The document discusses two studies that compared high dose vs low dose caffeine citrate for treatment of apnea of prematurity. The 2015 study found: 1) High dose caffeine (40/20 mg/kg loading/maintenance) was not associated with higher rates of extubation failure or more frequent apnea episodes compared to low dose (20/10 mg/kg). 2) Both doses were well-tolerated with no significant differences in adverse effects. 3) The authors concluded higher doses may reduce extubation failure and apnea frequency without increased side effects. However, the study had a small sample size. An earlier 2004 study found similar results, with high dose (80/20 mg/kg loading

1. Critical Appraisal:
High Dose vs Low Dose Caffeine Citrate
in Apnea of Prematurity (AOP)
Tauhid Ahmed Bhuiyan, PharmD
Pharmacy Practice Resident (R2)
King Faisal Specialist Hospital & Research
Center (KFSH&RC)

2. Definition & Terminology
• Gestational age (or “menstrual
age”)
– First day of the last normal
menstruation to day of delivery
• Chronological age (or “postnatal”
age)
– time elapsed after birth
• Corrected age (or “adjusted age”)
• Prematurity:
– Gestational age <37 weeks
• Birth weight:
– Normal: 2500 g +
– Low: <2500 g
– Very low: <1500 g
Blackmon LR et al. PEDIATRICS 2004; 114(5):1362-65

3. Apnea of Prematurity (AOP)
• Developmental disorder
– As a result of immature respiratory control
mechanisms
– Depends on gestational age and birth weight
• In premature infants:
– Defined as, “respiratory pauses >20 sec or pauses <20
sec accompanied by bradycardia (< 100 beats/min),
central cyanosis, and/or O2 saturation < 90%
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

4. Epidemiology
• Occur in almost all infants born at <29 weeks
gestation or <1000 g
• 50 % of infants born between 30 to 32 weeks
• 7 % of infants born at 34 to 35 weeks gestation
• Apneic episodes might persist beyond term in
infants born <28 weeks gestation
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

5. Prognosis
• Death is rare
• Typically, apneic spells stops (in most cases) by the time
infants reach 37 weeks gestation
• Intermittent hypoxemia deleterious
neurodevelopmental outcomes & retinopathy of
prematurity (ROP)
• Poor respiratory drive
– Prolongation of duration of mechanical ventilation
– Decrease chances of successful extubation
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

6. Treatment of Choice
• Non-pharmacological: continuous positive airway pressure
• Pharmacological: methylxanthines
– aminophylline, theophylline, and caffeine
• Theophylline: “narrow therapeutic window”
• Caffeine: multiple trials validated the use
– proven short-term effectiveness of apnea episodes
– need for assisted ventilation up to 7 days of life
• Duration: postmenstrual age of 34-35 wks
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

7. Caffeine Citrate
• Standard dose: 20 mg/kg loading followed by 5-
10 mg/kg/day
• Pros:
– higher therapeutic index, better enteral absorption,
and longer half-life (neonates: 72-96 hours)
• Cons:
– tachycardia, jitteriness, and feeding intolerance in
preterm infants
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

8. Evidence On Use
• Cochrane review of 5 trials (N = 108 preterm)
– caffeine was as effective as theophylline
• Reducing apnea and extubation failure during the first week of life with lower
adverse effects (e.g. tachycardia and feeding intolerance)
• Caffeine for Apnea of Prematurity (CAP) trial (caffeine vs placebo)
– Study population: 2006 preterm infants (gestational age: 27±2 wks,
weight: 964±186g with AOP)
– Caffeine therapy was associated with
• reduction of the duration of positive pressure ventilation,
• duration of supplemental oxygen,
• rate of bronchopulmonary dysplasia (BPD)
• rate of severe ROP
• Follow-up study of infants in CAP trial:
– caffeine was associated with improvement in motor coordination
and visual perception at age of 5 years
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

9. Dosing: Variable Evidence
• Scanlon et al. (1992)
– Loading dose of 50 mg/kg caffeine citrate (25 mg/kg caffeine
base) is more effective in reducing apneic episodes within 8 h
than a caffeine loading dose of 25 mg/kg
• Two studies (2004,2011) revealed
– daily administration of 20 mg/kg caffeine citrate starting in the
periextubation period was as well tolerated as the use of 5
mg/kg per day
• Steer et al. (2003)
– daily maintenance dose of 30 mg/kg caffeine can be used safely
in preterm infants
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

