorial mechanisms.
Significant progress has been made in the detection and treatment of PH over recent years. At the sixth World Symposium on Pulmonary Hypertension in 2018, it was proposed that the mPAP threshold used to define PH should be lowered from ≥25 mmHg to >20 mmHg [6]. The rationale for this change was that the ≥25 mmHg threshold was arbitrary, whereas the revised threshold was based on scientific evidence [7]. The threshold mPAP >20 mmHg has been shown to be significantly associated with increased risks for progression to overt PH, hospitalizations, and mortality [8,9,10]. In the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for pulmonary hypertension [11], the hemodynamic definition of PH has been officially updated using the new mPAP threshold >20 mmHg, but the threshold for pulmonary vascular resistance (PVR) was also updated based on current evidence, and it was stated that the upper limit of normal PVR and the lowest prognostically relevant threshold for PVR is 2 Wood units (WU) [11]. Furthermore, the new ESC/ERS guidelines gave an update of the therapy algorithm focusing on risk stratification and the importance of combination therapies at the right time [11]. These developments highlight the complexity of PH and the fact that its treatment requires a multifaceted, holistic, and multidisciplinary approach [12].
Given that mPAP above the upper limit of normal (>20 mmHg) but below 25 mmHg is associated with increased risk of morbidity and mortality compared with a normal mPAP [8,9,10,13,14,15], early identification of individuals who have mPAP between 20 and 25 mmHg is important to enable close monitoring and timely treatment initiation once clinically indicated, even if PAH−specific medications have not been widely approved for individuals who have a mPAP within this range [14]. However, some subgroups of individuals might be more likely to benefit from early treatment, including those with systemic sclerosis [16] or mutations associated with PH, who may need PAH−specific treatments early in their disease course.
In general, three factors are used for risk stratification in PH: functional class, 6 min walk distance, and B−type natriuretic peptide levels [12,17,18]. But blood gas analysis is also part of the approach to the management of PH, and the results of blood gas analysis are often not normal in these patients [19]. However, severe hypocapnia is more common than severe hypoxemia in patients with PH [20], and significant hypocapnia, defined as an arterial partial pressure of carbon dioxide (PaCO2) of <32 mmHg, has also been shown to be an independent predictor of mortality in individuals with idiopathic pulmonary arterial hypertension (iPAH) [19,21]. It has also been reported that measuring PaCO2 at diagnosis and during follow−up in people with PAH provided independent prognostic information and has the potential to improve current risk assessment strategies [22]. It has been hypothesized that the hypocapnia seen in patients with PH is due to hyperventilation, which is essentially related to increased chemosensitivity as a mechanism to compensate for underlying hypoxemia [19,20]. Nevertheless, there is no evidence to support this hypothesis, and hypocapnia could have other pathophysiological associations with PH, such as relationships with pathological changes in the pulmonary arteries and surrounding tissues. These relationships could have prognostic implications and interact with treatments for PH. In other words, peripheral hypocapnia might be related to pathological abnormalities in the pulmonary vasculature, which would make PaCO2 an important parameter in risk stratification of patients with PH.
Since hypocapnia may have a role to play in the risk stratification of individuals with PH, it is important to understand the relationships between PaCO2 and clinical features for each type of PH, other risk variables, and follow−up patterns during treatment. However, there is currently a lack of data about the significance of PaCO2 in different PH groups and when using the new hemodynamic definition of PH. Therefore, this study evaluated the importance of hypocapnia in individuals with different types of PH who were diagnosed using the new PH definition, and it investigated correlations between hypocapnia and disease course during follow−up.

2. Materials and Methods

2.1. Study Design

This retrospective study was conducted at the University Hospital Aachen of RWTH Aachen University. The study protocol was approved by the local ethics committee (The Independent Ethics Committee at the RWTH Aachen Faculty of Medicine, EK 041/21), and all study procedures were performed in accordance with the ethical standards laid down in the Declaration of Helsinki and its latest revision. Due to the retrospective study design, the requirement for informed consent to participate has been waived by the local ethics committee.

