Discussion
Our findings shed light on the diverse clinical landscape of central
apneas and highlight different considerations regarding the therapeutic
interventions2,5. For our study, we considered only
those patients with central apneas who required ventilation. During the
period spanning from January 1, 2012, to December 31, 2022, our center
attended to a total of 612 patients requiring ventilation. Among this
cohort, 67 individuals fulfilled the inclusion criteria for central
apnea, as indicated by a cAHI exceeding 1. The specific diagnoses
attributed to these patients encompassed a spectrum of disorders:
notable among these were hypoxic - ischemic encephalopathy (22.39%),
Ondine Syndrome 20.90% cases, multimalformation syndromes (14.93%),
Prader-Willi Syndrome (11.94%), brain tumors (8.96%), Down syndrome
(5.97%). Other diagnoses included ROHHAD Syndrome (2.99%),
Arnold-Chiari II (1.49%), Primary central apnea (1.49%), Epilepsy
(1.49%), Lisosomal diseases (1.49%), Hydrocephalus (1.49%), Myopathy
(1.49%), Obesity (1.49%), Rett Syndrome (1.49%). These findings are
consistent with the existing understanding that central apneas can be a
manifestation of a wide range of underlying pathologies. It is important
to note, that primary central apneas, although highly prevalent in
infants, our study demonstrates that rarely require ventilation when
occurring in the absence of underlying causes. In fact, over the course
of 10 years, ventilation was only initiated in one case. It is
noteworthy that in this particular instance, a pressure support mode,
rather than controlled pressure, was employed intentionally to promote
the neurological development of respiratory centers. Furthermore, the
prevalence of Ondine Syndrome and the variety of genetic, neurological,
and developmental disorders identified in our study underscore the
intricate interrelationships between respiratory control, neurological
function, and genetic factors. Literature suggests that in instances
where central apneas are unexpectedly observed during a PSG performed
for suspected obstructive apneas, it might be advisable to consider a
brain MRI. While this concept remains debatable due to limited strong
evidence, confounding factors such as the presence of gastroesophageal
reflux can induce central apneas in an otherwise healthy individual.
Therefore, a thorough investigation into the possibility of GERD is
warranted in cases of unexpected central apnea
findings22,23. Our results highlight a consistent
conditions with an overlapping of both obstructive and central apneas:
this association has been largely demonstrated. It’s noteworthy that in
children with central apneas and concurrent adenotonsillar hypertrophy,
adenotonsillectomy has been observed to lead to the resolution of
central apneas. While not considered a specific treatment for central
apneas, this association has been noted. It’s plausible that the
resolution of central apneas follows the alleviation of hyperventilation
and arousals caused by obstructive apneas18,24–29. An
intriguing study conducted by Hwang et al. highlighted that pediatric
patients with both central and obstructive apneas, in the context of
adenoid hypertrophy, exhibited a more adverse polysomnographic profile
compared to those with only obstructive events. Notably, children with
this overlapping pattern were usually younger. We agree with those in
literature speculate that central apneas in these cases might not be
independent events but rather triggered by arousals resulting from
airway obstruction30. Our study does not include
patients with adenoid hypertrophy who exhibit central apneas, as the
treatment in this case is typically medical or surgical rather than
ventilatory.
Within our study, in line with existing literature, we categorized
patients into three main groups based on the prevalence of specific
types of apneas, regardless of age. As showed in table 1 , these
categories include patients with ”exclusively central apneas” (MOAHI
<5), ”predominantly central apneas” (MOAHI 5-10), and
”predominantly obstructive apneas” (MOAHI >10). Notably,
patients with exclusively central apneas tend to exhibit a higher cAHI,
while those with primarily obstructive apneas show a lower cAHI11. Analysis of the data has revealed several
interesting observations:
- Brain Tumors, Prader-Willi Syndrome, and Hypoxic-Ischemic
Encephalopathy: these diagnoses exhibited a remarkable variability
among patients. Many of them presented with a combination of both
central and obstructive apnea forms.
- Arnold-Chiari Syndrome, idiopathic central apneas, multimalformation
syndromes, Rett syndrome, and Ondine Syndrome: in contrast, these
diagnoses showed a phenotype almost exclusively of ”exclusively
central apneas.”
- Down Syndrome and obese patients: these patients tend to have a
”predominantly obstructive apneas” phenotype. It is our opinion that
in these cases central apneas may likely be triggered by arousals and
hyperventilation, as previously explained;
- Hydrocephalus, epilepsy, and ROHHAD syndrome: it appears that these
patients exhibit a ”predominantly central apneas” phenotype;
As showed in table 2 , among infants under one year of age,
57.89% of cases were attributed to Ondine Syndrome, while 26.31% were
infants with hypoxic-ischemic encephalopathy. Only three infants had
different diagnoses, accounting for 5.26% each, including
multimalformation syndrome, Prader-Willi syndrome, and brain tumors.
