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Seminars in Fetal & Neonatal Medicine 22 (2017) 342e347

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Seminars in Fetal & Neonatal Medicine


journal homepage: www.elsevier.com/locate/siny

Caffeine use in the neonatal intensive care unit


Jalal M. Abu-Shaweesh a, *, Richard J. Martin b
a
The Cleveland Clinic Foundation, Cleveland, OH, USA
b
Rainbow Babies & Children's Hospital, Cleveland, OH, USA

a b s t r a c t
Keywords: Caffeine is the most frequently used medication in the neonatal intensive care unit. It is used for the
Caffeine prevention and treatment of apnea, although this has been associated with lower incidence of bron-
Apnea of prematurity
chopulmonary dysplasia (BPD) and patent ductus arteriosus as well as intact survival at 18e21 months of
NICU
Neurodevelopmental outcomes
life. Although neurodevelopmental advantage was no longer statistically significant at age 5 years,
Prematurity caffeine was associated with sustained improvement in co-ordination and less gross motor impairment
than placebo. The mechanism of action of caffeine on prevention of apnea and activation of breathing
seems to be through central inhibition of adenosine receptors. However, its impact on BPD and neuro-
developmental outcomes might be induced through its effects as anti-inflammatory mediator, protection
of white matter, and induction of surfactant protein B. Whereas long-term studies have documented the
safety of caffeine as used in current practice, further studies are clearly needed to identify optimum
dosing, and time of starting and discontinuing caffeine.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction 10 preterm infants demonstrated that apneic attacks were reduced


or eliminated with aminophylline suppositories [1]. This set the
Over the last 40 years neonatology has experienced a multitude stage for a series of studies in North America beginning in the mid-
of changes in practice. Survival has improved markedly as has the 1970s that apnea could be reduced with theophylline and caffeine
number of neurodevelopmentally intact survivors. This may be therapy [2,3]. Although concerns about safety were expressed, the
attributed to many advances, including our enhanced under- response was so beneficial that a randomized clinical trial was
standing of both respiratory and central nervous system matura- considered inappropriate and did not occur for several decades.
tion. Respiratory control provides a key link between the immature
lung and brain. It is, therefore, not surprising that xanthine therapy 2.2. Safety
has found a prominent place in the management of high-risk ne-
onates. Nonetheless, greater understanding of its mechanism of Concerns about safety included the known side-effects, such as
action and fine tuning of clinical practice are needed, as addressed tachycardia and possible diuresis, but were focused primarily on the
in this review. effects of xanthine therapy on behavioral state and metabolic rate.
Despite the obvious stimulant effect of caffeine in later life, sleep
organization did not appear to be affected in preterm infants, given
2. Historical perspective
the limits of available monitoring techniques; this impression per-
sists to this day. Not surprisingly, increased respiratory drive might
2.1. Introduction into neonatology
be associated with an increase in metabolic rate [4]. This has been
confirmed in the CAP Trial [5] by a lag in weight gain in caffeine-vs
There has been recognition since the 1930s and 1940s that both
placebo-exposed infants. However, this lower weight trajectory was
caffeine and aminophylline act as respiratory stimulants, presum-
not sustained and the benefits of caffeine appeared to supervene.
ably by increasing sensitivity to CO2. In 1973 a report from the UK in
Historically this concern led to a desire to maintain xanthine con-
centrations as low as possible. A final concern has been a potential
* Corresponding author. The Cleveland Clinic Foundation, Mail Code M31, 9500
effect on cerebral blood flow; numerous studies obviously
Euclid Avenue, Cleveland, OH 44195, USA. Tel.: þ1 216 444 2568. employing non-invasive techniques in neonates have given incon-
E-mail address: abuj2@ccf.org (J.M. Abu-Shaweesh). sistent results with no clear detrimental effect on outcome.

http://dx.doi.org/10.1016/j.siny.2017.07.011
1744-165X/© 2017 Elsevier Ltd. All rights reserved.
J.M. Abu-Shaweesh, R.J. Martin / Seminars in Fetal & Neonatal Medicine 22 (2017) 342e347 343