2.2. Participants

All patients admitted to our institution due to undergo right heart catheterization between January 2014 and April 2023 were retrospectively screened for eligibility. Patients were included only if the full results of hemodynamic measurements of right heart catheterization, pulmonary function tests (PFTs) including blood gas analysis (BGA), and an adequate risk stratification including NT−pro−BNP measurement were available. Individuals with confirmed PH based on the new ESC/ERS definition (i.e., mPAP > 20 mmHg and PVR > 2 WU) [11] were included in this study. Those with any type of PH were eligible, but the small number of individuals with Group 5 PH meant that no specific analysis was further performed in this subgroup.

2.3. Data Collection and Assessments

Clinical patient−related data and pulmonary and laboratory parameters were recorded anonymously in statistical spreadsheets. Patient data were retrieved from the patient data management system (CGM MEDICO; CompuGroup Medical Clinical Europe GmbH, Koblenz, Germany). Baseline information recorded included demographic data (i.e., age, height, weight, sex, smoking status), comorbidities, medication, results of right heart catheterization (RHC) (including PH group), PFT results, and BGA from the arterialized earlobe. Samples for arterial BGA were taken from the arterialized earlobes of all patients while breathing room air without supplemental oxygen (ABL 800 flex; Radiometer, Copenhagen, Denmark). In addition, data on the following were recorded at baseline, after 3–6 months, and after 7–12 months: blood results (hemoglobin, N−terminal pro−B−type natriuretic peptide [NT−pro−BNP], creatinine, alanine aminotransferase [ALT]; aspartate amino transaminase [AST]), World Health Organization (WHO) functional classification, and the 6 min walk distance (6MWD). Participants were divided into two groups based on their PaCO2 value from BGA performed at the time of PH diagnosis (<35 mmHg (i.e., hypocapnia) versus ≥35 mmHg (i.e., no hypocapnia)).

2.4. Statistical Analysis

The programming language Python 3.9.13, with statsmodels library version 0.13.2 and SciPy library version 1.9.1, was used for all statistical analysis. Jupyter Notebook Version 6.4.12 was used for data exploration and visualization.
Mean and standard deviation values or frequency distribution were summarized for all the demographic data, and for variables of interest for individuals with or without hypocapnia. A simplified one−year mortality risk assessment tool was used to predict mortality during follow−up (using the variables NT−pro−BNP, 6MWD, and WHO functional classification). Changes in risk assessment variables at each follow−up were calculated and mean and standard deviation values for NT−pro−BNP and the 6MWD were reported. The Kruskal–Wallis test was used to compare changes in NT−pro−BNP over time in individuals with versus without hypocapnia. The Mann–Whitney U−test was used to compare the NT−pro−BNP variable distribution at each timepoint in the subgroups with or without hypocapnia. Differences between the subgroups with and without hypocapnia were examined for each variable of interest at baseline and follow−up using a permutation test (one−tailed) for two independent samples with 10,000 random permutations. Significance level was set at α = 0.05.
The 6MWD is often used for the calculation of cohort sizes in drug trials in patients with PH. Therefore, assuming an effect size of 38.4 m with standard deviation at baseline of 77 m [23], with a one−sided significance of alpha = 0.05 and a power of 0.8, a sample size of 50 patients per group was estimated to be required.
Data were stratified according to the clinical classification of PH from the 2022 ESC/ERS guidelines for the diagnosis and treatment of PH [11]. The family−wise error rate was accounted for using the Holm–Šídák correction method. There was no imputation of missing values.

3. Results

3.1. Participants

A total of 157 individuals were included, of whom 30% had Group 1 PH, 29% had Group 2 PH, 28% had Group 3 PH, and 10% had Group 4 PH; several comorbidities were common (Table 1).

