Graphical abstract
Overview of the study. AECOPD: acute exacerbation in COPD; TR: tricuspid regurgitation; TAPSE: tricuspid annular plane systolic excursion.
Abstract
Background
Elevated pulmonary pressures can lead to right ventricular dysfunction, worsen respiratory status and increase overall morbidity in COPD patients. Yet, little is known about the impact of right-sided pressure changes during acute exacerbation in COPD (AECOPD) on patient outcomes. Our aim was to determine whether pulmonary pressures are elevated during AECOPD compared with the stable phase and to investigate the association between tricuspid regurgitation (TR) gradient during AECOPD and days alive and out of hospital (DAOH).
Methods
This was a multicentre, prospective study of pulmonary pressures changes in patients with AECOPD and stable-phase COPD. Inclusion criteria were diagnosis of COPD and admission with AECOPD. Transthoracic echocardiography (TTE), including TR gradient, tricuspid annular plane systolic excursion (TAPSE), right ventricular diameter and right atrial parameters, was performed during AECOPD and the stable phase.
Results
Of 250 patients, 232 underwent TTE during AECOPD and 107 completed stable-phase follow-up. Reasons for incomplete follow-up included death (n=46), withdrawal (n=23), poor TTE quality (n=21) and unmeasurable TR gradients (n=35). TR gradient increased significantly during AECOPD, with a mean difference of 6.0 (95% CI 2.5–9.6) mmHg, while TAPSE, right ventricular diameter and right atrial size showed no significant changes. Higher TR gradients during AECOPD correlated with lower DAOH.
Conclusion
TR gradients were significantly elevated during AECOPD, suggesting that transient right-sided pressure spikes are associated with COPD exacerbations. However, the direction of this association remains unclear and further research is needed to determine whether right-sided pressure changes contribute to exacerbations or whether exacerbations themselves drive these pressure spikes.
Shareable abstract
Increased tricuspid regurgitation gradient during acute exacerbation in COPD acts as an indirect marker of pulmonary hypertension and is associated with fewer days alive and out of hospital https://bit.ly/445R565
Introduction
COPD is the third leading cause of death globally, significantly straining healthcare systems with frequent encounters and hospitalisations due to acute exacerbation in COPD (AECOPD) [1–3]. COPD not only affects the lungs but also poses serious risks to cardiovascular health, including right-sided heart failure (cor pulmonale) caused by secondary pulmonary hypertension, chronic hypoxia and vascular changes [4–7].
While the link between COPD and cardiovascular complications such as cor pulmonale is well established, the role of fluctuating pulmonary pressures as a potential driver of AECOPD and worse outcomes has received limited attention.
Transthoracic echocardiography (TTE) is a validated tool in assessing right-sided heart function. Key echocardiographic measures used to evaluate the right side of the heart include tricuspid annular plane systolic excursion (TAPSE), which assesses right ventricular systolic function; tricuspid regurgitation (TR) gradient, which approximates pulmonary arterial systolic pressure (PASP) when added to estimated right atrial pressure (RAP); and right ventricular size [8]. These parameters provide valuable insights into the haemodynamic status and functional capacity of the right ventricle, aiding in the detection of pulmonary hypertension and right heart dysfunction [9, 10].
Our primary hypothesis is that pulmonary pressures may exhibit intermittent changes during acute exacerbations, which could precipitate right ventricular strain and contribute to exacerbation severity, ultimately increasing the risk of hospitalisation, length of stay and mortality risk.
This study aims to determine whether pulmonary pressures were elevated during hospitalisation with AECOPD compared with the stable phase, and to explore whether there is an association between TR gradient and days alive and out of hospital (DAOH).
Material and methods
Study design
The COPD Exacerbation and Pulmonary Hypertension (CODEX-P) study was a multicentre prospective paired-measurements study (ClinicalTrials.gov: NCT04538976). The Danish National Ethics Committee and Danish Data Protection Agency gave approval for the study protocol and thereby made the study possible.
“Stable phase” was defined as discharged for at least 1 month following hospitalisation from AECOPD, ensuring that participants were no longer in the acute phase of the AECOPD.
