AJRCCM Articles in Press. Published on 25-July-2017 as 10.1164/rccm.

201707-1402ED
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Caffeine - A lung drug for all very low birth weight preterms?

Author: Alan H. Jobe, M.D., Ph.D.

Professor of Pediatrics

Cincinnati Children's Hospital Medical Center

3333 Burnet Avenue, MLC7029

Cincinnati, OH 45229-3039

Funding: I have no funding or conflicts of interest relevant to the subject of this

editorial.

Word count: 1,029

Copyright © 2017 by the American Thoracic Society

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Doyle, Ranganathan, and Cheong report in the Journal the pulmonary outcomes

at 11 years of age of a cohort of infants with birth weight <1250g randomized to the

Caffeine for Apnea of Prematurity (CAP) trial (1). This landmark trial of 2006 infants

reported in 2006 and 2007 that infants treated with caffeine had less bronchopulmonary

dysplasia, fewer patent ductus arteriosus, and increased survival without

neurodevelopmental disability at 18-21 months (2,3). Subsequent reports

demonstrated subtle motor deficits in infants not treated with caffeine at 5 and 11 years

of age (4,5). Doyle and colleagues now report the pulmonary outcomes at 11 years in

the 142 infants randomized in Melbourne (1). Expiratory flow was higher and fewer

children had forced vital capacities <5th centile with caffeine treatment. As a

population, very preterm infants have abnormalities in respiratory physiology which

increase with a history of bronchopulmonary dysplasia (6). When the respiratory

outcomes were adjusted for the higher incidence of BPD in the no caffeine group, the

independent effect of caffeine was lost. Nevertheless, the clinical take home message

was that relative to no caffeine, caffeine treatment decreased bronchopulmonary

dysplasia and the end result was better pulmonary outcomes at 11 years of age.

This very good result must be understood within the context of the original trial

and current uses of caffeine. The CAP trial was performed primarily to test the safety of

caffeine for its indication of apnea of prematurity in the early 2000's. Caffeine is a drug

with pleotropic organ effects. Caffeine inhibits adenosine receptors, increases

respiratory drive, increases metabolic rate, increases diaphragm function, and diuresis

among other effects (7,8). The major clinical concern for infants was adverse effects of

caffeine on brain development. For perspective on dosing, the average cup of brewed

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coffee contains about 100 mg caffeine. The standard loading dose of caffeine for

infants and the dose used in the CAP trial is 20 mg/kg with a maintenance dose of 10

mg/kg for about 8 weeks. Thus, the infant receives the caffeine content of 10-14 cups

of coffee for an adult as a loading dose, and then is chronically exposed to high dose

caffeine. There is surprising little apparent toxicity in clinical practice.

But there are two considerations relevant to the comparison group. The CAP

trial randomized 38% of eligible infants for clinical indications: treatment of apnea of

prematurity (41%), facilitate discontinuation of mechanical ventilation and extubation

(36%), and treatment to prevent apnea (23%) (3). Infants were randomized on average

at 3 days of age. The trial did not record the incidence of apnea in either arm of the

study, but caffeine treated infants received significantly less mechanical ventilation,

oxygen therapy, and treatment with postnatal steroids, consistent with the decreased

incidence of bronchopulmonary dysplasia. Apnea events are frequently associated with

bradycardias and desaturations which result in short term interventions such as

increased ventilatory support, increased oxygen exposure, increased stimulation and

interventions such as evaluation for infection. Thus, the benefits of caffeine result from

prevention of interventions generally suspected of adverse long-term

neurodevelopmental effects. Caffeine likely is not a direct brain or a lung drug but

rather a drug that decreases adverse effects of interventions to treat apnea. The net

effect is a great benefit to infants with apnea of prematurity.

However, there has been a very large treatment creep in clinical practice as the

drug is assumed to have no toxicity. Many clinicians treat all very low birth weight

infants with caffeine to prevent apnea and at ages earlier than 3 days. Thus, infants

Copyright © 2017 by the American Thoracic Society

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without apnea are being treated with caffeine without any anticipated benefit. A pilot

trial reported that caffeine before 2 hrs. of age improved cardiovascular function in

infants <29 weeks' gestational age (9). Another small trial reported caffeine given in the

delivery room to improve breathing effort (7). An IV treatment in the delivery room, soon

after delivery would add another intervention to an already sensorily overloaded

environment and could increase risk. Caffeine clearly is a potent drug, and its use in

the already stressed preterm who is adapting to birth with large increases in

catecholamines, corticosteroids, and thyroid hormones may not be benign.

As with many therapies, if an already high dose of caffeine is good then an even

higher dose should be better. Caution is warranted based on several recent reports. A

loading dose of 40 mg/kg and a maintenance dose of 20 mg/kg may decrease failure of

extubation but with increased tachycardia (10). A loading dose of 80 mg/kg caffeine (40

cups of coffee!) was associated with cerebellar hemorrhage, hypertonicity, and an

increased seizure burden (11,12). Higher dose caffeine seems like a bad idea. In

postnatal mice, caffeine augments the neurotoxicity of sedative/anesthetic drugs (13).