3.2. Hypocapnia and Its Correlates

In total, 62 patients with PH (39%) had hypocapnia at the time of PH diagnosis. Considering the whole cohort, individuals with versus without hypocapnia tended to have higher NT−pro−BNP at baseline (p = 0.089) and at the first follow−up (p = 0.065), but NT−pro−BNP levels were similar in the two subgroups at the second follow−up (Table 2).
In individuals with PAH (PH Group 1), levels of NT−pro−BNP were significantly higher in those with versus without hypocapnia (4529 ± 5646 vs. 1380 ± 1429, p = 0.026) (Table 3). PAH patients with and without hypocapnia were comparable regarding comorbidities, pulmonary functions tests, and hemodynamic variables including cardiac output (CO), mPAP, PVR, and pulmonary arterial wedge pressure (PAWP). There was no significant difference in NT−pro−BNP between those with and without hypocapnia in individuals with PH Group 2 and 3 (p > 0.05). For individuals with PH Group 4, NT−pro−BNP levels were at time of diagnosis slightly, but not significantly, lower in those with versus without hypocapnia (p = 0.21) (Table 3).
Nearly all (46/48) individuals with PAH (PH Group 1) were treated with PAH−specific therapy. This included phosphodiesterase−5 inhibitors (PDE−5i), endothelin receptor antagonists (ERAs), prostanoids, and highly dosed calcium channel blockers (CCBs) by proven reversibility. The reduction in NT−pro−BNP levels during treatment was significantly greater in individuals with versus without hypocapnia (p = 0.017) (Figure 1); there was no difference in the effects of treatment on NT−pro−BNP in the other PH groups (all groups p > 0.05).
At the time of diagnosis, the 6MWD and WHO classification for individuals with PAH (PH Group 1) did not differ significantly between those with or without hypocapnia (p > 0.05).

4. Discussion

The results of this study showed that hypocapnia was associated with higher baseline levels of NT−pro−BNP in individuals with group 1 PH (PAH) diagnosed using the new hemodynamic definition. In addition, individuals with PAH who had hypocapnia showed greater improvements in NT−pro−BNP during PAH−specific treatment than those without hypocapnia.
Baseline PaCO2 at rest has been reported to influence survival in people with idiopathic PAH [21]. Survival rates were lower in those with a baseline PaCO2 (at first diagnosis) of <32 mmHg [21]. However, in that study, hypocapnia at rest and during exercise correlated with low cardiac output, low peak oxygen uptake, and reduced ventilatory efficacy, which may have been confounding factors. In our study, patients with and without hypocapnia were comparable regarding hemodynamic variables including cardiac output, exercise endurance represented in the 6MWD, and the WHO functional class. Despite this, individuals with baseline hypocapnia (PaCO2 <35 mmHg at first diagnosis) had higher NT−pro−BNP levels than those without hypocapnia, except for those with PH Group 4, which represents a specific phenotype of PH (the between−group difference was statistically significant in patients with PH Group 1). People with thromboembolic pulmonary disease (PH Group 4) are often hypocapnic, irrespective of the presence or absence of PH [24]. In this subgroup of people with PH, it could be speculated that hypocapnia indicates respiratory compensation and may be related to better prognosis. Our data support this because individuals with PH Group 4 had lower NT−pro−BNP when they had hypocapnia at baseline.
Regarding patients with PH Group 1 (PAH), we are not aware of any evidence to support the hypothesis of increased respiratory drive (hyperventilation due to an increased chemosensitivity of the respiratory center) to explain hypocapnia. Therefore, other pathophysiological explanations should be considered, which may be supported by our results. An analysis of postcapillary blood gases in a small retrospective study showed that patients with PAH had significantly lower PaCO2 values in blood gases derived from the pulmonary artery than patients with PH in Groups 2–5, and this difference becomes much more pronounced in postcapillary gases (i.e., with more pulmonary passage of blood) [25]. This implies that hypocapnia is a very consistent feature of PH Group 1 (PAH) and could have other explanations, perhaps due to specific features and pathophysiological changes in the pulmonary artery that play a central role in PAH, such as endothelial dysfunction. Our results may support this because patients with hypocapnia had higher NT−pro−BNP levels, which may indicate more severe vasculopathy and greater right ventricular stress. Logically, hypocapnia means that most of the blood passing through the pulmonary circulation is flowing through areas with good ventilation. Increased hyperventilation due to hypoxemia would be an explanation for hypocapnia. There are two other possible explanations: an increased amount of blood passing through the pulmonary vasculature and increased transport of CO2 into the alveoli. An increased amount of blood passing through the pulmonary vasculature could be due to inappropriately increased energy output from the right ventricle to overcome the uncoupling between the right ventricle and pulmonary artery, which could also explain the higher NT−pro−BNP values in patients with hypocapnia. However, endothelial hypertrophy in still open capillaries may facilitate CO2 transport into the alveoli, providing another possible explanation for both hypocapnia and increased stress on the right ventricle resulting in increased NT−pro−BNP levels.
High NT−pro−BNP is known to be a biomarker for severe disease in individuals with PAH [26], and the current findings might indicate that PaCO2 could be a useful marker of risk at first diagnosis in individuals with PAH. However, future studies with larger sample sizes are needed to investigate this further.
Along with the NT−pro−BNP level at diagnosis, levels during follow−up might be just as important in terms of prognosis and allow more precise risk stratification [27]. Elevated plasma NT−pro−BNP levels are associated with increased mortality in patients with PAH, but a fall in NT−pro−BNP levels after therapy is associated with improved survival [28,29]. Interestingly, in our study, individuals with PAH who had hypocapnia at baseline showed greater improvements of NT−pro−BNP during follow−up than similar individuals without hypocapnia. This might simply indicate greater effectiveness of PAH−specific treatment, meaning that, while hypocapnic individuals with PAH might have more severe disease at presentation, this phenotype might actually benefit more from PAH−specific therapy. One can speculate that hypocapnia is associated with more pulmonary circulation changes that may partially improve with therapy, whereas patients without hypocapnia may have more chronic refractory abnormalities. Also, hypocapnic individuals with PAH might be a subgroup who have severe illness but also have better reserves (reflected by the ability to hyperventilate) and may therefore benefit better from PAH−specific treatments. Importantly, PAH patients with and without hypocapnia in our study were comparable regarding some significant confounders (including hemodynamic variables such as cardiac output, exercise endurance (6MWD), and the WHO functional class), which could explain why hypocapnia at baseline had favorable effects at follow−up compared with previous studies.
Independent of underlying disease, the development of PH is associated with clinical deterioration and a substantial increase in mortality risk. Global population ageing and increased life expectancy will increase the number of cases presenting to the medical system with an illness that was, until relatively recently, not widely understood, suspected, diagnosed, and treated. Efforts to refine evaluation algorithms therefore continue, and several authors have suggested that using a combination of parameters may better identify those at high risk of PH, perhaps due to the limitations of currently available tools [30]. Of these parameters, we have shown that PaCO2 can and should be considered in the diagnosis of PH and during patient follow−up. It represents an easy−to−use tool to help identify individuals who should be monitored closely and for whom early therapy should be considered. It will also be interesting to determine whether hypocapnia should be considered in the treatment decision making process for PH (e.g., in those with “borderline” PH).

