Lung function and gas exchange in Eisenmenger syndrome and their impact on exercise capacity and survival

doi:10.1016/j.ijcard.2013.11.047

International Journal of Cardiology

Volume 171, Issue 1, 15 January 2014, Pages 73-77

https://doi.org/10.1016/j.ijcard.2013.11.047 Get rights and content

Abstract

Background

Eisenmenger physiology may contribute to abnormal pulmonary mechanics and gas exchange and thus impaired functional capacity. We explored the relationship between lung function and gas exchange parameters with exercise capacity and survival.

Methods

Stable adult patients with Eisenmenger syndrome (N = 32) were prospectively studied using spirometry, lung volumes, diffusion capacity, and blood gas analysis, as well as same day measurement of 6-minute walk distance and cardiopulmonary maximal treadmill exercise. Patients were followed prospectively to determine survival (7.4 ± 0.5 years). Abnormalities were identified and appropriate comparisons were made between affected and unaffected individuals between respiratory mechanics, exercise function, and survival.

Results

Obstruction (FEV₁/FVC ratio < 0.70) was found in 13 patients (41%), who were older but not otherwise different. Restriction was uncommon. Diffusion transfer coefficient, which was < 80% in half the patients, correlated with exercise duration (r = 0.542, P = 0.005), and was worse in non-survivors (N = 6). Nearly all patients had a compensated respiratory alkalosis (PaCO₂ 32 ± 4.4 mm Hg). PaCO₂ was less reduced in older patients (r = 0.438, P = 0.022), and correlated independently with exercise duration (R = − 0.463, P = 0.03), yet PaO₂, not PaCO₂, was associated with survival.

Conclusions

Eisenmenger patients show evidence of obstructive lung disease, diffusion abnormalities, and hypocapnia; likely from hyperventilation. Understanding expected lung mechanics and gas exchange may facilitate more appropriate clinical management.

Introduction

Eisenmenger syndrome (ES) develops from an unrestricted communication between the systemic and pulmonary circulation (such as a large intracardiac shunt or patent ductus arteriosus), which if unrepaired progresses to elevated pulmonary artery pressures, pulmonary vascular disease, and reversal of shunt leading to hypoxemia, cyanosis, and erythrocytosis [1]. There are several potential mechanisms for abnormal lung mechanics, in addition to the pulmonary vascular changes themselves. These include scoliosis, present in roughly 10% of patients with congenital heart disease, or significant enlargement of the heart and/or central pulmonary arteries that may have space-occupying effects [2]. Patients with ES have very impaired exertional capacity, the lowest of any group of patients with congenital heart disease [3]. It is unknown to what extent, if any, lung function contributes to this physical limitation.

Our institution recently published a large series evaluating restrictive lung disease in congenital heart patients including ES [4]. However, patients with obstructive lung disease were excluded, and the study did not focus on the unique aspects of ES. While there are few studies describing pulmonary function parameters such as obstructive lung disease in other groups with pulmonary arterial hypertension (PAH) [5], [6], [7], including a small number of patients with Eisenmenger physiology [8], none, to our knowledge, have specifically explored lung mechanics specifically in ES, nor their potential impact on exercise capacity or survival. Therefore, in this prospective study we aim to describe all aspects of lung mechanics and gas exchange specifically in a stable cohort of ES patients, and explore their prognostic value.

Section snippets

Methods

Consecutive adults with ES seen at our tertiary referral center between 2003 and 2005 were prospectively invited to participate and all patients gave informed consent. The study received approval from the Ethics Committee at the Royal Brompton Hospital. Inclusion criteria were known ES syndrome patients with a resting oxygen saturation < 92%, seen as stable outpatients. Inpatients or those with acute illness such as bronchitis/pneumonia or recent large-volume hemoptysis were initially excluded,

Results

Thirty-two patients were enrolled in the study, of which 23 (71%) were female. Mean age was 41 ± 14 years, resting oxygen saturation 81 ± 7%, hemoglobin 20 ± 3 g/dl, all consistent with confirmed Eisenmenger physiology. Three patients had atrial septal defects, 20 had ventricular septal defects, and 9 had a patent ductus arteriosus as their main source of shunting. Not all patients could or wished to complete all aspects of the study. Six patients had some form of developmental delay. Boxplots for

Discussion

Our study describes expected respiratory mechanics in adult patients specifically with ES. Generally, obstructive lung disease was fairly common, with physiologic evidence of air trapping. We found reduced diffusion capacity as in other etiologies of PAH [8], [15]. While some studies of pulmonary mechanics in patients with PAH of other etiologies showed them to be largely normal [5], [6], subsequent work found an association between obstructive pulmonary disease [7], [16] and peripheral airway

Conclusions

Obstructive lung disease and diffusion abnormalities are common findings in ES, though not universal. Patients exhibit a compensated respiratory alkalosis with PaCO₂ levels that seem to rise with age. Patients with lower PaCO₂ have a better exercise capacity. The data pose several questions about the nature of CO₂ clearance and its relation to functional capacity in ES.