10. High Dose Vs. Low Dose
2015
2004

11. Major Differences
Steer P et al. (2004) Mohammed S et al. (2015)
Study
Design
Multicenter (4 centers, Australia),
randomized, double-blinded
Dosing regimen (per day):
• High dose: 80 mg/kg loading,
followed by 20 mg/kg
• Low dose: 20 mg/kg loading,
followed by 5 mg/kg
Study duration: 31 months
Randomized, double-blinded,
prospective trial, in Egypt
Dosing regimen (per day):
• High dose: 40 mg/kg loading,
followed by 20 mg/kg
• Low dose: 20 mg/kg loading,
followed by 10 mg/kg
Study duration: 12 months
Sample
Size/Pop-
ulation
N= 234 preterm infants, gestational
age <30 weeks, ventilated for >48
hours
N= 120 preterm infants, gestational
age <32 weeks, exhibited AOP
within the first 10 days of life
Major
Exclusions
Major congenital abnormality, sepsis
(confirmed by blood culture), major
neurological condition, grade 3 or 4
intraventricular hemorrhage,
previous methylxanthine treatment
Major congenital malformations and
chromosomal anomalies
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Steer P. et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F499–F503

12. Mohammed S. et al.
• Study objective:
– Feasibility of using high-dose, compared to low-dose, of
caffeine citrate for prevention of extubation failure and
treatment of apnea in preterm infants
• Endpoints:
– Primary: extubation failure in mechanically ventilated
infants (need of re-intubation within 72 h of extubation
from mechanical ventilation)
– Secondary:
• Frequency (per the whole duration of caffeine therapy) and documented
days of apnea as recognized by daily tracing of monitor review performed
by co-authors
• Need for mechanical ventilation (for the purpose of AOP) in on ventilated

13. Randomization
• Internet-based random table technique
• A designated pharmacist was responsible for
the randomization of selected infants and the
preparation of caffeine dose
• Blinding: the investigators, nursing staff, and
family
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

14. Study Procedure
• Two treatment arm:
– Low dose group: 20 mg/kg/day loading, followed by 10
mg/kg/day
– High dose group: 40 mg/kg loading, followed by 20 mg/kg
– Equivalent caffeine base: 2:1
• Oxygen saturation, heart rate, and respiratory rate were
continuously monitored (Tachycardia: >180 beats/min)
• Blood pressure was checked twice daily (High: BP > 95th
percentile)
• Frequency of apnea and bradycardia were taken from the
monitor and validated by attending qualified nurses
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

15. Statistical Analysis
• Inferential statistics:
– Student t test, Mann–Whitney U test, Chi-square test
or Fisher exact test (if necessary), or Kolmogorov–
Smirnov test
• P < 0.05; considered to be statistically significant
• All statistical analysis was done on an intention-
to-treat base
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

16. Results

17. Study Profile
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

18. Baseline demographics:
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

19. Primary Outcomes
MohammedS.etal.(2015)
SteerP.etal.(2004)

20. Kaplan-Meier for Secondary
Outcomes
MohammedS.etal.(2015)

21. Adverse Effects
(Impact on Neonatal Outcome)
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

22. Adverse Effects
(Side Effects of Caffeine)
Mohammed S. et al. (2015)
Steer P. et al. (2004)

23. Authors’ Conclusion
• “The use of higher, than current standard,
dose of caffeine may decrease the chance of
extubation failure in mechanically ventilated
preterm infants and the frequency of apnea in
preterm infants without significant side
effects”
• Consistent with earlier study
Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8

24. Study Limitations
• Smaller sample size than previous study that
validated same results
• No power calculation to detect difference of
clinical and statistical significance
• Lack of long-term follow-up of neonatal
outcome

25. Long-Term Follow-up
(Steer P. et al.)
Outcomes at 12 months corrected for prematurity

26. Practice in KFMC

27. • Question of the day:
“Are we willing to change our
practice?????”