The primary outcome was TR gradient (mmHg).
Secondary outcomes were: DAOH, TAPSE (cm), right ventricular diameter (cm), left ventricular diameter (cm), interventricular septum thickness (cm), ratio of left to right ventricular size, right atrial area (cm2), RAP (mmHg) and PASP (mmHg) [11, 12].
Sample size
To detect a mean difference of 0.5 mmHg in TR gradient with a standard deviation of 1.5 mmHg, using a two-tailed test with 80% power and an α-level of 0.05, we needed at least 71 patients. Due to high risk of death and multiple comorbidities in the selected patient population, we decided to include 250 patients to account for a potential large loss to follow-up.
Study population
A total of 250 consecutive participants hospitalised with AECOPD were enrolled between February 2020 and December 2023 (figure 1). This multicentre study in Denmark was initiated at Copenhagen University Hospital – Gentofte, with active participation from Respiratory Departments at Copenhagen University Hospital – Herlev, Copenhagen University Hospital – Bispebjerg, Copenhagen University Hospital – Hvidovre, Odense University Hospital and Aarhus University Hospital.
FIGURE 1.
Patient flowchart. AECOPD: acute exacerbation in COPD; TTE: transthoracic echocardiography; TR: tricuspid regurgitation.
The inclusion criteria were: 1) COPD verified by a specialist in respiratory medicine based on clinical assessment and spirometry, in accordance with the recommendations from the Global Initiative for Chronic Obstructive Lung Disease [13]; 2) inclusion within the first 72 h of hospitalisation; and 3) ability to provide informed consent.
Exclusion criteria were: 1) diagnosed with idiopathic pulmonary arterial hypertension verified by right heart catheterisation [14]; 2) moderate to severe aortic, mitral, tricuspid or pulmonary valvular heart disease in accordance with international guidelines [15]; 3) history of left-sided heart failure prior to enrolment; 4) males <40 years old; 5) females <55 years old; and 6) non-menopausal females aged >55 years.
Study material: TTE
TTE during exacerbation was performed bedside with a portable Vivid IQ Ultrasound System, M5Sc transducer (GE Healthcare, Horten, Norway). When possible, stable-phase TTE was performed using a Vivid 9 Ultrasound System, 4Vc transducer (GE Healthcare). However, if follow-up at the stable phase needed to take place in the participant's home, a portable Vivid IQ Ultrasound Systems (GE Healthcare) was used. All examinations were performed by trained sonographers according to a predefined protocol. While Vivid IQ and Vivid 9 systems were used at different phases of the study, both devices were from the same manufacturer (GE Healthcare) and were calibrated to ensure consistency in measurements. This setup has been demonstrated to provide reliable results in a previous study conducted by our group, where similar devices and methodology were employed [16]. TAPSE was measured using M-mode in the apical four-chamber projection. Right ventricular diameter was measured from the apical four-chamber view from the base of the ventricle. An optimal view of the tricuspid valve was obtained using the apical four-chamber, parasternal or subcostal views. Colour Doppler imaging was used to visualise the TR jet across the tricuspid valve. RAP was calculated using the inferior vena cava with a variation of ±50% collapse, converted to mmHg. This assessment was feasible during both exacerbation and follow-up in 84 of the 107 patients. PASP was calculated by adding estimated RAP to TR gradient in the 53 patients with measurable values during both time-points. PASP/TAPSE ratio was calculated in these same 53 patients.
Statistical analyses
Descriptive analysis of demographic and clinical characteristics of the study participants at the date of study entry (baseline) was conducted. Categorial variables were presented as count and percentage, while continuous variables were presented as mean and standard deviation or median and interquartile range (IQR).
Main analysis
The paired t-test was used to assess changes in TR gradient between exacerbation TTE and stable-phase TTE. The same method was used for the secondary outcomes. Participants who died or refused follow-up were excluded from the main analyses. A p-value of 0.05 was considered statistically significant.