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Patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) have reduced exercise capacity. Recently, the 1-minute sit-to-stand test (1MSTST), which measures the number of repetitions from sitting to standing position in 1 minute, has been proposed as an alternative test to the 6-minute walking test (6MWT). The aim of our study was to assess the safety and results of the 1MSTST in comparison to the 6MWT in patients with PAH-CHD.
Consecutive adult patients with PAH-CHD underwent the 6MWT and the 1MSTST on the same day. The 6-minute walking distance in meters and the number of repetitions on the 1MSTST were measured. Heart rate, peripheral oxygen saturations, Borg dyspnea score, and lower limb fatigue were recorded before and immediately after testing. Correlations between both tests and clinical, laboratory, and imaging parameters were statistically analyzed.
The study included 40 patients (50% female, mean age 43 ± 15 years), of whom 29 (72%) had Eisenmenger syndrome and 14 (35%) had Down syndrome. The number of 1MSTST repetitions correlated significantly with 6MWT distance (r = 0.807, p = 0.000). There were no adverse events, and the 1MSTST results correlated with the WHO functional class. Heart rate increase and oxygen desaturation after both tests correlated significantly, but less desaturation was observed after 1MSTST.
Our study showed that the 1MSTST is a safe and easily applicable test in adult patients with PAH-CHD, including patients with Down syndrome. The results of the 1MSTST correlate significantly with the 6MWT, providing an alternative tool for exercise capacity assessment in patients with PAH-CHD.
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Citation Excerpt :
These symptoms may be difficult to explain based on cardiac dysfunction and hemodynamic abnormalities alone. Restrictive lung ventilation disorder has previously been identified as a contributing factor [1–3], and respiratory muscle weakness in particular has been hypothesized to play a role in reduced exercise capacity in a subgroup of ACHD patients [1,4]. However, quantitative studies on this issue have not been published to date.
In adult patients with congenital heart disease (ACHD), both underlying disease and lung restriction contribute to exercise intolerance. In ACHD the yet incompletely understood mechanism underlying restricted ventilation may be inspiratory muscle weakness. Therefore, this study comprehensively evaluated inspiratory muscle function in ACHD and associations with systemic inflammation and the clinical severity of exercise intolerance.
30 ACHD patients (21 men, 35 ± 12 years) and 30 healthy controls matched for age, gender and body mass index underwent spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound. Six-minute walking distance (6MWD) and New York Heart Association functional class were used to quantify exercise intolerance. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assays.
ACHD patients showed lower forced vital capacity (FVC), and maximum inspiratory (PImax) and expiratory (PEmax) pressures compared with controls (all p < 0.05). On ultrasound, ACHD patients showed a lower diaphragm thickening ratio (2.3 ± 0.5 vs. 2.8 ± 0.9, p < 0.01) and lower diaphragm excursion velocity during a voluntary sniff maneuver (5.7 ± 2.2 vs. 7.6 ± 2.0 cm/s, p < 0.01). Respiratory parameters, such as FVC (r = 0.53; p < 0.01) and PImax (r = 0.43; p = 0.02), correlated with 6MWD. Furthermore, amino terminal pro B-type natriuretic peptide levels were inversely correlated with FVC (r = −0.54; p < 0.01). Circulating pro-inflammatory cytokines were markedly increased, and IL-6 was correlated with 6MWD, dyspnea, and biomarkers of heart, lung and inspiratory muscle function (all p < 0.05).
Our findings show that diaphragm dysfunction is present in ACHD and relates to restrictive ventilation disorder and exercise intolerance, possibly mediated by increased IL-6 levels.
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Citation Excerpt :
Broberg et al. described diffusion abnormalities and hypocapnia in patients with ES. These alterations are likely to evolve with hyperventilation during exercise [31]. In the present study, when patients received oxygen supplementation, the breathing rate was lower in post exercise.
Eisenmenger syndrome (ES) precipitates the extreme manifestation of pulmonary hypertension, which leads to severe functional limitation and poor quality of life. The propose of the current study was: 1) examined the acute effects of 40% oxygen supplementation during the 6-minute walk test (6MWT); and 2) evaluate the relation between exercise capacity and clinical cardiac parameters in patients with ES.
Thirty subjects were prospectively included; all were submitted to a 6MWT with compressed air and with 40% of oxygen. Heart rate recovery at the first minute (HRR₁) and perceived effort Borg scale for dyspnea and lower limb fatigue were recorded in both tests scenarios.
The 6MWT distance was modestly, negatively associated with pulmonary vascular resistance (PVR) [r = 0.46, p = 0.02]. Patients improved 6MWT distance (p < 0.001) and exhibited a faster HRR₁ (p < 0.001) with 40% supplemental oxygen compared to compressed air. With 40% supplemental oxygen, subjects revealed lower dyspnea and lower limb fatigue compared to 6MWT without oxygen supplementation (p < 0.001). The amount of change in the 6MWT distance from air to oxygen was moderate, positively associated with tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RV_FAC) [r = 0.50, p = 0.03; r = 0.64, p < 0.001, respectively].
Acute 40% oxygen supplementation in patients with Eisenmenger syndrome led to an improvement in 6MWT distance, faster HRR₁ and lower dyspnea and lower limb fatigue perception. Moreover, functional capacity was positively associated with right ventricular parameters.

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¹: Each author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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Lung function and gas exchange in Eisenmenger syndrome and their impact on exercise capacity and survival

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Conclusions

Am J Med

Respir Med

J Am Coll Cardiol

J Am Coll Cardiol

Respir Med

Chest

J Am Coll Cardiol

Respir Physiol Neurobiol

The Eisenmenger syndrome in adults

Ann Intern Med

Massive pulmonary artery thrombosis with haemoptysis in adults with Eisenmenger's syndrome: a clinical dilemma

Heart

Comprehensive use of cardiopulmonary exercise testing identifies adults with congenital heart disease at increased mortality risk in the medium term

Circulation

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival

Circulation