Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension

doi:10.1016/j.ijcard.2013.10.012

International Journal of Cardiology

Volume 169, Issue 6, 30 November 2013, Pages 445-448

https://doi.org/10.1016/j.ijcard.2013.10.012 Get rights and content

Abstract

Background

Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.

Methods

Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.

Results

Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p < 0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r = 0.61), pulmonary artery pressure (r = 0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r = 0.52), and peak VO₂ (r = − 0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p < 0.001).

Conclusions

Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO₂, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.

Introduction

Cardiopulmonary exercise testing (CPET) allows for reproducible assessment of exercise capacity and provides valuable information on gas exchange, ventilation, and oxygen consumption. As a result, exercise testing has been widely used as a marker for functional capacity, disease severity, prognosis, and treatment response in a variety of cardiovascular conditions including pediatric pulmonary hypertension (PH) [1], [2]. Peak oxygen consumption (peak VO₂) has historically been the most frequently analyzed cardiopulmonary exercise test parameter and correlates well with cardiopulmonary disease severity and survival [3]. Peak VO₂, however, can be particularly difficult to obtain in a pediatric population and may be underestimated because of a lack of patient motivation. Ventilatory efficiency slope (VE/VCO₂ slope), defined as the relationship between minute ventilation and carbon dioxide production obtained during exercise testing, has recently demonstrated prognostic value in adults with heart failure [4], [5], [6] and PH [3], [7], [8], [9]. VE/VCO₂ slope can be derived from submaximal exercise testing and is therefore independent of patient motivation. There are no studies, however, that have described the relationship between VE/VCO₂ slope and disease severity in pediatric PH populations. The present study sought to evaluate the utility of VE/VCO₂ slope in relation to functional capacity, outcomes, and disease severity in pediatric patients with PH.

Section snippets

Methods

This study was reviewed and approved by the Colorado Multiple Institutional Review Board (protocol #12-1570) prior to initiation. At our institution, patients older than 7–8 years of age with PH routinely undergo cardiopulmonary exercise testing, typically on an annual basis. Younger children do not routinely undergo CPET due to an inability to reliably perform the testing or to tolerate metabolic data collection. We retrospectively reviewed all seventy six children and young adults with a

Statistical methods

Means tables were computed for each group of paired data and the differences between the group means were tested with paired T-tests. The effect of WHO functional class on VE/VCO₂ slope was investigated in PH patients, excluding patients with a WHO functional class of 4, due to the small number of patients in this group. A linear regression model treated WHO functional class as a continuous variable and determined the effect of an incremental increase in WHO functional class on expected VE/VCO₂

Results

PH and CON subjects are described in Table 1. There were 258 maximal CPET performed by 76 patients with PH. Most patients had WHO group 1 PH, which was idiopathic in 24, familial in 4, associated with congenital heart disease in 32 (secondary to a septal defect in 13, Eisenmenger physiology in 4, pulmonary vein stenosis in 2, absent pulmonary artery in 3, coarctation in 4, patent ductus arteriousus in 2, d-transposition in 2, single ventricle physiology in1 and heterotaxy with polysplenia in

Discussion

Pulmonary hypertension is an important cause of morbidity and mortality in children. For idiopathic PH and PH secondary to congenital heart disease, the point prevalence in a cohort in the Netherlands was 15.6 and 4.4 cases per million children [15]. Though somewhat dependent on the etiology, survival in pediatric patients with PH has improved significantly with the addition of medical therapy and overall survival in children at 1, 3, and 5 years is comparable to adults [16], [17]. With these

Conclusions

The present study demonstrates for the first time that VE/VCO₂ slope correlates well with invasive and noninvasive markers of disease severity including peak VO₂, WHO functional class, pulmonary vascular resistance, and pulmonary artery pressures in pediatric patients with PH. Given that CPET is noninvasive and reproducible, combined with the ability to measure VE/VCO₂ slope from submaximal exercise, VE/VCO₂ slope may prove useful as a clinical measure of disease severity and marker for

Christopher M. Rausch, MD: has made substantial contributions to conception and design, acquisition, and interpretation of data; has drafted the submitted article; and has provided final approval of the version to be published. Dr. Rausch had full access to all the data in the study and takes responsibility for all aspects of the reliability and freedom from bias of the data presented and the discussed interpretation.