5. Conclusions

In individuals with PAH diagnosed using the new hemodynamic criteria, hypocapnia was a marker of disease severity at baseline, but was associated with better response to PAH−specific therapy. It therefore seems important to include determination of PaCO2 to detect hypocapnia as part of the assessment and follow−up of individuals with PAH.

Author Contributions

Conceptualization, M.A., M.D. and A.D.; methodology, M.A., M.D. and A.D.; formal analysis, M.A., L.W., M.D. and A.D.; data curation, M.A., L.W.; writing—original draft preparation, M.A.; writing—review and editing, M.A., M.D. and A.D.; project administration, M.D.; All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

The study protocol was approved by the Institutional Review Board for Human Studies at RWTH University, Aachen, Germany and was performed in accordance with the ethical standards laid down in the Declaration of Helsinki.

Informed Consent Statement

Due to the retrospective study design, the requirement for informed consent to participate has been waived by the local ethics committee.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.


The authors gratefully acknowledge the staff of the Clinical Study Center (KKS) of the Clinic for Cardiology, Angiology, and Intensive Care Medicine and the Clinic for Pneumology and Intensive Care Medicine of RWTH Aachen University Hospital for their help and their diligence during the conduct of this study. English language editing assistance was provided by Nicola Ryan, independent medical writer, funded by University Hospital RWTH Aachen, Germany.

Conflicts of Interest

The authors declare no conflict of interest relating to this work.