3. Theophylline versus caffeine et al. reported an increase in diaphragmatic electrical activity in


extremely low birth weight infants 30 min after a caffeine-loading
Although not universally available, caffeine is now the most dose [17].
widely used xanthine therapy, constituting 96% of all methylxan- Whereas increased airway reactivity is a major longer-term
thines used in clinical practice. This is the result of many compar- problem in former preterm infants, the benefits of bronchodilator
ative studies done over several decades. Bairam et al. documented therapy in the neonatal intensive care unit (NICU) are mixed.
in a double-blind study that whereas both theophylline and Xanthines can serve a bronchodilator function and a group of in-
caffeine were effective, the former tended to have more side- fants with bronchopulmonary dysplasia (BPD) did demonstrate
effects, and the latter exhibited greater pharmacologic stability, improved respiratory function after caffeine administration [18].
allowing for single maintenance daily dosing [6]. This has led to the Nonetheless, it is doubtful that this is a major physiologic mecha-
broad consensus that therapeutic drug-monitoring of caffeine, nism for the beneficial effects of caffeine in preterm infants.
when used for apnea of prematurity, is generally unhelpful and
unnecessary [7]. Interestingly, theophylline can be methylated to 4.1.3. CNS white matter protection
caffeine in the neonate [8]. This may contribute to its efficacy, Neonatal animal data support the concept that chronic hypoxia
raising questions whether plasma concentrations of both xanthines induces periventricular white matter injury via adenosine receptor
should be measured in theophylline-treated infants. activation (see below). This raises the possibility that caffeine may
provide a protective effect via adenosine receptor blockade. In
4. Mechanism of action neonatal mice caffeine reversed hypoxia-induced abnormal oligo-
dendrocyte maturation [19]. However, since adenosine release
4.1. Physiologic/biologic mechanisms induced by hypoxia may, in theory, also have a neuroprotective
effect, it is questionable whether caffeine, as is used in preterm
4.1.1. Enhanced respiratory control infants, directly elicits white matter protection [20].
There is little doubt that respiratory neural output is increased
by xanthines, and it appears that it is particularly prominent in the 4.1.4. Anti-inflammatory effect
neonatal period [9] (Fig. 1). The prominent effect on respiratory Apart from enhancement of respiratory neural output, inhibi-
control in the neonate may relate to, as-yet poorly understood, tion of inflammation is possibly the most likely mechanism
neurodevelopmental maturational differences and/or the relatively whereby caffeine exerts its benefit in neonates. Three recent
high circulating concentrations of caffeine we deliver to preterm studies in neonatal animal models support this concept. In one
infants. Both central and peripheral mechanisms have been study, hyperoxia-induced pulmonary inflammation, which is a
implicated. The former includes reversal of adenosinergic inhibi- well-established neonatal model, and the resultant cellular in-
tion (as discussed later) of inspiratory neurons in the brainstem, flammatory response were reversed by caffeine in infant rats [21].
enhanced CO2 responsiveness, and possibly decreased hypoxic In another study employing preterm rabbits, caffeine additionally
depression of breathing [10,11]. An effect of xanthines on peripheral reversed the functional and structural lung injury induced by
chemosensitivity has also been implicated in animal models hyperoxic exposure [22]. We have studied cytokine expression and
[12,13]. Peripheral chemoreceptors need to be intact for caffeine or respiratory function in rat pups in which proinflammatory lung
aminophylline to increase ventilation and reverse hypoxic respi- pathophysiology was induced by injecting lipopolysaccharide into
ratory depression. the amniotic sac prior to delivery. Postnatal caffeine significantly
reduced proinflammatory cytokine expression in the lung and
4.1.2. Improved diaphragmatic contractility and airway function improved postnatal respiratory system resistance in the pups [23].
In recent years the concept of diaphragmatic fatigue appears to Given the immunomodulatory potential of caffeine, drug and
have received less attention as a cause of respiratory failure. Pre- cytokine concentrations have been correlated together in preterm
vious studies in adult patients with chronic obstructive pulmonary infants. Available data suggest that whereas caffeine, at therapeutic
diseases demonstrated that theophylline enhanced trans- concentrations, may inhibit activation of a proinflammatory
diaphragmatic pressures via an effect on cellular calcium meta- cascade, and its adverse clinical consequences, these benefits may
bolism, as shown in a mature rodent model [14,15]. Whereas be diminished when caffeine concentrations exceed the thera-
neonatal data were unable to confirm an effect of aminophylline on peutic range [24].
diaphragm contraction in a quietly breathing piglet [16], Parikka
4.1.5. Induction of surfactant protein B transcription
Caffeine has been shown to induce the transcription of various
surfactant protein B transcription factors through a c-AMP-
dependent pathway [25]. Furthermore, there was a synergistic
action between various steroids and caffeine in induction of
endogenous surfactant protein production, indicating the ability of
caffeine to amplify the signaling pathways of glucocorticoids.