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Cited by (26)

Pediatric Pulmonary Arterial Hypertension
2020, Pediatric Clinics of North America
Citation Excerpt :
Specifically, CPET can determine peak oxygen consumption (Vo2max), ventilatory efficiency (Ve/Vco2), the anaerobic threshold, and oxygen consumption at the anaerobic threshold (Vo2 at AT).33,34 Ve/Vco2 is significantly higher in patients with PAH than in healthy controls and increases on average by 7.2 for each increase in WHO functional class.35 Among adult patients, measurement of brain natriuretic peptide (BNP) level is a useful tool to trend severity of disease, therapy response, and mortality risk.36
Ventilatory Efficiency Identifies Patients Prone to Hypoxemia During One-Lung Ventilation
2019, Journal of Cardiothoracic and Vascular Anesthesia
Citation Excerpt :
VE/VCO2 is increased with increased ventilation (low PaCO2) and/or increased ventilation of dead space (VD /VT [ie, ventilation-perfusion mismatch]).13 Moreover, the VE/VCO2 slope has been shown to be increased in patients with PAH.22 Both ventilation-perfusion mismatch14 and PAH may cause hypoxemia.15
One-lung ventilation (OLV) may be complicated by hypoxemia. Ventilatory efficiency, defined as the ratio of minute ventilation to carbon dioxide output (V_E/VCO₂), is increased with ventilation/perfusion mismatch and pulmonary artery hypertension, both of which may be associated with hypoxemia. Hence, the authors hypothesized increased V_E/VCO₂ will predict hypoxemia during OLV.
Prospective observational study.
Single-center, university, tertiary care hospital.
The study comprised 50 consecutive lung resection candidates.
All patients underwent cardiopulmonary exercise testing before surgery. Patients who required inspired oxygen fraction (F_iO₂) ≥0.7 to maintain arterial oxygen (O₂) saturation >90% after 30 minutes of OLV were considered to be hypoxemic. The Student t or Mann-Whitney U test were used for comparison of patients who became hypoxemic and those who did not. Multiple regression analysis adjusted for age, sex, and body mass index was used to evaluate which parameters were associated with the V_E/VCO₂ slope. Data are summarized as mean ± standard deviation.
Twenty-four patients (48%) developed hypoxemia. There was no significant difference in age, sex, and body mass index between hypoxemic and nonhypoxemic patients. However, patients with hypoxemia had a significantly higher V_E/VCO₂ slope (30 ± 5 v 27 ± 4; p = 0.04) with exercise and lower partial pressure of oxygen/F_iO₂ (129 ± 92 v 168 ± 88; p = 0.01), higher mean positive end-expiratory pressure (6.6 ± 1.5 v 5.6 ± 0.9 cmH₂O; p = 0.02), and lower mean pulse oximetry O₂ saturation/F_iO₂ index (127 ± 20 v 174 ± 17; p < 0.01) during OLV. Multiple regression showed V_E/VCO₂ to be independently associated with the mean pulse oximetry O₂ saturation/F_iO₂ index (b = –0.28; F = 3.1; p = 0.05).
An increased V_E/VCO₂ slope may predict hypoxemia development in patients who undergo OLV.
Pulmonary Limitations in Heart Failure
2019, Clinics in Chest Medicine
Citation Excerpt :
The prevalence of this comorbidity is high in patients with HFrEF (up to 72%)102 and in patients with HFpEF (up to 83%).103 PAH is associated with exercise dyspnea, increased VE/Vco2 slope, and poor prognosis.104 Physiologically, VE/Vco2 decreases and PETco2 increases from rest to peak exercise.105
Diagnostics in Children and Adolescents with Suspected or Confirmed Pulmonary Hypertension
2017, Paediatric Respiratory Reviews
Citation Excerpt :
In older children, a routine CPET should be considered for an objective evaluation of their exercise capacity, as this provides a greater range of physiologic variables [69], such as peakVO2, peak blood pressure and ventilatory equivalent of CO2, which is predictive of survival and hospital admission. VE/VCO2-slope, which can be derived from submaximal exercise testing, has been shown to correlate with disease severity and mortality in children with PH [70]. Particularly for patients with a relatively preserved exercise tolerance, CPET may give a more accurate reflection of their actual exercise capacity [69].
We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH.
Pulmonary Hypertension in Children
2016, Cardiology Clinics
Citation Excerpt :
Cardiopulmonary exercise testing in children older than 7 years of age is useful to determine peak oxygen consumption, ventilator efficiency (VE) slope (Ve/VCO2), and anaerobic threshold.71,72 VE slope is significantly higher in patients with PAH, with an estimated increase of 7.2 for each increase in WHO class, and correlates strongly with invasive measures of disease severity, including PAP, PVRI, and outcome.73 In adults, brain natriuretic peptide (BNP) is a useful tool to assess mortality risk, progression of the disease, and response to therapy.74
Oxygen upta ke effi ciency slope, an objecti ve submaxi mal parameter in evaluating exercise capacity in pulmonary thromboembolism
2016, American Journal of the Medical Sciences
Citation Excerpt :
The fact that the intercepts of OUES versus peak VO2 are so close to zero both in patients with PE and in normal subjects in this study (Figure 3) strongly suggests that OUES and peak VO2 measure similar phenomenon. Christopher׳s study also demonstrated that OUES correlates well with invasive and noninvasive markers of disease severity including peak VO2, WHO functional class and catheterization by performing CPET in 76 patients with pulmonary hypertension.30 Our previous study done by Shi X et al. and Liu H et al. also showed that OUES was markedly lower in patients with pulmonary hypertension than in normal subjects and significantly related to peakVO2.31,32
The objective of this article was to study the oxygen uptake efficiency, an index of cardiopulmonary functional reserve that can be based upon a submaximal exercise effort, in pulmonary thromboembolism (PE) by performing the cardiopulmonary exercise test.
The cardiopulmonary exercise test with simultaneous respiratory gas measurement was performed in 50 patients with PE and in 50 healthy individuals. All subjects also underwent the pulmonary function test. Peak oxygen uptake (peak VO₂), anaerobic threshold (AT), oxygen uptake efficiency slope (OUES), oxygen uptake efficiency plateau (OUEP) and oxygen uptake efficiency at anaerobic threshold (OUE@AT), were determined.
(1) Compared with the controls, the patients with PE had lower peak VO₂, AT, OUES, OUEP and OUE@AT (P < 0.001). (2) In patients with PE, oxygen uptake efficiency (OUE = VO₂/VE) at warming up, AT and peak exercise but not rest, were indicated statistically lower than the controls. The OUE in normal subjects increased as unloaded exercise began, and then increased further to OUEP just before the AT. Thereafter, the OUE decreased gradually until peak exercise. In contrast, the rate of changes of the OUE in patients with PE was relatively mild during exercise. (3) Of all the submaximal parameters, OUES correlated best with peak VO₂ (r = 0.712, P < 0.001).
The oxygen uptake efficiency of patients with PE was lower than the controls during exercise. The OUE is an objective measure of cardiopulmonary reserve that does not require a maximal exercise effort. Therefore, OUES could be helpful to assess exercise performance in patients with PE who are unable to perform a maximal exercise test in early recovery stage.