Days alive and out of hospital
DAOH within the first 30 days following study inclusion were recorded for all patients. Participants were stratified according to DAOH quartiles. TR gradient was analysed in relation to DAOH, with a box plot used to illustrate the distribution across quartiles. The Kruskal–Wallis test was used to assess the relationship between TR gradient and DAOH. A supplementary analysis of the association between initial echo findings (right atrial area and TR gradient) and patient-related outcomes such as length of hospital stay and risk of readmission or death was conducted, and is included in the supplementary material.
Data analyses
All analyses and illustrations were performed using R version 4.3.3 (www.r-project.org) and SAS Enterprise 7.1 Guide (SAS Institute, Cary, NC, USA).
Ethics
This study was approved by the Danish National Ethics Committee (H-18020463) and the Danish Data Protection Agency (p-2020-85). All participants provided written consent.
Results
Of the 250 patients recruited, 232 were initially assessed with TTE during admission for AECOPD; 150 were reassessed at the stable phase to establish a control reference, 107 of these had a measurable TR gradient at baseline and at follow-up. 46 participants died before completing the follow-up, 23 declined to participate, were unreachable or had illness progress and 35 were missing a TR gradient either at baseline or follow-up (figure 1). A total of 107 participants were finally included in the main analysis. A comparison of the baseline characteristics between these two groups revealed no significant differences in age (75±9 years), gender (63% female), smoking status, pulmonary function (forced expiratory volume in 1 s: 40±17% predicted versus 43±18% predicted) or comorbidities such as hypertension (50.4% versus 47.7%) and diabetes mellitus (14.8% versus 17.8%), suggesting that the group with a measurable TR gradient at follow-up was representative of the original cohort. The groups were also similar in terms of body mass index (24±6 versus 24±5 kg·m−2), chest radiography findings during exacerbation and medication use (e.g. long-acting muscarinic antagonists: 84.4% versus 76.6%). However, some differences were observed in clinical findings, such as a higher percentage of participants with kidney failure in the all-patient group (6.0% versus 1.9%) and a slightly higher average oxygen supply (2.5±2.12 versus 2.1±1.41 L·min−1) in the full cohort. A detailed comparison is provided in table 1.
TABLE 1.
Demographics and characteristics of the 250 patients recruited and 107 participants in the main analyses
| All recruited participants (n=250) | Main analysis population (n=107) | |
|---|---|---|
| Female | 157 (63) | 66 (62) |
| Age, years | 75±9 | 75±9 |
| Body mass index, kg·m−2 | 24±6 | 24±5 |
| Smoking status | ||
| Ex-smoker | 151 (61) | 66 (62) |
| Current smokers | 91 (37) | 37 (35) |
| Never-smokers | 6 (2) | 3 (3) |
| Pack-years | 44.2±24.7 | 44.6±27.4 |
| Pulmonary function | ||
| FEV1, L | 0.93±0.45 | 0.96±0.47 |
| FEV1 % pred | 40±17.0 | 43±18.6 |
| FVC, L | 1.95±0.76 | 2.00±0.79 |
| FVC % pred | 66.8±23.2 | 70.23±24.93 |
| FVC/FEV1 | 0.49±0.22 | 0.49±0.29 |
| MRC score | ||
| 1 | 4 (2) | 2 (2) |
| 2 | 31 (15) | 15 (16) |
| 3 | 64 (32) | 27 (29) |
| 4 | 68 (34) | 35 (38) |
| 5 | 36 (18) | 14 (15) |