4.1.6. Potentially adverse biologic effects


Whereas human infant data clearly demonstrate benefit for
caffeine therapy, questions have been raised about potential safety
concerns and adverse effects. Much of this concern is derived from
rodent data. In contrast to the anti-inflammatory effect described
above, lung inflammation and alveolar apoptosis were increased
after caffeine exposure in hyperoxic mouse pups, but this may
Fig. 1. Proposed pathways by which neonatal caffeine therapy results in improved
relate to a relatively high caffeine dosage [26]. In the brain of
longer-term outcomes. Other pathways, such as white matter protection and enhanced developing mice, a dose-dependent effect of caffeine was observed
surfactant production, have been proposed. in decreasing astrocytogenesis [27]. Furthermore, early caffeine
344 J.M. Abu-Shaweesh, R.J. Martin / Seminars in Fetal & Neonatal Medicine 22 (2017) 342e347

administration to rat pups was associated with increased A1R and regarding short- and long-term effects of caffeine.
A2AR labelling in several cardio-respiratory regions of the brain,
including the hypothalamus and medulla [28]. As adenosine re- 5.1.1. Short-term effects
ceptors are important in cardiovascular regulation, especially of Compared with placebo, caffeine was associated with significant
blood pressure, these data raise concern about the long-term effect decrease in the incidence of BPD (36.3% vs 46.9%). Furthermore,
of early adenosine receptor inhibition. Finally, a pilot trial of a very infants who received caffeine spent an average of one week less
high loading dose of caffeine demonstrated evidence of cerebellar each on ventilator, positive airway pressure and supplemental ox-
injury on magnetic resonance imaging [29]. As described later, ygen and were less treated with postnatal steroids (14.4% vs 20.2%)
these data suggest a need for caution when high-dose caffeine is [5]. Additionally, caffeine use was associated with less need for
employed unless part of a well-designed clinical trial. medical or surgical treatment for patent ductus arteriosus (PDA).
Apnea, however, was not measured as an outcome, although this
4.2. Cellular/molecular mode of action would have presented a significant challenge. As previously indi-
cated, infants treated with caffeine showed poor weight gain when
Adenosine is a normal constituent of cells, and numerous en- compared to infants in the placebo group only on the first three
zymes regulate its intracellular concentration [9]. It serves multiple weeks of treatment. Apnea in 90% of patients in the placebo group
roles in normal physiology, including neuronal excitability, cerebral was managed using alternative mechanisms other than caffeine,
blood flow, and energy metabolism. Caffeine has a similar molec- including ventilatory support, a fact that might have contributed to
ular structure to adenosine and four adenosine receptors are their higher incidence of BPD.
characterized. Two receptors (A1 and A2A) are activated at low
concentrations of adenosine that are likely targets for caffeine as 5.1.2. Long-term effects
used in neonates. Other molecular pathways, such as caffeine- Follow-up data at 18e21 months were available for 93% of initial
induced phosphodiesterase inhibition, are probably not relevant participants. Caffeine improved the chance of survival without
to neonatal caffeine concentrations. neurodevelopmental delay. In the caffeine group 40.2% of infants
A1 and A2A receptors have somewhat opposing cellular actions, had died or suffered at least one developmental delay versus 46.2%
with A1 activation leading to inhibition of adenylyl cyclase and in the placebo group [34]. Caffeine was found to be associated with
some Ca2þ channels, whereas A2A receptors activate these path- decreased incidence of cerebral palsy (4.4% vs 7.3%; adjusted odds
ways. A1 receptors are more abundant than A2A receptors, and both ratio (aOR): 0.58; 95% confidence interval (CI): 0.39e0.87;
are located at multiple sites in the brain. Based on the inhibitory P ¼ 0.009) and of cognitive delay (33.8% vs 38.3%; aOR: 0.81; 95% CI:
effects of A1 receptor activation and expression of that receptor 0.66e0.99; P ¼ 0.04). Caffeine had no effect on mortality, deafness,