  1. Maron, B.A. Revised Definition of Pulmonary Hypertension and Approach to Management: A Clinical Primer. J. Am. Heart Assoc. 2023, 12, e029024. [Google Scholar] [CrossRef]
  2. Hoeper, M.M.; Humbert, M.; Souza, R.; Idrees, M.; Kawut, S.M.; Sliwa-Hahnle, K.; Jing, Z.C.; Gibbs, J.S. A global view of pulmonary hypertension. Lancet Respir. Med. 2016, 4, 306–322. [Google Scholar] [CrossRef]
  3. Lam, C.S.; Borlaug, B.A.; Kane, G.C.; Enders, F.T.; Rodeheffer, R.J.; Redfield, M.M. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation 2009, 119, 2663–2670. [Google Scholar] [CrossRef]
  4. Simonneau, G.; Montani, D.; Celermajer, D.S.; Denton, C.P.; Gatzoulis, M.A.; Krowka, M.; Williams, P.G.; Souza, R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J. 2019, 53, 1801913. [Google Scholar] [CrossRef]
  5. Hoeper, M.M.; Ghofrani, H.A.; Grünig, E.; Klose, H.; Olschewski, H.; Rosenkranz, S. Pulmonary Hypertension. Dtsch. Ärzteblatt Int. 2017, 114, 73–84. [Google Scholar] [CrossRef]
  6. Kovacs, G.; Olschewski, H. Debating the new haemodynamic definition of pulmonary hypertension: Much ado about nothing? Eur. Respir. J. 2019, 54, 1901278. [Google Scholar] [CrossRef]
  7. Tanyeri, S.; Akbal, O.Y.; Keskin, B.; Hakgor, A.; Karagoz, A.; Tokgoz, H.C.; Dogan, C.; Bayram, Z.; Kulahcioglu, S.; Erdogan, E.; et al. Impact of the updated hemodynamic definitions on diagnosis rates of pulmonary hypertension. Pulm. Circ. 2020, 10, 2045894020931299. [Google Scholar] [CrossRef]
  8. Maron, B.A.; Hess, E.; Maddox, T.M.; Opotowsky, A.R.; Tedford, R.J.; Lahm, T.; Joynt, K.E.; Kass, D.J.; Stephens, T.; Stanislawski, M.A.; et al. Association of Borderline Pulmonary Hypertension with Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 2016, 133, 1240–1248. [Google Scholar] [CrossRef]
  9. Assad, T.R.; Maron, B.A.; Robbins, I.M.; Xu, M.; Huang, S.; Harrell, F.E.; Farber-Eger, E.H.; Wells, Q.S.; Choudhary, G.; Hemnes, A.R.; et al. Prognostic Effect and Longitudinal Hemodynamic Assessment of Borderline Pulmonary Hypertension. JAMA Cardiol. 2017, 2, 1361–1368. [Google Scholar] [CrossRef]
  10. Kolte, D.; Lakshmanan, S.; Jankowich, M.D.; Brittain, E.L.; Maron, B.A.; Choudhary, G. Mild Pulmonary Hypertension Is Associated With Increased Mortality: A Systematic Review and Meta-Analysis. J. Am. Heart Assoc. 2018, 7, e009729. [Google Scholar] [CrossRef]
  11. Humbert, M.; Kovacs, G.; Hoeper, M.M.; Badagliacca, R.; Berger, R.M.F.; Brida, M.; Carlsen, J.; Coats, A.J.S.; Escribano-Subias, P.; Ferrari, P.; et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Heart J. 2022, 43, 3618–3731. [Google Scholar] [CrossRef]
  12. Rosenkranz, S. 2022 ESC/ERS guidelines on the diagnostics and treatment of pulmonary hypertension: A focussed review. Herz 2023, 48, 23–30. [Google Scholar] [CrossRef]
  13. Douschan, P.; Kovacs, G.; Avian, A.; Foris, V.; Gruber, F.; Olschewski, A.; Olschewski, H. Mild Elevation of Pulmonary Arterial Pressure as a Predictor of Mortality. Am. J. Respir. Crit. Care Med. 2018, 197, 509–516. [Google Scholar] [CrossRef]
  14. Hoeper, M.M.; Humbert, M. The new haemodynamic definition of pulmonary hypertension: Evidence prevails, finally! Eur. Respir. J. 2019, 53, 1900038. [Google Scholar] [CrossRef]