| CAT score | 23±8 | 21±9 |
| Alcohol use, units·week−1 | 9±20 | 10±24 |
| Clinical findings | ||
| Systolic blood pressure, mmHg | 136±24 | 138±23 |
| Diastolic blood pressure, mmHg | 78±16 | 79±17 |
| Heart rate, beats·min−1 | 99±20 | 100±19 |
| Oxygen saturation with nasal oxygen, % | 91±6 | 91±4 |
| Oxygen supply, L·min−1 (n=134 versus n=60) | 2.5±2.12 | 2.1±1.41 |
| Respiratory rate, breaths·min−1 | 23±6 | 23±5 |
| Chest radiography during exacerbation | ||
| New infiltrate | 80 (32) | 32 (30) |
| Stasis | 26 (10) | 10 (9) |
| Atelectasis | 22 (9) | 4 (4) |
| Pneumothorax | 2 (1) | 0 (0) |
| Pleural effusion | 27 (11) | 7 (7) |
| Tumour | 0 (0) | 0 (0) |
| Other | 139 (56) | 65 (61) |
| Arterial gas analysis | ||
| pH | 7.4±0.21 | 7.4±0.05 |
| PCO2, mmHg | 6.2±1.40 | 6.0±1.41 |
| HCO3− (standard), mmol·L−1 | 27.5±4.54 | 27.1±5.03 |
| Base excess, mmol·L−1 | 4.0±5.58 | 3.4±6.04 |
| PO2, mmHg | 8.6±2.12 | 9.0±2.45 |
| SaO2, % | 9.5±26.30 | 13.3±30.91 |
| Laboratory measurements | ||
| Ca2+, mmol·L−1 | 1.2±0.08 | 1.2±0.05 |
| Lactate, mmol·L−1 | 1.4±0.84 | 1.5±0.96 |
| CRP, μmol·L−1 | 50.4±65.30 | 47.6±65.35 |
| Creatinine, mmol·L−1 | 75.7±48.41 | 71.8±25.12 |
| Carbamide, mg·L−1 | 7.0±5.18 | 6.1±2.63 |
| Non-invasive ventilation during admission | 78 (31) | 26 (25) |
| NT-proBNP | 244±346 | 243±327 |
| Medication | ||
| Long-acting muscarinic antagonists | 211 (84.4) | 82 (76.6) |
| Long-acting β2-agonists | 216 (86.4) | 91 (85.0) |
| Short-acting anticholinergics | 98 (39.2) | 36 (33.6) |
| Short-acting β2-agonists | 199 (79.6) | 84 (78.5) |
| Inhaled corticosteroids | 169 (67.6) | 72 (67.3) |
| Roflumilast | 3 (1.2) | 0 (0.0) |
| Antileukotrienes (montelukast) | 6 (2.4) | 3 (2.8) |
| Theophylline (Theo-dur, Unixan) | 11 (4.4) | 8 (7.5) |
| Prednisolone short term | 201 (80.4) | 89 (83.2) |
| Prednisolone long term | 26 (10.4) | 9 (8.4) |
| Antibiotics use short term | 162 (64.8) | 59 (55.1) |
| Antibiotics use long term | 32 (12.8) | 15 (14.0) |
| Biologics# | 0 (0) | 0 (0) |
| Comorbidities | ||
| Diabetes mellitus | 37 (14.8) | 19 (17.8) |
| Asthma | 53 (21.2) | 23 (21.5) |
| Atopic dermatitis | 31 (12.4) | 8 (7.5) |
| Atrial fibrillation | 47 (19.2) | 18 (16.8) |
| Previous VTE | 18 (7.2) | 8 (7.5) |
| Hypertension | 126 (50.4) | 51 (47.7) |
| Kidney failure | 15 (6.0) | 2 (1.9) |
| Osteoporosis | 74 (29.6) | 24 (22.4) |
| Peripheral vascular disease | 21 (8.4) | 8 (7.5) |
| Cerebrovascular disease | 39 (15.6) | 9 (8.4) |
| Haematological disease | 15 (6.0) | 6 (5.6) |
| Prior myocardial infarct | 15 (6.0) | 4 (3.7) |
| Depression | 38 (15.2) | 17 (15.9) |
| Previous pulmonary malignancy | 18 (7.2) | 4 (3.7) |
| Previous non-pulmonary malignancy¶ | 37 (14.8) | 16 (15.0) |
Data are presented as n (%) or mean±sd. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; MRC: Medical Research Council; CAT: COPD Assessment Test; PCO2: carbon dioxide tension; PO2: oxygen tension; SaO2: arterial oxygen saturation; CRP: C-reactive protein; NT-proBNP: N-terminal pro-brain natriuretic peptide; VTE: venous thromboembolism. #: biologics of types omalizumab (Xolair), mepolizumab (Nucala), reslizumab (Cinqaero), benralizumab (Fasenra), dupilumab (Dupixent) or tezepelumab (Tezspire); ¶: including all malignancies apart from pulmonary malignancies, basal cell carcinoma and squamous cell carcinoma.
