Open Field Exercise Testing in Pediatric Congenital Heart Disease Patients: A Subsumption of Cardiovascular Parameters

Heart failure is a common phenomenon in congenital heart disease patients. Cardiopulmonary exercise testing is used for a reliable assessment of heart failure but is still challenging, especially for young children. Implementing mobile cardiopulmonary exercise testing (CPET) can close that diagnostic gap. While average values for healthy children have already been published, this study aims to describe typical ranges of cardiovascular performance parameters of young children with congenital heart disease performing an 8-min running cardiopulmonary exercise test. Children aged 4–8 years with common congenital heart defects after corrective surgery (Tetralogy of Fallot; transposition of the great arteries and univentricular hearts after palliation) were included. The outdoor running protocol consisted of slow walking, slow jogging, fast jogging, and maximum speed running. Each exercise was performed for 2 min, except the last, in which children were instructed to keep up maximal speed as long as possible. A total of 78 children (45 male/33 female, mean age 6,24) with congenital heart disease participated in the study, of which 97% completed the CPET successfully. A detailed description of participating patients, including data on cardiac function and subjective fitness levels, is given to help physicians use this method to classify their patients. This study presents a typical range for cardiovascular performance parameters in a population of 4–8-year-old children with congenital heart disease tested in a newly developed outdoor running protocol for CPET.


Introduction
Congenital heart disease patients often suffer from congestive heart failure or reduced physical exercise capacity [1].Both situations are associated with a substantial morbidity and mortality in affected children [2].While patients and parents easily recognize acute congestive heart failure due to new onset of symptoms, chronic congestive heart failure remains challenging to stratify as symptoms progress constantly and most patients are well adapted to their individual limits.It is crucial to catch the slow deterioration of physical exercise capacity in time to treat chronic congestive heart failure [3].In addition, a reduced cardiovascular fitness, reflected by the lower VO 2 peak values, represents an indi- vidual cardiovascular risk factor.In particular, a reduced VO 2 peak at a young age seems to be hard to compensate throughout the adolescent and young adulthood period.This points to the importance of an early recognition of these parameters in young children with congenital heart disease, to provide the possibility for early intervention [4,5].
Besides clinical examination, symptom-based classification systems [6,7] and imaging techniques, such as MRI, CT and echocardiography, were performed.As a possible influence of baseline systolic or diastolic function may significantly influence the physical exercise capacity, echocardiographic parameters were taken to evaluate this possible confounder [8].Furthermore, two main methods are used to grade heart failure in children.The first method is the measurement of brain natriuretic peptide (proBNP) levels [9,10].However, studies indicated that using proBNP as a prognostic value in adults cannot be equally applied to pediatric patients [7].Moreover, venous blood sampling represents an invasive diagnostic tool and can be difficult and traumatizing for the child.The second method for a reliable assessment of congestive heart failure is cardiopulmonary exercise testing (CPET) [11].This method is also considered the gold standard [12].The peak oxygen uptake ( VO 2 peak ) [13] as well as the oxygen uptake efficiency slope (OUES) [14], a surrogate parameter for VO 2 peak , are important prognostic parameters in patients with congenital heart disease [15].Typically, CPET has been performed on a bicycle or a treadmill [16] and it is a suitable diagnostic tool for adults and older children.However, specific reasons complicate these methods for use in young children.First, peak cardiopulmonary performance in children under the age of 8 years is difficult to achieve: on a bicycle because of weak leg muscle strength [17] and on a treadmill due to the unfamiliar exercise form and the fear to fall.Secondly, body size may limit the bicycle method [18].
The currently introduced method by Schöffl et al. [18] uses mobile cardiopulmonary exercise equipment with a protocol tailored to young children and closes that diagnostic gap.While average values for healthy children have already been established, this study evaluates a typical range of performance parameters in patients with congenital heart disease.Values are tested according to the reported protocol in terms of the individual anatomy and objective and subjective degree of congestive heart failure.The results should enable physicians to better assess the individual performance of children with congenital heart disease.

