DISCUSSION
Our study is the first to compare prevalence of CSA in children with and without HF. Contrary to adults, using the pediatric definition, prevalence of CSA is similar in children with and without HF. After adjusting for age, frequency of central apneic events did not differ between the two groups. Instead, CAI correlated inversely to age at time of sleep study. Children with elevated CAI were younger and had a higher prevalence of prematurity. Unlike the adult population, in children, CAI is not associated with LVEF.
We compared our results with the only other study on sleep disordered breathing in children with HF5. This was a prospective observational study, where the prevalence of CSA was 19% in children with HF secondary to dilated cardiomyopathy. This study used the pediatric CSA definition of central apnea/hypopnea per hour of sleep >1 as abnormal. Using similar criteria of pediatric CSA definition, prevalence of pediatric CSA in the +HF group of our study was high at 78.9% compared to the den Boer study (19%) (Table 3). However, the children with +HF in our study were younger with a median age of 24 months compared to the den Boer study with a median age of 11.1 years. Using the same definition for pediatric CSA as the den Boer study (CAI+HI >1/hr., with >50% of events being central), the prevalence of CSA did not differ between children with and without HF in our study. If we only compared the CAI in the two groups, it was found to be significantly lower in the +HF group. After adjusting for age, CAI was no longer different between the two groups. Thus, we conclude that, unlike the adult population, central apneic events were not increased in children with HF. Instead, central apneic events were more commonly seen in younger aged children, regardless of cardiac function.
Our results support previous findings, which did not show any correlation between AHI and severity of cardiac dysfunction measured by LVEF5,13. One study focused on assessing frequency of sleep disordered breathing and its relationship to cardiac function in children with cardiomyopathy found significant correlations between CAI+HI and both LV end diastolic volume index and LV end systolic volume index13. We did not have data on LV end diastolic volume or end systolic volume index. 2D LV End-diastolic Septal Thickness vs BSA z-score and 2D LV End-systolic Dimension vs BSA z-score were higher in the +HF group. The septal thickness being significantly higher is not an intuitive result as the assumption is that dilated, poorly functioning hearts have a thinner septal thickness. With the presence of a subject with hypertrophic cardiomyopathy in conjunction with a small n of the +HF group showing a wide range up to a z-score of 19.34, this was most likely enough to skew the average to significance. However, these parameters did not correlate with CAI or OAI. This finding contrasts the adult literature, where sleep disordered breathing is associated with left ventricular remodeling18. However, this is supported by previous studies in pediatric literature which suggests that pediatric sleep disordered breathing is not associated with significant cardiovascular strain and the majority of cardiovascular parameters in children with sleep disordered breathing are within the normal range at baseline19.
The relationship between age and CAI demonstrated in our study is intriguing and a key finding for future research in this field. In the previous study by den Boer, the median age of the 7 children with pediatric CSA was 2.9 years compared to 30 patients without CSA who had a median age of 12.3 years5. One of the biggest challenges of pediatric CSA is to have a consistent definition. While some authors have defined CSA as CAI+HI >1/hr., many have used a cut off of 5/hr. While healthy term infants have an estimated median CAI of 5.5/hr. at 1 month of age20, older children aged 7.3 (4) years of age with Chiari 1 malformation had median CAI of 2.4 (0.63 – 8.95)21. In our cross-sectional study, we found that CAI is inversely correlated to age. This has previously been described in children with trisomy 2122. Infants are particularly vulnerable to sleep apnea due to their upper airway structure23, ventilatory control 24, arousal threshold25, laryngeal chemoreflex26, REM-predominant sleep state distribution27 and physiologically exaggerated laryngeal chemoreflexes that actively induce protective apneas28. Central respiratory pauses from immaturity of control of breathing are frequent during REM sleep in infants20.
While there are no studies exploring the relationship between age and central apnea, there are a few possible physiologic explanations involving central and carotid body chemoreception sensitivities. Thus far, chemoreceptor responsiveness has been evaluated in animal and cellular models29,30. However, the actual implications of this as a causative reason for the relationship between age and central apnea is still grounds for speculation and requires investigation with future study.
The primary limitation of our study is its retrospective nature. Hypopneas scored in the study could be obstructive or central in nature, thereby elevating CAHI and overestimating prevalence of CSA. We did not have data on medications used in heart failure which could also affect control of breathing. We did not have data on Cheyne Stoke breathing. Prospective cohort studies correlating objective measurements of ejection fraction to polysomnographic parameters are needed to gain a better understanding of the relationship between heart failure and CSA. Due to the cross-sectional nature of the study, we were unable to prove causality. Longitudinal studies can provide insight regarding the relationship between central apnea index and age. Finally, this is the experience of a single center, and practices may vary between different centers. This study is a pilot initiative to gain a better understanding of this patient population.
Ultimately, unlike adults, after adjusting for age, there is no difference in frequency of central apneic events in children with and without HF. CAI appears to be a function of age in children, rather than a function of ejection fraction, with younger patients demonstrating higher CAIs. Future studies exploring the relationship between CAI and age can gain a better understanding of determinants of CSA in children.