Primary analysis
TR gradient was reduced from AECOPD (mean 35.7±16.0 mmHg) to the subsequent stable phase (mean 29.7±16.6 mmHg), with a mean difference of 6.0 (95% CI 2.5–9.6) mmHg (p=0.001) (figure 2). The investigated secondary outcomes (TAPSE, right ventricular diameter, right atrial area, right ventricular function and pulmonary arterial pressure) did not change significantly from AECOPD to the stable phase (table 2).
FIGURE 2.
Box plot of tricuspid regurgitation (TR) gradient during hospitalisation with exacerbation and at follow-up in the stable phase, 30 days after hospital discharge, showing median and interquartile range.
TABLE 2.
Transthoracic echocardiography parameters of cardiac structure and function during acute exacerbation in COPD (AECOPD) and the stable phase
| AECOPD | Stable phase | Mean difference (95% CI) | p-value | |
|---|---|---|---|---|
| RA area, cm2 | 16.5±5.7 | 15.7±5.7 | 0.7 (−0.35–1.77) | 0.19 |
| RV diameter, cm | 3.7±0.7 | 3.5±0.8 | 0.2 (−0.00–0.33) | 0.06 |
| LV diameter, cm | 4.5±0.9 | 4.4±0.9 | 0.0 (−0.10–0.16) | 0.56 |
| Interventricular septum, cm | 1.2±0.3 | 1.2±0.3 | 0.0 (−0.05–0.07) | 0.80 |
| LV/RV ratio | 0.6±0.4 | 0.6±0.4 | 0.0 (−0.06–0.11) | 0.57 |
| TAPSE, cm | 2.1±0.6 | 2.2±0.5 | 0.0 (−0.13–0.12) | 0.85 |
| TR gradient, mmHg | 35.7±16.0 | 29.7±16.6 | 6.0 (2.5–9.6) | 0.001 |
| RAP, mmHg | 6.9±4.2 | 6.0±3.6 | 0.9 (−0.1–1.8) | 0.009 |
| PSAP, mmHg | 41.4±16.6 | 33.9±17.4 | 7.6 (3.4–11.7) | 0.001 |
| PSAP/TAPSE ratio | 2.0±0.9 | 1.6±0.8 | 0.5 (0.2–0.7) | 0.000 |
Data are presented as mean±sd, unless otherwise stated. RA: right atrial; RV: right ventricular; LV: left ventricular; TAPSE: tricuspid annular plane systolic excursion; TR: tricuspid regurgitation; RAP: right atrial pressure; PSAP: pulmonary arterial systolic pressure.
Secondary analyses
Out of the 232 participants with an index TTE, 158 had a measurable TR gradient during AECOPD and available data to measure DAOH; they were included in the secondary analysis (see reasons for exclusion in figure 1). The group with the lowest DAOH exhibited a median (IQR) TR gradient of 41 (29–51) mmHg. The second lowest DAOH group demonstrated a median (IQR) TR gradient of 33 (27–42) mmHg. Conversely, the second highest DAOH group had a median (IQR) TR gradient of 33 (24–43) mmHg, while the highest DAOH group showed a median (IQR) TR gradient of 32 (17–39) mmHg. Figure 3 presents a box plot illustrating the distribution of DAOH across four quartiles (p=0.0394, Kruskal–Wallis test).
FIGURE 3.
Box plot of tricuspid regurgitation (TR) gradient stratified according to quartiles of days alive and out of hospital (DAOH), showing median and interquartile range. First quartile: 0–19 days, fourth quartile: 26–29 days; p=0.0394 (Kruskal–Wallis test).