Materials and Methods
During the period of 2021-2022, children aged 4-8 years with common congenital heart defects [Tetralogy of Fallot (TOF), Transposition of the great arteries (TGA), and after univentricular palliation (TCPC)] were included.These common, complex groups of CHD with symptomatic patients were selected based on clinical need according to the assessment of cardiovascular fitness and performance.
Voluntary participants were recruited consecutively with inclusion of children meeting the inclusion criteria.Written informed consent was obtained from each child and the respective parent using age-appropriate consent forms.This prospective investigator-initiated study was approved by the Ethics Committee of the University of Erlangen-Nuremberg (159_19B) and the Heart Center Leipzig (063/20-ek).
Before cardiopulmonary exercise testing, a thorough clinical examination was performed to rule out contraindications like an acute infection or other non-cardiac preexisting medical conditions.We obtained each patient's history, an ECG, an echocardiography (including the baseline measurements for evaluation of systolic and diastolic cardiac function), a standardized questionnaire to evaluate subjective physical exercise capacity and a proBNP level.The mobile cardiopulmonary exercise testing device (Cortex Metamax 3B, Cortex Biophysik GmbH, Leipzig, Germany) was fitted to each child using a backpack that could be adapted accordingly to the respective size of each child.A respiratory mask for children (Hans Rudolph, Shawnee, Kansas, USA) was adapted using standard headgear.A Custo ECG 3-lead monitoring was installed.
All tests were performed on flat ground, either gravel or asphalt.A physician accompanied the children for instructions, motivation, and safety monitoring.The outdoor running protocol consisted of 2 min of slow walking, 2 min of slow jogging, 2 min of fast jogging, and a maximum of 2 min of maximum-speed running as previously described by Schöffl et al. [18].Before each step, the children received instructions about the aimed speed and were then allowed to set the running speed for each exercise according to their capabilities.During the fastest stage, children were instructed to run as fast as possible for as long as possible and received verbal encouragement.The test ended with a recovery period of 3-5 min of slow walking.
A trained study nurse was at the exercise site to monitor the cardiopulmonary exercise testing recordings.
After test completion, values were analyzed using the Metasoft Studio software (Cortex Metamax 3B, Cortex Biophysik GmbH, Leipzig, Germany).Graphs were averaged over 20 data points.The following parameters were recorded constantly throughout the exercise test: oxygen uptake ( VO 2 ) as well as CO 2 elimination ( V CO 2 ) , heart rate, respiratory exchange ratio (RER = ĊO 2 ∕ V/ VO 2 ∕ ), oxy- gen pulse (O 2 pulse = VO 2 ∕HR), minute ventilation ( VE ) and the time of each test (exercise time).First ventilatory threshold (VT1) was calculated using the v-slope method [19] and second ventilatory threshold (VT2) was calculated according to Binder et al. [20].Oxygen uptake efficiency slope was displayed as the slope of VO 2 on the y-axis plot- ted against the logarithm of minute ventilation on the x-axis ( VO 2 a*log V ⋅ Eþb, a representing oxygen uptake efficiency slope in l/min).All OUES values were calculated from the onset of cardiopulmonary exercise testing to VT2 and were thus only reported in children having achieved VT2.Physiological criteria for having reached exhaustion included two criteria: peak HR ≥ 195/min, and/or RER at VO 2 peak ≥ 1.0 [21].
Statistical analysis was calculated using SPSS V27 (IBM, Armonk, New York, USA).Comparisons of normally distributed CPET data between sexes were performed using two-sided T-test.For the comparison of the datasets for the patient characteristics, ANOVA testing was used.Differences in VO 2 peak/OUES/kg values between TOF, TGA and TCPC patients were also compared using ANOVA testing.To evaluate the correlation between age and VO 2 peak /OUES/kg, linear regression was performed.Pearson correlation coefficients were calculated to examine for possible associations between echocardiographic measurements and VO 2 peak/OUES/kg values.Data are presented as mean values and were considered statistically significant with p < 0.05.

Patient Characteristics
A total of 78 children with congenital heart disease performed CPET.Two children had to be excluded due to monitoring equipment failure (defect of heart rate sensor, data not stored and displayed in software) resulting in 97% technically flawless tests.12 children were excluded from data analysis as they did not meet the exhausting criteria (peak HR ≥ 195/min, and/or RER at VO 2 peak ≥ 1.0) because of patient imminent motivational reasons, that sometimes occur in young children.Of the remaining children, 64 completed the cardiopulmonary exercise test successfully while reaching their full exercise capacity.
Ranges of cardiovascular performance parameters are presented for a homogenous group of 24 TOF, 20 TGA, and 20 TCPC patients with no significant differences in baseline parameters like age, body weight, and systemic ventricular pump function.Only the echocardiographic parameters of tissue doppler, TAPSE and RV-Strain showed significant differences between the groups.All patients were Caucasian.Patient characteristics are shown in Table 1.