The possibility of drug interactions is a concern as sick infants receive multiple drugs,

and I am not aware that drug interactions with caffeine have been explored. If virtually

all very low birth weight infants receive caffeine, then we may not be able to detect drug

interactions.

Caffeine is an extremely useful drug to minimize apnea of prematurity. It is

associated with improved lung function and improved motor function at 11 years of age

(1)(5). Its respiratory effects in infancy do not change abnormalities of sleep duration or

sleep apnea in childhood (14). Caffeine is surprisingly nontoxic in very low birth weight

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infants, but it is a potent drug being given in high dose over many weeks. Caffeine is

not a lung drug per se - it minimizes interventions for respiratory control abnormalities in

the very preterm infant that result in lung injury that persists into childhood. My view is

that there needs to be a substantial indication for treatment of infants with caffeine.

References

1, Doyle LW, Ranganathan S, Cheong JLY. Neonatal Caffeine Treatment and

Respiratory Function at 11 Years in Children <1251 g Birth Weight. Am J Respir Crit
Care Med [online ahead of print] 26 June 17;
www.atsjournals.org/doi/abs/10.1164/rccm.201704-0767OC

2. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A,
Tin W, Caffeine for Apnea of Prematurity Trial G. Caffeine therapy for apnea of
prematurity. N Engl J Med 2006; 354: 2112-2121.
3. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A,
Tin W, Caffeine for Apnea of Prematurity Trial G. Long-term effects of caffeine
therapy for apnea of prematurity. N Engl J Med 2007; 357: 1893-1902.
4. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG,
Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS,
Caffeine for Apnea of Prematurity Trial I. Survival without disability to age 5 years
after neonatal caffeine therapy for apnea of prematurity. JAMA 2012; 307: 275-
282.
5. Schmidt B, Roberts RS, Anderson PJ, Asztalos EV, Costantini L, Davis PG, Dewey
D, D'Ilario J, Doyle LW, Grunau RE, Moddemann D, Nelson H, Ohlsson A,
Solimano A, Tin W, Caffeine for Apnea of Prematurity Trial G. Academic
Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine
Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP
Randomized Clinical Trial. JAMA Pediatr 2017; 171: 564-572.
6. Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, Thomas S, Stocks J.
Lung function and respiratory symptoms at 11 years in children born extremely
preterm: the EPICure study. Am J Respir Crit Care Med 2010; 182: 237-245.
7. Dekker J, Hooper SB, van Vonderen JJ, Witlox R, Lopriore E, Te Pas AB. Caffeine to
improve breathing effort of preterm infants at birth: a randomized controlled trial.
Pediatr Res 2017.
8. Kraaijenga JV, Hutten GJ, de Jongh FH, van Kaam AH. The Effect of Caffeine on
Diaphragmatic Activity and Tidal Volume in Preterm Infants. J Pediatr 2015; 167:
70-75.
9. Katheria AC, Sauberan JB, Akotia D, Rich W, Durham J, Finer NN. A Pilot
Randomized Controlled Trial of Early versus Routine Caffeine in Extremely
Premature Infants. Am J Perinatol 2015; 32: 879-886.

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10. Mohammed S, Nour I, Shabaan AE, Shouman B, Abdel-Hady H, Nasef N. High

versus low-dose caffeine for apnea of prematurity: a randomized controlled trial.
Eur J Pediatr 2015; 174: 949-956.
11. McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE. A pilot randomized trial of
high-dose caffeine therapy in preterm infants. Pediatr Res 2015; 78: 198-204.
12. Vesoulis ZA, McPherson C, Neil JJ, Mathur AM, Inder TE. Early High-Dose Caffeine
Increases Seizure Burden in Extremely Preterm Neonates: A Preliminary Study.
J Caffeine Res 2016; 6: 101-107.
13. Cabrera OH, O'Connor SD, Swiney BS, Salinas-Contreras P, Manzella FM, Taylor
GT, Noguchi KK. Caffeine combined with sedative/anesthetic drugs triggers
widespread neuroapoptosis in a mouse model of prematurity. J Matern Fetal
Neonatal Med 2016: 1-8.
14. Marcus CL, Meltzer LJ, Roberts RS, Traylor J, Dix J, D'Ilario J, Asztalos E, Opie G,
Doyle LW, Biggs SN, Nixon GM, Narang I, Bhattacharjee R, Davey M, Horne RS,
Cheshire M, Gibbons J, Costantini L, Bradford R, Schmidt B, Caffeine for Apnea
of Prematurity-Sleep S. Long-term effects of caffeine therapy for apnea of
prematurity on sleep at school age. Am J Respir Crit Care Med 2014; 190: 791-
799.

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