Methods
A retrospective chart review was done on patients with pectus referred
to CCHMC who completed a symptom questionnaire recorded at the time of
initial assessment and performed a cardiopulmonary exercise test (CPET),
pulmonary function tests (PFT), and chest magnetic resonance imaging
(cMRI). Patients with incomplete records and evidence of submaximal
effort on CPET were excluded from the analysis. Testing on all patients
was completed using the same equipment and methodology thereby allowing
uniform comparison of data.
All CPET were performed on a cycle ergometer (Ergoline ViaSprint 150p;
Germany) using a 15-25 Watt/ min ramping protocol under the supervision
of clinical exercise physiologists. Continuous breath-by-breath
measurements (Vmax Encore metabolic cart, Vyaire Medical; Yorba Linda,
CA), pulse oximetry (Masimo Corp; Irvine, CA), and a 12-lead
electrocardiogram (Cardiosoft, GE Healthcare; Milwaukee, WI) were
recorded throughout exercise., Tests were determined maximal effort if
meeting 2 of the 3 following criteria:1) peak heart rate ≥85%
age-predicted maximum (220-age); 2) respiratory exchange ratio ≥ 1.1; or
peak minute ventilation was >50% of FEV1x40. Endpoints
were compared to published normative standards14,15.
Tests were classified as normal aerobic fitness if the percent predicted
peak oxygen uptake (VO2) was 80% or greater of
predicted. For tests with reduced aerobic fitness, gradation of severity
was based on the VO2 percent of predicted and was
defined as mild: (70-79%), moderate (60-69%), and moderate-severe
(50-59%). CPET were classified as demonstrating pulmonary limitation if
the VO2 was < 80% predicted and the ratio of
tidal volume (Vt) during exercise divided by resting inspiratory
capacity (IC) was greater than 85% or if the breathing reserve (BR)
during exercise was either less than 12 liters or 12% of predicted.
Hyperventilation was defined by a VO2 >
80% predicted with the ventilatory equivalent for oxygen
(VE/VO2) greater than 40, a respiratory rate (RR)
greater than 60 breaths/minute, and end-tidal carbon dioxide
(PETCO2) less than 34 mmHg. Tachypnea was defined as a
RR >60 breaths/minute in the absence of a low
VO2 or criteria for hyperventilation.
Spirometry and plethysmography were performed on one of three
flow-sensing spirometers and whole-body boxes (Vyaire, Yorba Linda, CA)
with calibration performed prior to testing daily per American Thoracic
Society (ATS) recommendations16,17. All measurements
were body temperature, pressure and saturation corrected. Only
pre-bronchodilator maneuvers were evaluated. The respiratory therapists
supervising tests evaluated if each maneuver met all ATS criteria for
acceptability and testing was discontinued once the patient produced
efforts which met acceptable criteria that were also repeatable. These
tests were classified as acceptable and repeatable. Spirometry which did
not reach end of test criteria but had satisfactory start and no
artifacts with repeatable FEV1 were classified as
usable. Testing was discontinued if the subject was unable to produce
any acceptable, usable, or repeatable efforts after 8 attempts. PFTs
were classified as uninterpretable if both spirometry and
plethysmography were unacceptable or not repeatable, or if spirometry
was usable but plethysmography was not acceptable or repeatable.
Spirometry endpoints included the FVC, FEV1,
FEV1/FVC and the forced expiratory flow at 25-75% of
the FVC (FEF25-75). Each flow-volume curve was inspected
for evidence of coving, defined as concavity on expiratory limb of the
flow-volume curve. Each volume time curve assessed for volume plateau,
defined as volume change of < 25 ml/s16.
Plethysmography endpoints included the total lung capacity (TLC), the
residual volume (RV) and the RV/TLC.
PFTs were interpreted as normal if both spirometry and plethysmography
endpoints fell within the 95% confidence intervals (95% CI) of
published normative standards18-20. Tests were
interpreted as obstructive if the FEV1/FVC was reduced
and one of the following: reduced FEF25-75, coving,
failure to plateau, or an elevated RV/TLC16. Tests
were interpreted as restrictive if both the TLC and FVC were reduced and
the FEV1/FVC normal. Tests were interpreted as a
non-specific ventilatory limitation (NSVL) if the FVC was reduced but
the TLC fell within the 95% CI21. Tests with both
obstructive and restrictive patterns were categorized as mixed.
Gradation of the severity for obstructive defects was based on the
FEV1 percent of predicted and gradation for the severity
of restrictive and NSVL defects was based on the FVC as follows: mild
> 70% up to 95% ci; moderate 60-69%; moderate-severe
50-59%22.