  15. Kovacs, G.; Avian, A.; Tscherner, M.; Foris, V.; Bachmaier, G.; Olschewski, A.; Olschewski, H. Characterization of patients with borderline pulmonary arterial pressure. Chest 2014, 146, 1486–1493. [Google Scholar] [CrossRef]
  16. Coghlan, J.G.; Wolf, M.; Distler, O.; Denton, C.P.; Doelberg, M.; Harutyunova, S.; Marra, A.M.; Benjamin, N.; Fischer, C.; Grünig, E. Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis. Eur. Respir. J. 2018, 51, 1701197. [Google Scholar] [CrossRef]
  17. Boucly, A.; Weatherald, J.; Savale, L.; Jaïs, X.; Cottin, V.; Prevot, G.; Picard, F.; de Groote, P.; Jevnikar, M.; Bergot, E.; et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur. Respir. J. 2017, 50, 1700889. [Google Scholar] [CrossRef]
  18. Hoeper, M.M.; Pittrow, D.; Opitz, C.; Gibbs, J.S.R.; Rosenkranz, S.; Grünig, E.; Olsson, K.M.; Huscher, D. Risk assessment in pulmonary arterial hypertension. Eur. Respir. J. 2018, 51, 1702606. [Google Scholar] [CrossRef]
  19. Rich, S.; Dantzker, D.R.; Ayres, S.M.; Bergofsky, E.H.; Brundage, B.H.; Detre, K.M.; Fishman, A.P.; Goldring, R.M.; Groves, B.M.; Koerner, S.K.; et al. Primary pulmonary hypertension. A national prospective study. Ann. Intern. Med. 1987, 107, 216–223. [Google Scholar] [CrossRef]
  20. Mélot, C.; Naeije, R. Pulmonary vascular diseases. Compr. Physiol. 2011, 1, 593–619. [Google Scholar] [CrossRef]
  21. Hoeper, M.M.; Pletz, M.W.; Golpon, H.; Welte, T. Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension. Eur. Respir. J. 2007, 29, 944–950. [Google Scholar] [CrossRef]
  22. Harbaum, L.; Fuge, J.; Kamp, J.C.; Hennigs, J.K.; Simon, M.; Sinning, C.; Oqueka, T.; Grimminger, J.; Olsson, K.M.; Hoeper, M.M.; et al. Blood carbon dioxide tension and risk in pulmonary arterial hypertension. Int. J. Cardiol. 2020, 318, 131–137. [Google Scholar] [CrossRef]
  23. Moutchia, J.; McClelland, R.L.; Al-Naamani, N.; Appleby, D.H.; Blank, K.; Grinnan, D.; Holmes, J.H.; Mathai, S.C.; Minhas, J.; Ventetuolo, C.E.; et al. Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 2023, 207, 1070–1079. [Google Scholar] [CrossRef]
  24. Weatherald, J.; Boucly, A.; Montani, D.; Jaïs, X.; Savale, L.; Humbert, M.; Sitbon, O.; Garcia, G.; Laveneziana, P. Gas Exchange and Ventilatory Efficiency During Exercise in Pulmonary Vascular Diseases. Arch. Bronconeumol. 2020, 56, 578–585. [Google Scholar] [CrossRef]
  25. Khirfan, G.; Ahmed, M.K.; Faulx, M.D.; Dakkak, W.; Dweik, R.A.; Tonelli, A.R. Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension. Respir. Res. 2019, 20, 6. [Google Scholar] [CrossRef]
  26. Al-Naamani, N.; Palevsky, H.I.; Lederer, D.J.; Horn, E.M.; Mathai, S.C.; Roberts, K.E.; Tracy, R.P.; Hassoun, P.M.; Girgis, R.E.; Shimbo, D.; et al. Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Ann. Am. Thorac. Soc. 2016, 13, 25–30. [Google Scholar] [CrossRef]
  27. Frantz, R.P.; Farber, H.W.; Badesch, D.B.; Elliott, C.G.; Frost, A.E.; McGoon, M.D.; Zhao, C.; Mink, D.R.; Selej, M.; Benza, R.L. Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. Chest 2018, 154, 126–135. [Google Scholar] [CrossRef]