CPET Data
Data from the cardiopulmonary exercise testing of children with Tetralogy of Fallot are presented in Table 2.There was a significant difference between girls and boys in O 2 pulse (p = 0.033), HR at VT1 (p = 0.002) and VO 2 at VT2 (p = 0.021).
Data from the cardiopulmonary exercise testing of children with Transposition of Great Arteries are presented in Table 3. VO 2 at VT1 (p = 0.018) as well as OUES (l/min) (p < 0.01) and VO 2 at VT2 (p < 0.01) are significantly dif- ferent between the two sexes.
Data from the cardiopulmonary exercise testing of children after TCPC are presented in Table 4.There were no significant differences between girls and boys for any of the measured variables.
TGA patients reached the highest VO 2 peak values fol- lowed by patients with Tetralogy of Fallot and children with TCPC (Tables 2, 3, 4).
Data from TOF, TGA, and TCPC patients were compared and showed a significant difference in VO 2 peak (p = 0.014) and oxygen uptake efficiency (p = 0.026).The relationship between VO 2 peak , OUES and age in each congenital heart disease group using linear regression analysis is shown in Figs. 1 and 2.
The following formulas were deduced to determine a typical range of VO 2 peak/kg in children aged 4-8.Results of the correlation between OUES/kg and age groups are shown in Fig. 2. OUES/kg values did not differ significantly between the congenital heart disease groups with increasing age [TOF to OUES/kg (p = 0.823) TGA to OUES/kg (p = 0.178); TCPC to OUES/kg (p = 0.710)].
The following formulas were deduced to determine average values of OUES/kg in children aged 4-8.

Discussion
The current study presents cardiovascular performance parameters for young children from 4 to 8 years with  Typical ranges of VO 2 peak are depicted in Fig. 1 com- pared to the limits of healthy children.Overall, lower VO 2 peak values can be observed in congenital heart dis- ease patients.Yet, a substantial number of patients with TGA or TOF seem to be able to reach normal VO 2 peak limits.
As shown in Tables 2, 3, and 4, it seems that TCPC patients show the lowest VO 2 peak values compared to patients with Tetralogy of Fallot and children with TGA.The statistical comparison between the individual groups can underline the evidence of our assumption (comparing TGA and TCPC: p = 0.008; TOF and TCPC: p = 0.021).With regard to other protocols for cardiopulmonary exercise testing, these findings are in accordance with the current literature [15].With this in mind, the currently depicted 8-min open-field cardiopulmonary exercise testing seems to provide good quality data for CPET in young children with congenital heart disease.
Apart from the diagnosis, we identified no other influences on the VO 2 peak values recorded in this study.In particular, there was no significant influence of cardiac function, evaluated by echocardiography, on CPET performance parameters.And in consistency with previous studies in healthy children, who, according to Kalden et al. [21], showed no significant differences of VO 2 peak between healthy boys and girls in this range of age, the current data seem to underline these findings.We assume that differences in cardiopulmonary performance between sexes become visible only in older children and therefore, cannot be demonstrated in our study population of children of prepubertal age [16].
Consequently, the presented formulas to estimate an expectable VO 2 peak/OUES/kg in a certain type of CHD are calcu- lated independent of sex.While the type of congenital heart disease seems to predict a certain level of VO 2 peak , the cur- rent study could not demonstrate any influence of echocardiographic parameters on VO 2 peak .It is likely that several factors influence the VO 2 peak .As a result, it cannot be expected that there is a significant influence of a single echocardiographic finding that might be found in a relatively small patient cohort.
It has to be stated that CPET measurements, like the VO 2 peak, differ with regard to the applied CPET protocol.For example, VO 2 peak is about 10% higher on a treadmill than on a cycle ergometer [12,22].Therefore it has to be kept in mind that the ranges reported in this study are linked to the reported CPET protocol.A comparison to other common protocols, with regard to maximum values, is difficult as mostly the percentage of really young children in these studies is limited [23,24].
Finally, the study's findings shall help physicians interpret the individual performance of young children with congenital heart disease and evaluate the patient for heart failure on the one hand side and to guide physical training to improve the

Conclusion
This study presents cardiovascular performance parameters of children aged 4-8 years with congenital heart disease tested in a newly developed outdoor running protocol for CPET.

Limitations
In this study, only voluntary participants were included.Therefore, the possibility of a selection bias leading to an underrepresentation of children with high limitations of cardiopulmonary performance cannot be excluded.Almost exclusively Caucasian participants were included, limiting the applicability of results to children from other ethnic groups.

Fig. 1
Fig. 1 Correlation between Vo2 peak and age

Table 1
Patient characteristics

Table 4 TCPC
Values are displayed as mean ± 1 standard deviation (minimum/maximum)