This data highlights a crucial distinction, underscoring the importance
of early intervention in cases of Ondine Syndrome, as nearly 78.57% of
such cases required ventilation within the first year of life. This
underscores the critical need for prompt diagnosis and ventilatory
support in infants with this condition. A study conducted by Felix et
al. aligns with ours in demonstrating that diagnoses of central apneas
occurring after the first year of life are rarely Ondine’s syndrome but
rather neurological disorders such as Arnold-Chiari malformation,
encephalopathies, and brain tumors. The study also reports several cases
of Prader-Willi syndrome5.
The choice of ventilation strategy for patients with central apneas
remains a clinical challenge, compounded by the scarcity of established
guidelines. Table 3 summarizes the ventilation modes among our
patients. Pressure-controlled ventilation (PCV) and pressure-supported
ventilation (PSV) are well-established techniques that provide varying
degrees of respiratory assistance31. When it comes to
selecting the most appropriate ventilation mode for patients with
central apneas, several factors have to be evaluated: these include the
severity of the patient’s central apneas, the underlying medical
conditions, and the patient’s response to different ventilation
strategies. PSV assists patients in initiating their own breaths while
providing additional support in the form of positive pressure during
inspiration. This support is synchronized with the patient’s own
respiratory efforts, making it an excellent choice for those who can
still breathe spontaneously but may require assistance to maintain
adequate ventilation. PSV mode can be complemented with a timed
spontaneous mode in which the patient is given a window of time to
initiate inspiration on their own. If the patient delays in initiating
inspiration, the ventilator provides support to facilitate
inhalation32. We used the PSV ventilation mode in the
majority of cases (45/67 patients), which reflects its effectiveness and
safety in managing central apneas. It was applied across a wide range of
diagnoses, underscoring its versatility as a ventilation mode. In our
opinion, PSV is reasonably considered for patients with mild to moderate
central apneas without important desaturations or severe periodic
breathing and it is an excellent ventilation mode in cases of residual
functionality of the bulbar respiratory centers. On the other hand, in
PCV, the ventilator takes full control of the inspiratory pressure,
determining both the maximum and minimum lung
pressures33. In the context of our ventilated
patients, those who have used the PCV mode (15/67) were the ones
presenting a more challenging underlying medical condition to manage,
along with more severe central apneas. Consistent with what has been
explained, it is important to note that the majority of patients who
underwent PCV were suffering from Ondine’s syndrome, hypoxic-ischemic
encephalopathy and brain tumors. On our opinion, this level of control
can be beneficial in cases of severe central apneas when the patient is
unable to initiate breaths independently or when there is a complete
loss of respiratory drive. Thus, we used CPAP among a minimal subset of
patients (7/67). This approach indicates a focus on maintaining an open
airway during both inspiration and expiration and it is particularly
beneficial in cases where obstructive events might coexist with central
apneas or where upper airway patency needs to be preserved. In fact, the
CPAP mode is primarily known for treating obstructive sleep apnea (OSA)
and it can also help in cases where central apneas are related to
hypercapnia or arousals. In fact, we reserved CPAP in the case of
patients with multimalformation syndromes or patients with Down
syndrome. However, it’s essential to remember that CPAP may not be
suitable for all individuals with central apneas, particularly those
with underlying neurological issues or complex factors. Similar optimal
results are reported in the literature5,34–37.
Another approach for managing central apneas, which has been
underexplored in the literature, is the use of low-flow oxygen.
Interestingly, very few reports document the effectiveness of low-flow
oxygen in managing central apneas and PB. Specifically, an older study
from 1982 reported that in a 58-year-old man with primary alveolar
hypoventilation and central sleep apnea, after initiating treatment with
low-flow nocturnal oxygen, there was a significant reduction in the
number and duration of sleep apneas and an increase in ventilation
levels during sleep38. Another study from 2018 by Das
et al. demonstrated that low-flow oxygen supplementation significantly
reduced cAHI in children during both REM and non-REM
sleep39. The underlying mechanism remains unclear.
However, our study did not include patients treated with low-flow
oxygen, as we enrolled individuals who required mechanical ventilation.
A very important concept is the effectiveness of ventilation in central
apneas: as showed in table 4 , our study reflects that all
diagnostic categories showed a significant improvement in cAHI.
Specifically, a statistically significant reduction (p<0.05)
in mean cAHI was observed in patients with multimalformation syndromes,
hypoxic-ischemic encephalopathy and Prader-Willi Syndrome. The reduction
in mean cAHI was not statistically significant in the case of patients
with brain tumors. Indeed, brain tumors affecting the respiratory
centers are very challenging pathological conditions to treat, often
requiring high pressures and controlled modes of ventilation. However,
as demonstrated by our study, in these cases significant improvement in
central apneas is often not achieved. The rest of the diagnoses
exhibited a substantial decrease in the mean cAHI value, but the sample
sizes were not sufficient to conduct statistical comparisons. Our
findings align with those reported by Ghirardo et al. who showed that
the more challenging forms of central apnea are associated with
encephalopathies and brain tumors. These categories pose significant
diagnostic complexities. They reported that these diagnostic categories
exhibit the highest cAHI11.
