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Dose & administration
Loading dose 20 mg/kg of caffeine citrate (corresponding to 10 mg/kg of caffeine base), intravenously over 30 minutes. Maintenance dose 5-10 mg/kg once daily, intravenously over 10 minutes or by oral administration, 24 h after the loading dose. A higher maintenance dose can be considered but the possibility of accumulation should be taken into account.
Can be discontinued when the infant has been free from significant apneas 5-7 days.
Can be diluted in sterile solutions for infusion with glucose 50 mg/ml or sodium chloride 9 mg/ml.

Apnea of prematurity. BPD prevention.

Contraindications and special considerations
Apnea of prematurity is a diagnosis of exclusion. Always consider other possible causes of instable breathing.
Caffeine stimulates the CNS and the cardiovascular system, and should be used  cautiously in infants with seizure disorders and congenital heart defects.
Caffeine increase metabolism which may result in higher energy and nutrition requirements during therapy.
Measurement of plasma levels of caffeine is possible. A range of 8-30 mg/l has been associated with clinical benefit and levels above 50 mg/l could be regarded as elevated.

Adverse effects
Infusion site phlebitis
Exacerbation of gastro-esophageal reflux

Pharmacological  aspects
Caffeine acts by antagonism of adenosine receptors and act as a CNS stimulant. Several mechanisms have been proposed for its effect on apnea of prematurity, such as respiratory center stimulation, increased minute ventilation, decreased threshold to hypercapnia, and increased response to hypercapnia.
Onset of action is within minutes after intravenous infusion and after oral administration the peak concentration is reached in 30-120 minutes.
Elimination is predominantly by renal clearance and to some extent by hepatic clearance (Cytochrome P450 1A2).  Mean half-life (T1/2) are inversely related to gestational / postmenstrual age. In newborn infants, the T1/2 is approximately 3-4 days but increases over time. By 9 months of age, caffeine metabolism approximates that of adults (T1/2 = 5 hours).
The pharmacokinetics in newborn infants with hepatic or renal insufficiency have not been studied. Infants with significant renal impairment may risk accumulation. Cholestasis may also prolong half-life.


European Medicines Agency. European public assessment report (EPAR) for Peyonahttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001014/human_med_000940.jsp
Schmidt. Caffeine Therapy for Apnea of Prematurity. N Engl J Med 2006;354:2112-21. PMID 16707748.
Schmidt. Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. N Engl J Med 2007;357:1893-1902. PMID 17989382.
Eichenwald. Apnea of prematurity. Pediatrics 2016:e20153757. PMID 26628729.

Document version history
Created 2016-05-15 / Stefan Johansson

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Thanks very informative.

What is your protocol for giving Caffeine in apnea of prematurity i.e. Preventive or therapeutic? 

If preventive when do you start giving it?

Do you give Caffeine before extubation of prematures ? Even if no apnea is seen during intubation and mechanical ventilation?

If apnea is still present beyond 34 weeks corrected GA will you keep giving caffeine? (after excluding GERD). 

Are you with giving a 2nd loading if apnea is still present despite being on caffeine (taken that caffeine serum level measurement is not available)?

Are you weaning by maintaining the initial dose of caffeine and the infant is BW is growing and thus inducing a spontaneous weaning? 

Thank you.



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@Hamed we give mostly therapeutic, but that means that virtually all infants <28 weeks get it, and we are very liberal to start it up till week 32. We tend to continue it until week 35-36 (although my personal take is that we should discont it in very stable and well infants around week 33-34, to avoid any side-effects).

We do not measure serum levels, but increase up to 10 mg/kg if apneas persists 5 mg/kg. We usually keep the same dose once an infant is stable and then let infants "grow out of the dose" (which is not 100% rational as the turnover of caffeine increase with postconceptional/postnatal age)

My personal opinion is also - caffeine is not a magic bullet, and some apnea tendency will be there in most cases if you surveille infants closely. I am mostly convinced that there is a BPD-risk-reduction among the most immature infants (see Schmidt / the CAP-study in NEJM)

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