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Amy L. Taylor, PhD: has made substantial contributions to conception and design and interpretation of data; has revised the submitted article critically for important intellectual content; and has provided final approval of the version to be published.

Hayley Ross, MD: has made substantial contributions to acquisition and interpretation of data; has revised the submitted article critically for important intellectual content; and has provided final approval of the version to be published.

Stefan H. Sillau, MS: has made substantial contributions to the analysis and interpretation of data; has revised the submitted article critically for important intellectual content; and has provided final approval of the version to be published.

D. Dunbar Ivy, MD: has made substantial contributions to conception and design and interpretation of data; has revised the submitted article critically for important intellectual content; and has provided final approval of the version to be published. Dr. Ivy assumes full responsibility for the integrity of the submission as a whole, from inception to published article.

^☆: Disclosures: None.

^☆☆: Funding information: Amy Taylor received a Biostatistics award in partial support of this project. This was supported by NIH/NCATS Colorado CTSI Grant Number UL1 TR000154. This study was also supported by R01 HL114753, P50 HL084923, UL1 RR02578, and the Jayden DeLuca Foundation. Contents are the authors' sole responsibility and do not necessarily represent official NIH views.

^★: Notation of prior abstract publication/presentation: This abstract was presented as a poster at the American Thoracic Society meeting in San Francisco, CA. This meeting was May 18–23, 2012.

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Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension☆,☆☆,★

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Statistical methods

Results

Discussion

Conclusions

Am J Cardiol

Chest

Am Heart J

Am Heart J

Am J Cardiol

Chest

Chest

J Am Coll Cardiol

Am J Cardiol

Am Heart J

Am J Cardiol

Chest

J Am Coll Cardiol

J Heart Lung Transplant