In our study, an intriguing aspect that emerged was the diversity in the
choice of ventilation methods dependent on their underlying diagnoses.
The table 5 provides an insightful breakdown of the number of
patients who received NIV as opposed to IMV for various diagnostic
categories. For patients diagnosed with brain tumors, all six cases were
managed with NIV. Interestingly, none of these patients required IMV.
While NIV was the chosen approach, it is essential to note that patients
with brain tumors exhibited the least significant improvement in central
apnea, presenting a non-statistically significant reduction
(p>0.05) in the cAHI. This observation raises the
possibility that for this specific diagnostic category, NIV may not
yield substantial benefits in terms of central apnea reduction. Despite
the limited therapeutic response, it is plausible that IMV was not
pursued in these cases, potentially due to ethical considerations
surrounding the avoidance of overtreatment and the anesthetic risks
associated with invasive ventilation. Four patients with Down syndrome
received NIV, and none required IMV. The choice of NIV aligns with the
clinical consideration that central apneas in patients with Down
syndrome often result from physiological immaturity and upper airway
anomalies, which can be effectively managed with NIV. For Arnold-Chiari
II and Primary Central Apnea NIV was the selected mode of ventilation,
with no patients needing IMV. Among patients with multimalformation
syndromes and hypoxic-ischemic encephalopathy, a significant portion
received NIV, and less necessitated IMV. This mixed response
demonstrates the complexity within this category, as central apneas
could stem from a variety of anatomical and neurological factors.
Interestingly, the only one patient with epilepsy required IMV. The
results for Ondine Syndrome are particularly noteworthy. A substantial
number of patients (nine out of fourteen) received NIV, while five
necessitated IMV. It’s important to emphasize that patients with Ondine
syndrome often require tracheostomy ventilation during the early years
of life and, subsequently, NIV during the puberty and young adulthood
years. This emphasizes the severity and complexity of central apneas in
this syndrome, which often demand invasive ventilation methods. Eight
patients with Prader-Willi Syndrome were successfully managed with NIV,
with no requirement for IMV. This aligns with the idea that NIV is an
effective approach for central apneas associated with this syndrome,
which frequently presents with obesity-related breathing issues. These
results underscore the importance of tailoring ventilation strategies to
the specific diagnostic category and characteristics of each patient.
The findings also emphasize the diverse nature of central apneas,
ranging from milder cases that can be addressed with NIV to more severe
instances necessitating IMV. It’s essential to consider the individual
patient’s condition and needs when determining the most suitable
ventilation method.
While our retrospective study provides valuable insights into the
diverse clinical manifestations and ventilatory strategies for central
apneas in pediatric patients, some limitations must be acknowledged.
Firstly, the study’s retrospective nature inherently carries the risk of
incomplete or inconsistent data collection. Additionally, the relatively
modest sample size within specific diagnostic categories may limit the
generalizability of our findings. The study exclusively focuses on
patients who required mechanical ventilation, potentially overlooking
cases of central apneas managed through non-ventilatory means.
Furthermore, the absence of a control group and the lack of a
standardized protocol for ventilatory management across different
diagnoses introduce potential biases in the assessment of treatment
effectiveness. Lastly, the study’s reliance on a single-center dataset
may restrict the generalizability of our findings to a broader
population. Despite these limitations, our study offers a comprehensive
retrospective analysis, providing a foundation for future research
endeavors in understanding and addressing central apneas in pediatric
populations. In conclusions, central apneas, while often considered
benign in infancy, can emerge as significant clinical challenges when
they occur in the context of various underlying pathologies. Our
findings underscore the multifaceted nature of central apneas,
reflecting the interplay of genetics, neurological function, and
respiratory control. Patients with central apneas can be broadly
categorized into those with predominantly central apneas, predominantly
obstructive apneas, or a combination of both. The choice of ventilation
mode often depends on the underlying diagnosis and the severity of
central apneas. PSV was the most commonly employed mode, proving
effective in various diagnostic conditions and severity levels. PCV was
utilized in cases of more severe central apneas when patients were
unable to initiate breaths independently. CPAP was also employed in
select cases. While NIV was frequently used, IMV was selectively
employed in severe cases. A statistically significant reduction
(p<0.05) in mean cAHI was observed in patients with
multimalformation syndromes, hypoxic-ischemic encephalopathy and
Prader-Willi Syndrome. The reduction in mean cAHI was not statistically
significant in the case of patients with brain tumors. The rest of the
diagnoses exhibited a substantial decrease in the mean cAHI value, but
the sample sizes were not sufficient to conduct statistical comparisons.