The cMRI was performed on a 1.5 T scanner (Philips Ingenia; Best,
Netherlands) for assessment of the Haller and correction index. The
Haller index is a ratio of the transverse diameter of the chest to the
anterior-posterior diameter, measured from the inner aspect of the
sternum to the anterior aspect of the vertebral body at the level of
greatest sternal depression23. The correction index
was evaluated according to previously described
methods24.
Categorical data are presented as frequencies and percentages, while
continuous variables are reported as mean (standard deviation) or median
(first and third quartiles). ANOVA, chi-square, and Kruskal-Wallis tests
were used to evaluate demographic and clinical characteristics by PFT
classification. Pearson correlation coefficients were calculated for the
relationships between correction index and PFT/CPET metrics.
Multivariable linear regression was used to assess the association of
VO2 with demographic and clinical characteristics.
Results from the final model are presented as beta estimates with 95%
CI. Data were analyzed using the SAS v9.4 (Cary, NC). All reported
p-values are two-sided and considered statistically significant when
< 0.05.
Results
From September 2016 through February 2019, 259 patients with pectus
completed maximal effort CPET, PFTs and cMRI. Patients were
predominantly male (86%), white race (98%), with an average age of
15.8 years. Most were healthy with no known underlying co-morbidities.
Twenty-one patients (8%) had an underlying connective tissue syndrome
including hypermobility (12 patients), Ehlers-Danlos syndrome (8
patients) and Marfan syndrome (1 patient). Demographic and clinical
characteristics data including PFT and CPET primary endpoints are
presented in Table 1. A high percentage of pectus patients reported
dyspnea on exertion (64%) and chest pain (41%). Mean lung volumes on
spirometry and plethysmography were normal with the FVC 96.6% and TLC
96.9%. Measures of aerobic fitness on CPET were low-normal with the
mean percent predicted VO2 peak 89.0% and oxygen pulse 90.8%.
Aerobic fitness was normal in 181 patients (70%) and reduced in 78
(30%) (Figure 1A). Reduced aerobic fitness was classified as mild in
51, moderate in 21 and moderate-severe in 6. Six patients (2.3%)
demonstrated a pulmonary limitation with reduced fitness. Among patients
with normal aerobic fitness 18 (7%) demonstrated tachypnea and 7
(2.7%) hyperventilation. Among the 164 patients reporting dyspnea on
exertion 119 (72.6%) exhibited normal fitness and 17 (10.3%)
demonstrated tachypnea, hyperventilation, or a pulmonary limitation
(Figure 1B).
Among those completing maximal CPET, six could not perform spirometry
and plethysmography and were excluded from further analysis (Figure 2).
For the remaining 253, spirometry was classified as acceptable and
repeatable for 133 (53%) and usable for 120 (47%). Pulmonary function
testing were normal in 188 (74%) with a resting ventilatory limitation
identified in 65 (26%). Obstruction was the most common limitation
pattern in 27 (11%) followed by 7% with a NSVL and 7% with a
restrictive pattern. Two had mixed obstructive and restrictive defects.
Of the 65 patients with any resting ventilatory limitation pattern, 55
(85%) fell into the mild category.
Pectus patients with normal PFTs were compared against those with
obstructive, NSVL or restrictive patterns (Table 2). There were no
differences between groups for the degree of pectus malformation or CPET
endpoints. Patients with abnormal patterns did not have increased
dyspnea on exertion or chest pain than those with normal patterns.
Scatter plots depicting correction index with TLC% and peak
VO2% show significant inverse relationships between
degree of the pectus deformity and lower lung volumes (r=-0.26;
p<0.001) and reduced aerobic fitness (r=-0.20;
p<0.001) (Figure 3 A, B). A similar pattern also exists with
FEV1% (data not shown). In contrast, there was no
significant correlation between an increase in the degree of the pectus
deformity and BR (r=-0.004; p=0.95) or Vt/IC (r=-0.11; p=0.09) (Figure 3
C, D).
Multivariable linear regression modeling was used to evaluate pectus
severity indices and PFT/CPET measurements as predictors of peak
VO2 (Figure 4, Panel A). After adjustment, increasing
correction index values were associated with decreasing
VO2 (p<0.001). A similar inverse relationship
was also noted for BR (p<0.001). Peak VO2 was
found to increase as body mass index (BMI) and FEV1increased (each p<0.001). Also, peak VO2 was
significantly higher for those with tachypnea (no hyperinflation)
compared to patients without the condition (p<0.001). A
significant interaction was noted between Vt/IC values and sex (p for
interaction <0.001). The Vt/IC was positively associated with
VO2 peak for both males and females, with a greater
increase in VO2 noted in females (Figure 4, Panel B). No
associations were noted with TLC, FVC, Haller Index, symptoms of dyspnea
or chest pain.