The supplementary analysis showed a significant association between high values of TR gradient and length of hospital stay but failed to demonstrate significant association to the probability of readmission or death within 6 months. Right atrial area was not significantly associated with length of hospital stay or survival without readmission (see supplementary material).
Discussion
In this multicentre, prospective cohort study with patients hospitalised due to AECOPD, we observed that patients had a significantly higher TR gradient during hospitalisation for severe COPD exacerbation compared with stable-phase COPD 1 month after exacerbation. Additionally, we found that TR gradient during AECOPD correlates with the clinical outcome, summarised as DAOH. However, right-sided heart measurements, including TAPSE, right atrial volume, right ventricular diameter, left ventricular diameter, interventricular septum, and the ratio between left and right ventricles, showed no significant changes from hospitalisation to follow-up, although numerically, most of these pointed in the same direction as the primary analysis, being more abnormal during exacerbation.
Our findings suggest that a higher TR gradient during AECOPD was associated with a longer hospital stay, but it is not possible to determine the direction of causality from our data. Further studies, ideally longitudinal and randomised, are required to explore whether elevated pulmonary pressures contribute to exacerbation development or are simply a consequence of the acute exacerbation phase.
The observed increase in TR gradient during exacerbations could be explained by the pathophysiological mechanisms associated with COPD. AECOPD often leads to worsening in hypoxaemia, airway resistance and lung hyperinflation [1, 4, 13]. Hypoxic pulmonary vasoconstriction and the release of inflammatory mediators can elevate pulmonary vascular resistance, possibly contributing to an increased TR gradient as the right ventricle faces greater resistance in the pulmonary circulation [3, 17].
Our study demonstrated a reduction in TR gradient from the acute phase of AECOPD to the stable phase. However, it is important to note that we did not have a baseline TR gradient measurement prior to exacerbation. As such, while we observe a decrease in TR gradient after recovery, the direction of change during exacerbation itself remains unclear. Future studies with baseline assessments are needed to fully understand the dynamics of TR gradient changes during AECOPD.
It is also important to consider the potential contribution of elevated intrathoracic pressure during AECOPD to the observed increase in pulmonary pressures. Increased airway resistance, hyperinflation and respiratory distress during exacerbations can raise intrathoracic pressure, which may, in turn, impair venous return and elevate right atrial and right ventricular pressures, contributing to pulmonary hypertension. This mechanism could potentially amplify TR gradient observed during exacerbations, although further research is needed to elucidate the precise interactions between intrathoracic pressures and pulmonary haemodynamics during AECOPD.
Limited retrospective studies have explored the impact of pulmonary pressure in patients with COPD [18]. However, our study differs in several important ways. Unlike earlier research, our analysis is based on echocardiographic assessments, allowing for a direct and non-invasive measurement estimation of the pulmonary pressure through TR gradient during AECOPD and follow-up [6, 18]. This provides a real-time evaluation of changes in pulmonary haemodynamics rather than relying solely on registry data or retrospective diagnoses of pulmonary hypertension. Additionally, we included a much larger sample size, whereas former dated multicentre studies investigating pulmonary pressure and treatment in COPD patients have included from 20 to 30 participants only; the larger sample size enhances the statistical power and, together with the multicentre design, further improves the generalisability of our findings compared with the smaller cohorts in previous studies [6, 18–21].
The absence of significant changes in other right-sided heart measurements, such as TAPSE and right ventricular size, suggests that the acute increase in TR gradient during AECOPD may not immediately translate to detectable changes in right ventricular function or remodelling. This phenomenon may be attributed to the transient nature of AECOPD and the ability of the right ventricle to temporarily compensate for increased pressures without significant structural or functional changes [22]. However, chronic exposure to elevated pulmonary pressures, as seen in long-standing COPD, may eventually lead to right ventricular remodelling and dysfunction [22]. Another explanation could be that the pressure increase in the pulmonary circulation has not been sufficient to cause acute right ventricular failure [23].