  28. Nagaya, N.; Nishikimi, T.; Uematsu, M.; Satoh, T.; Kyotani, S.; Sakamaki, F.; Kakishita, M.; Fukushima, K.; Okano, Y.; Nakanishi, N.; et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000, 102, 865–870. [Google Scholar] [CrossRef]
  29. Casserly, B.; Klinger, J.R. Brain natriuretic peptide in pulmonary arterial hypertension: Biomarker and potential therapeutic agent. Drug Des. Devel. Ther. 2009, 3, 269–287. [Google Scholar] [CrossRef]
  30. Valerio, C.J.; Schreiber, B.E.; Handler, C.E.; Denton, C.P.; Coghlan, J.G. Borderline mean pulmonary artery pressure in patients with systemic sclerosis: Transpulmonary gradient predicts risk of developing pulmonary hypertension. Arthritis Rheum. 2013, 65, 1074–1084. [Google Scholar] [CrossRef]
Figure 1. Change in N−terminal pro−B−type natriuretic peptide (NT−pro−BNP) values over time in individuals with pulmonary artery hypertension (PH Group 1) in individuals with versus without hypocapnia (PCO2 <35 vs. ≥35 mmHg); shaded areas on either side of the lines indicate the confidence intervals.
Figure 1. Change in N−terminal pro−B−type natriuretic peptide (NT−pro−BNP) values over time in individuals with pulmonary artery hypertension (PH Group 1) in individuals with versus without hypocapnia (PCO2 <35 vs. ≥35 mmHg); shaded areas on either side of the lines indicate the confidence intervals.
Jcm 12 06307 g001
Table 1. Participant characteristics at baseline.
Table 1. Participant characteristics at baseline.
CharacteristicsParticipants (n = 157)
Age, years70 ± 11
Male sex, n (%)65 (41)
Smoking status
Smoker, n (%)23 (15)
Ex−smoker, n (%)55 (35)
Smoking pack−years40
Pulmonary hypertension group 1, n (%)
148 (30)
245 (29)
344 (28)
416 (10)
Comorbidities, n (%)
Heart failure with reduced ejection fraction5 (3)
Heart failure with mid−range ejection fraction21 (13)
Heart failure with preserved ejection fraction106 (68)
Arterial hypertension113 (72)
Atrial fibrillation50 (32)
Coronary heart disease42 (27)
Valvular cardiomyopathy8 (5)
Chronic obstructive pulmonary disease54 (35)
Asthma13 (8)
Interstitial lung disease32 (20)
Diabetes mellitus55 (35)
Systemic sclerosis13 (8)
Connective tissue disease15 (10)
Obstructive sleep apnea syndrome30 (19)
Pulmonary embolism52 (33)
History of lung cancer6 (4)
Dyslipidemia77 (49)
Obesity52 (33)
Chronic renal insufficiency53 (34)
Medications n (%)
β−blockers73 (47)
Angiotensin converting enzyme inhibitors50 (32)
Angiotensin receptor blockers33 (21)
Calcium channel blockers28 (18)
Thiazide diuretics36 (23)
Mineralocorticoid receptor antagonist44 (28)
Long−acting β−agonists64 (41)
Long−acting muscarinic antagonists62 (40)
Inhaled corticosteroids37 (24)
Phosphodiesterase−5 inhibitor61 (39)
Riociguat14 (9)
Endothelin receptor antagonists37 (24)
Prostanoids5 (3)
Highly dosed calcium channel blocker by proven reversibility4 (3)
Laboratory tests
Hemoglobin, g/dL13.27 ± 2.08
Creatinine, mg/dL1.20 ± 0.72
Aspartate aminotransferase, U/L29.4 ± 14.0
Alanine aminotransferase, U/L26.7 ± 21.2
NT−pro−BNP, pg/mL3428.8 ± 5079.7
Values are mean ± standard deviation or number of participants (%). 1 Based on the current European Society of Cardiology/European Respiratory Society guidelines. NT−pro−BNP, N−terminal pro−B−type natriuretic peptide.
Table 2. Characteristics of participants with versus without hypocapnia for individuals with pulmonary hypertension of all groups.
