Intermittent Hypoxia and Caffeine in Infants Born Preterm

Acute morbidities can contribute to adverse neurodevelopment outcomes in preterm infants born
at ≤30 wks gestation, but neural damage occurring after resolution of acute morbidities may
be more subtle and related to cycles of inflammation and repair in the developing brain. One
possible contributor to these more subtle injuries is intermittent hypoxia (IH), defined as
repetitive cycles of hypoxia and re-oxygenation, which occur commonly in convalescent
premature infants. Caffeine treatment can improve both motor and cognitive neurodevelopmental
outcome in premature infants, especially at higher doses, but mechanisms are unclear.The
Caffeine for Apnea of Prematurity (CAP) Trial in infants born preterm at <1250 g reported 1)
shorter duration of positive pressure ventilation and reduced rate of bronchopulmonary
dysplasia (BPD) in infants treated with caffeine during the early postnatal wks prior to
34-35 wks postmenstrual age (PMA), 2) improved motor function and reduced rates of
developmental coordination disorder at 5 years, and 3) diffusion changes by MRI consistent
with improved white matter microstructural development. Although potential mechanisms for
this caffeine effect were not studied in these reports, a recent study of very preterm
infants in postnatal weeks 1-10 showed for the first time a direct link between IH and motor,
cognitive and language impairment at 18 months corrected age (adjusted risk gradient
p<0.005).Notably, the greatest risk gradient was at postnatal ages 9-10 wk, consistent with a
contributory role of later IH present after stopping routine caffeine treatment. These data
emphasize the potential importance of recurrent episodes of IH, as convalescing infants
approach term-equivalent age, on later cognitive, language and motor impairments.

Studies of IH during the early postnatal wks of life in very preterm infants may be due to
other mechanisms, including ineffective ventilation or other acute morbidities. However, H in
spontaneously breathing convalescing infants is due to ventilatory immaturity with associated
respiratory pauses or brief apneas, and has a characteristic pattern of brief desaturation
from a normoxic baseline followed by reoxygenation and return to normoxia. This study will
assess IH only during spontaneous breathing in infants after resolution of acute morbidities
or need for supplemental O2, and approaching term-equivalent age, a time when IH has been
shown by other studies to be the consequence of immature breathing regulation.

IH during spontaneous breathing related to ventilatory immaturity requires continuous high
resolution pulse oximetry recordings for detection, and consists of brief, repetitive cycles
of O2 desaturation from a normoxic baseline, followed by return to baseline saturations.
These repetitive cycles of reoxygenation following each IH episode are pro-inflammatory and
cause oxidative stress, free radical production, and release of pro-inflammatory cytokines.
Studies show increased levels of inflammatory biomarkers in animal models of IH-associated
obstructive sleep apnea (OSA) and in human subjects with OSA. Although inflammatory
biomarkers may be elevated in the first 2-3 postnatal weeks in very preterm infants who
develop BPD and neurodevelopmental sequelae, it is unknown if later IH during spontaneous
breathing in convalescing preterm infants is associated with inflammation or other
biochemical, structural or metabolic acute injury or adverse consequences.

Clinically unrecognized IH events are still common after discontinuing routine caffeine
treatment, typically at 34-35 weeks PMA. Except for 1 study, however, the potential adverse
consequences of IH have not been investigated in human infants. In obstructive sleep apnea,
however, even modest amounts of chronic IH have been associated with significant
neurocognitive morbidity. Evidence from animal models also shows that IH has significant and
long lasting effects on multiple physiological control mechanisms and neurological outcomes.
It's hypothesized that persistent IH in spontaneously breathing preterm infants after
stopping routine caffeine treatment is associated with acute adverse consequences.

The relationship between IH, adenosine, caffeine and brain development is complex and not
fully understood. At clinically effective doses, caffeine exerts effects in the brain by
blocking adenosine (Ado) A1 and A2A receptors, resulting in respiratory stimulation and
increased alertness, vigilance and arousal.44-60 Ado A1 receptor activation contributes to
hypoxia-induced reduction in cerebral myelination and ventriculomegaly. Caffeine treatment
attenuates the effects of hypoxia, presumably through blockade of Ado A1 receptors. It is
thus reasonable to hypothesize that similar mechanisms may be active in the human preterm
infant. Caffeine may thus be neuroprotective through two major mechanisms: 1) reducing
incidence and severity of IH due to its respiratory stimulatory effects, and 2) reducing pre-
and immature oligodendrocyte injury.

Brain development progresses through a highly programmed series of events. Myelination in the
cerebral hemispheres begins to accelerate at ~30-32 wks and continues to term and beyond, and
disturbances in these late gestation developmental processes often result in failure of
normal brain growth, abnormal cortical organization, impaired myelination, and connectivity,
commonly observed in surviving preterm infants. Persisting IH thus has even greater potential
for later neurodevelopmental disability than the IH associated with obstructive sleep apnea.
Since IH can be attenuated with extended caffeine, persisting IH may thus be a modifiable
cause of a previously unrecognized additional risk for disabilities associated with preterm
birth.

The period from 33-35 to 42 weeks PMA is a critical time for brain development, and is also a
time when significant IH during spontaneous breathing is present, but the adverse effects of
this IH are unknown. As the 1st step in understanding acute injury from IH, the investigators
address a fundamental and critically important question with high potential public health
benefit: does continued caffeine treatment after receiving the last dose of routine caffeine
at 32 weeks + 0 days PMA and 36 weeks + 5 days PMA reduce extent of IH and attenuate
indicators of acute injury at 43-44 wks PMA? The investigators will assess injury in 4
domains: biochemical (inflammation), structural (MRI), functional and metabolic (MRS). Our
proposed study thus has the potential to have major impacts on clinical practice: 1) how
clinicians assess and interpret IH, and 2) duration of pharmacological treatment with
caffeine. This will be the 1st study in human infants to assess the effects of continuing
caffeine treatment in attenuating acute injury indicators associated with IH.

Inclusion Criteria:

1. Male and female infants born preterm at ≤30 weeks + 6 days post menstrual age

2. Current treatment with routine caffeine

3. PMA 32 weeks + 0 days - 36 weeks + 6 days

4. Anticipated last dose of routine caffeine will be by 36 weeks + 5 days

5. Breathing room air with no ventilatory support or nasal air flow therapy

6. Able to tolerate enteral medications

7. It is feasible to administer the first dose of study drug no later than 36 weeks + 6
days PMA

Exclusion Criteria:

1. Intraventricular hemorrhage Grade III-IV or cystic periventricular leukomalacia

2. Current or prior treatment for seizures

3. Current or prior treatment for cardiac arrhythmias

4. Known renal or hepatic dysfunction that in the opinion of the investigator would have
a clinically relevant impact on caffeine metabolism

5. Major malformation, inborn error of metabolism, chromosomal abnormality

6. Presence of a condition for which survival to discharge unlikely

7. Social, mental health, logistical or other issues that, in the opinion of the
investigator, would impact the ability of the family to complete the study