Please select the eligibility criteria that correspond to the clinical trial below.
Title: Efficacy and Safety of Methylxanthines in Very Low Birthweight Infants
Brief Summary: At least 5 of every 1000 live-born babies are very premature and weigh only 500 to 1250 grams at birth. Approximately 30-40% of these high-risk infants either die or survive with lasting disabilities. The aim of this research is to reduce this heavy burden of illness. A multi-center randomized controlled trial has been designed in which 2000 very low birth weight infants will be enrolled. Our goal is to determine whether the avoidance of methylxanthine drugs will improve survival without disability to 18 months, corrected for prematurity.

Methylxanthine drugs such as caffeine are used to prevent or treat periodic breathing and breath-holding spells in premature infants. However, there is a striking lack of evidence for the long-term efficacy and safety of this therapy. Methylxanthines block a naturally occurring substance, called adenosine, which protects the brain during episodes of oxygen deficiency. Such episodes are common in infants who are treated with methylxanthines. It is possible that methylxanthines may worsen the damage caused by lack of oxygen. Therefore, this trial will clarify whether methylxanthines cause more good than harm in very low birth weight infants.


Options:
A: Inclusion Criteria:

1. Preterm infants being treated with high flow nasal cannula therapy
2. A need for supplemental oxygen as demonstrated by an required FiO2 \> 0.25 at enrollment
3. Requiring a flow rate of greater than 2 L/min such that the assumed inspired oxygen fraction matched delivered oxygen fraction (definition of HFNC).

Exclusion Criteria:

1. Major congenital abnormalities
2. Hemodynamic instability, defined as being outside of a normotensive range based on each infant's individual characteristics
3. Seizures
4. Ongoing sepsis
5. Meningitis
6. Clinician's concern regarding stability of the infant
B: Inclusion Criteria:

* postmenstrual age \<30 wks GA at study time
* on nasal/nasopharyngeal CPAP or mechanical ventilation (including nasopharyngeal IMV)
* at least 4 desaturations (SpO2 \<80%) during an 8 hour period within the 24h before the study using a standard pulse oximeter incorporated in the NICU (Dash 3000, General Electric, Freiburg; 10s averaging time, delay 10s)

Exclusion Criteria:

* postnatal age \<96h (to exclude rapidly changing conditions during the early phase of RDS and to avoid handling of the infant during the critical period for IVH)
* congenital cyanotic heart disease
* no decision for full treatment support
* Average FiO2 during the last 24h bevor the active study phase \>0.60
* Congenital malformations of the lung or the diaphragm (i.e. diaphragmatic hernia, congentital cystic lung diseases...)
* Clinically clear evidence for seizures
* Ongoing Sepsis (CRP \> 10mg/l, or positive blood culture, requirement of catecholamines)
* Need of blood-transfusion during study
C: Inclusion Criteria:

* Preterm infants with a gestational age (GA) at birth of 24 - 29+6/7 weeks
* Receiving invasive mechanical ventilation or non-invasive respiratory support (NCPAP or NIPPV)
* Receiving supplemental oxygen (defined as FiO2 ≥ 0.25) at the time of enrollment and for at least 18 hours during the previous 24 hours; Or a coefficient of variation in supplemental oxygen of ≥ 0.1 in the previous 24 hours.
* Expected to complete the 49-hour or 50-hour study period in the current form of respiratory support, i.e. invasive mechanical ventilation or non-invasive respiratory support
* Written informed parental consent must be present.

Exclusion Criteria:

* Major congenital anomalies
* Arterial hypotension requiring vasopressor therapy within 48 hours prior to enrollment.
* If the attending physician considers the infant not stable enough for a switch to another ventilator.
D: Inclusion Criteria:

* birthweight 500 to 1250 grams
* postnatal age day 1 to day 10
* infant considered a candidate for methylxanthine therapy by clinical staff

Exclusion Criteria:

* dysmorphic features or congenital malformations that adversely affect life expectancy or neurodevelopment
* unlikely to comply with long-term follow-up
* prior treatment with a methylxanthine

Answer: D