Intermittent Hypoxia and Caffeine in Infants Born Preterm
Intermittent Hypoxia and Caffeine in Infants Born Preterm
Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF) Our proposal will address
 the critical question: is persisting intermittent hypoxia (IH) in preterm infants associated
 with biochemical, structural, or functional injury, and is this injury attenuated with
 extended caffeine treatment? The investigators will study the effects of caffeine on IH in
 220 preterm infants born at ≤30 weeks + 6 days gestation. Infants who are currently being
 treated with routine caffeine, and who meet eligibility criteria, will be enrolled between 32
 weeks + 0 days and 36 weeks + 6 days PMA. At enrollment, infants will be started on
 continuous pulse oximeter recording of O2 saturation and heart rate. If, based on standard
 clinical criteria, the last dose of routine caffeine is given on or before the day the infant
 is 36 weeks + 5 days PMA, then on the day following their last dose of routine caffeine
 treatment, infants will be randomized (110/group) to extended caffeine treatment or placebo.
 Randomized infants should begin receiving study drug (i.e. 5 mg/kg/of caffeine base, or equal
 volume of placebo) on the day of randomization, but no later than the third calendar day
 following the last dose of routine caffeine. Prior to 36 weeks + 0 days PMA, study drug will
 be given once daily (i.e. 5mg/kg/day) and beginning at 36 weeks + 0 days PMA, study drug will
 be given twice daily (i.e. 10 mg/kg/day). The last dose of study drug will be given at 42
 weeks + 6 days PMA. Pulse oximeter recordings will continue 1 additional week after
 discontinuing study drug. Two caffeine levels will be obtained, the 1st at one week after
 beginning study drug, and the 2nd at a target date of 40 weeks + 0 days PMA, but no later
 than the last day of study drug, whether in hospital or at home. Inflammatory biomarkers will
 be measured at study enrollment and again at 38 weeks + 0 days PMA, or within 2 calendar days
 prior to hospital discharge, whichever comes first. Quantitative MRI/MRS should be obtained
 between study enrollment and 3 calendar days after starting study drug and again at a target
 date of 43 weeks + 0 days, but no later than 46 weeks + 6 days PMA.
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. At least 12 hours of breathing room air with no ventilatory support other than on room
 air nasal air flow therapy regardless of flow rate, or on room air and receiving nasal
 CPAP, and relapse not anticipated.

 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