Table 2. Characteristics of participants with versus without hypocapnia for individuals with pulmonary hypertension of all groups.
CharacteristicsPulmonary Hypertension
With Hypocapnia
(n = 62)
Without Hypocapnia
(n = 95)
Age, years69.7 ± 9.570.2 ± 12.10.998
Hemoglobin, g/dL13.31 ± 2.313.29 ± 1.950.998
Creatinine, mg/dL1.23 ± 0.571.19 ± 0.810.994
HFpEF, n (%)37 (24)67 (43)
Arterial hypertension, n (%)39 (25)71 (45)
Atrial fibrillation, n (%)14 (9)35 (22)
Coronary heart disease, n (%)21 (13)19 (12)
COPD, n (%)17 (11)36 (23)
Interstitial lung disease, n (%)11 (7)17 (11)
Diabetes mellitus, n (%)20 (13)33 (21)
Connective tissue disease, n (%)4 (3)11 (7)
Systemic sclerosis, n (%)9 (6)4 (3)
Dyslipidemia, n (%)31 (20)44 (28)
Chronic renal insufficiency, n (%)20 (123)33 (21)
At diagnosis/baseline
Right atrial pressure9.5 ± 4.710.3 ± 4.90.145
Cardiac index2.5 ± 0.72.7 ± 1.00.096
Stroke volume index0.034 ± 0.0110.036 ± 0.0160.217
Venous oxygen saturation62.6 ± 10.360.4 ± 9.00.12
WHO functional class3.1 ± 0.72.9 ± 0.70.188
NT−pro−BNP4252.6 ± 5404.72926.7 ± 4845.60.089
At 3− to 6−month follow−up
WHO functional class2.4 ± 0.82.4 ± 0.80.444
NT−pro−BNP3342.3 ± 10,333.91173.1 ± 1729.70.065
At 7− to 12−month follow−up
WHO functional class2.4 ± 1.02.5 ± 0.90.512
NT−pro−BNP1427.0 ± 1975.71634.8 ± 2571.90.374
Values are mean ± standard deviation or number of participants (%). COPD, chronic obstructive pulmonary disease; HFpEF, heart failure with preserved ejection fraction; NT−pro−BNP, N−terminal pro−B−type natriuretic peptide; WHO, World Health Organization.
Table 3. NT−pro−BNP values of participants with versus without hypocapnia for individuals within each pulmonary hypertension group.
Table 3. NT−pro−BNP values of participants with versus without hypocapnia for individuals within each pulmonary hypertension group.
NT−Pro−BNPPulmonary Artery Hypertension
With HypocapniaWithout Hypocapniap-Value
At diagnosis/baseline
PH Group 14529 ± 56461380 ± 14290.026
PH Group 25711 ± 63633220 ± 43930.31
PH Group 33617 ± 54331917 ± 34420.31
PH Group 41433 ± 155012,821 ± 11,0930.21
At 3− to 6−month follow−up
PH Group 14452 ± 13,623827 ± 9630.33
PH Group 23802 ± 38192545 ± 37230.51
PH Group 31591 ± 1506847 ± 9530.36
PH Group 4873 ± 8242750 ± 35240.37
At 7− to 12−month follow−up
PH Group 1832 ± 8102026 ± 34280.23
PH Group 23795 ± 44262865 ± 15790.64
PH Group 33288 ± 585645 ± 7860.07
PH Group 4601 ± 2501806 ± 3400.18
NT−pro−BNP, N−terminal pro−B−type natriuretic peptide.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Aetou, M.; Wahab, L.; Dreher, M.; Daher, A. Significance of Hypocapnia in the Risk Assessment of Patients with Pulmonary Hypertension. J. Clin. Med. 2023, 12, 6307.

AMA Style

Aetou M, Wahab L, Dreher M, Daher A. Significance of Hypocapnia in the Risk Assessment of Patients with Pulmonary Hypertension. Journal of Clinical Medicine. 2023; 12(19):6307.

Chicago/Turabian Style

Aetou, Maria, Lora Wahab, Michael Dreher, and Ayham Daher. 2023. "Significance of Hypocapnia in the Risk Assessment of Patients with Pulmonary Hypertension" Journal of Clinical Medicine 12, no. 19: 6307.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop