Intermittent Hypoxia and Caffeine in Infants Born Preterm
Condition: Intermittent Hypoxia
MeSH terms: Hypoxia
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Caffeine; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): Infants will be started on oral caffeine base at 5 mg/kg/day. At 36 weeks + 0 days PMA drug dose will be increased to 5 mg/kg BID (total daily dose 10 mg/kg). Dose will be weight-adjusted weekly until NICU (neonatal intensive care unit) discharge. After discharge, all new doses will be calculated from the last weight recorded prior to discharge. The research pharmacy will prepare a bulk oral solution with active drug (caffeine base). While in the hospital, a daily 24-hour supply will be prepared and dispensed. For home administration of study drug, the research pharmacy at each clinical site will prepare and dispense a sufficient quantity of caffeine base solution for outpatient treatment up to 42 weeks + 6 days.; SyrSpend SF Unflavored will be used as the placebo for the control group infants. The volume of the placebo will match the volume of the study drug.
Intervention MeSH terms: Caffeine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, placebo-controlled, double-blinded clinical trial A site-stratified randomly-permuted blocked randomization design will be used to ensure balance at each site. Randomization will also be stratified into 2 birth gestational age categories of <28 wks and 28 wks + 0 days to 30 wks + 6 days gestation to ensure balance. The randomization scheme will be developed by the DCC using specialized software, and clinical sites will be provided appropriate enrollment logs and randomization procedures from the research pharmacy.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Caffeine; Prematurity