Notably, our study is unique in specifically examining the impact of AECOPD on the right side of the heart. To the best of our knowledge, no previous research has systematically evaluated these acute haemodynamic changes and their potential implications for right ventricular function during AECOPD. This novel focus enhances our understanding of cardiovascular dynamics during AECOPD and highlights the importance of monitoring pulmonary pressures during these acute episodes, as we demonstrate an important association between a lower TR gradient and increased DAOH. TR gradient seems to be a component to DAOH and may provide valuable insight into the prognosis of AECOPD.
While we observed a significant association between TR gradient and DAOH, it is important to note that this association is correlational rather than causative. Given the observational nature of our study, we cannot definitively determine whether the elevated TR gradient directly influences DAOH or if it is merely a marker of exacerbation severity and underlying pulmonary or cardiovascular dysfunction. Further research is needed to explore whether TR gradient plays a causal role in determining clinical outcomes such as DAOH in patients with COPD.
Strengths and limitations
This study has several strengths. First, participants served as their own controls, which mitigates the risk of confounding by common causes. Second, this represents a sufficiently powered study population, and the largest study investigating right-sided cardiac structure, function and pressure in a well-characterised COPD cohort. Third, participants unable to attend outpatient visits for stable-phase TTE were offered TTE assessment at home, reducing the risk of attrition bias. Fourth, this is a multicentre study involving an unselected COPD population, which enhances the generalisability of the findings.
However, the study also has limitations. First, the TTEs were performed by different sonographers, which may introduce interobserver variability, and the TTEs were performed using bedside TTE or outpatient TTE, both factors could influence the consistency and accuracy of the pulmonary pressures measurements; however, had we not opted to perform bedside TTEs, we would likely have missed the most critically ill patients who were immobile due to their condition during hospitalisation. This consideration was a key factor in the decision to implement bedside TTE. Second, approximately 18% of participants died prior to follow-up, and another 5.6% refused follow-up, allowing for some degree of attrition bias. Assuming the hypothesis of TR gradient elevation (i.e. increased pulmonary arterial pressure) during exacerbation is true and that this would amplify exacerbation severity, this would bias our findings towards the null. Yet, we still found a signal on the primary end-point. While a larger dropout rate than initially anticipated was observed, this was expected, and therefore a larger sample size was included to ensure enough power to support the findings and minimise the risk of random errors. Lastly, the decision to exclude males <40 years of age and females <55 years of age was made to minimise the potential confounding effect of asthma, which is more commonly diagnosed in younger individuals. However, we recognise that this approach may have introduced a sex-based bias, potentially limiting the generalisability of our findings to younger female COPD patients. Future studies should consider evaluating the impact of exacerbations in a broader age range of both male and female COPD patients to better understand the role of sex and age in COPD pathophysiology.
Conclusion
In this multicentre, prospective cohort study of patients hospitalised for AECOPD, we found a substantial and clinically relevant increase in TR gradient during AECOPD compared with the stable phase. Additionally, a higher TR gradient was associated with a longer hospital stay. It should be determined whether higher pulmonary pressures are a driver of exacerbations in COPD or merely a physiological response to the exacerbated state in COPD.
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Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.01508-2025
Ethics statement: This study was approved by the Danish National Ethics Committee (H-18020463) and the Danish Data Protection Agency (P-2020-85). All participants provided written consent.
Conflict of interest: T. Biering-Sørensen reports grants from Sanofi Pasteur and GE Healthcare, payment or honoraria for lectures, presentations, manuscript writing or educational events from Novartis and Sanofi Pasteur, participation on a data safety monitoring board or advisory board with Sanofi Pasteur and Amgen, and a leadership role on the steering committee of the Amgen-financed GALACTIC-HF trial. E. Bendstrup reports fees and grants from Boehringer Ingelheim, Hoffman-La Roche, Galapagos and Bristol Myers Squibb. C.B. Laursen reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi and GSK, and royalties or licences from Munksgaard. J. Carlsen is a member of an advisory board for Merck and has received institutional research grants and institutional speaker fees. The remaining authors have no potential conflicts of interest to disclose.
Support statement: J-U.S. Jensen received a research grant from Novo Nordisk Foundation to conduct the study (grant number NNF20OC0060657). Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
ERJ-00169-2025.Supplement
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