protein in the brainstem, it is widely assumed that this is the major blindness or on growth parameters. The number of infants needed
mechanism for caffeine's effect [30]. However, A2A receptor acti- to be treated to prevent one developmental delay was 16.
vation may also play a role in the ability of caffeine to stimulate Furthermore, caffeine decreased the incidence of severe retinop-
neonatal respiratory output. We have documented that a subpop- athy of prematurity (ROP). The main factor explaining the effect of
ulation of gamma-aminobutyric acid (GABA)-ergic neurons in the caffeine in decreasing neurodevelopmental delay was its ability to
medulla oblongata express A2A receptor message, and A2A receptor decrease the duration of positive pressure ventilation. This alone
activation may, therefore, release GABA, well known to inhibit explained 50% of caffeine effect. However, the other 50% remained
respiratory neural output in the neonatal period as also observed unexplained. Possible mechanisms include direct central action of
after laryngeal stimulation [31,32]. Finally, it needs to be recognized caffeine or lower incidence of hypoxic episodes in the caffeine
that caffeine may also protect against inflammatory lung injury by group. As apnea, bradycardia or desaturation spells were not
A2A receptor-independent mechanisms in a murine model [33]. measured in this study, the later explanation remains speculative.
These and other data point to the importance of caffeine doses Secondary subgroup analysis revealed that caffeine was most
activating or inhibiting downstream cellular pathways, and sound a effective in decreasing the compound outcome of mortality or
note of caution regarding the clinical consequences of large neurodevelopmental morbidity at 18e21 months of age in infants
changes in dosing during early postnatal life. who were receiving mechanical ventilation through an endotra-
cheal tube as compared to those with no support or with non-
5. Controversies in clinical practice invasive ventilation. Furthermore, caffeine administration before
3 days of life was associated with shorter duration of respiratory
5.1. Conclusions from the Caffeine for Apnea of Prematurity trial support [35]. Cost-effectiveness analysis revealed that caffeine
treatment is a winewin strategy in that it improves outcome and
The Caffeine for Apnea of Prematurity (CAP) trial is the most decreases cost for treated infants when compared to placebo [36].
comprehensive study involving caffeine use in the NICU. It has also The effects of caffeine on major neurodevelopmental disability
influenced and shaped current clinical practice. The study was were no longer observed on follow-up at 5 years of age in the 84.9%
concluded in October 2004 and enrolled a total of 2006 infants with of infants available for the analysis. Although the observed rates of
a birth weight between 500 and 1250 g who were admitted to the combined main outcome of death or disability continued to
multiple USA and international centers. Infants who were deemed favor caffeine over placebo treatment, the difference between the
eligible for caffeine treatment for the purposes of treating or pre- groups was no longer statistically significant [37]. However, the full
venting apnea of prematurity or for planned extubation were ordinal scale analysis of motor activity indicated that caffeine-
randomized either to caffeine or to placebo. Treatment medication treated infants had less gross motor impairment, improved scores
was discontinued before a median gestational age of 35 weeks on the movement Assessment Battery for Children, and had lower
based on clinical assessment that treatment was no longer needed. incidence of developmental co-ordination disorder: 11.3% vs 15.2%
The primary outcome of the study was neurodevelopmental in controls [38]. This significant improvement in motor scores ap-
outcome at 18e21 months corrected postconceptional age. Inter- pears to be sustained. The overall incidence of morbidity was much
estingly, the study authors hypothesized a potential adverse effect lower at age 5 years than at 18e21 months, indicating ongoing
of this therapy. plasticity and adaptation in developing children.
The study has contributed multiple sets of valuable data Further follow-up looking at the effect on sleep and sleep-
J.M. Abu-Shaweesh, R.J. Martin / Seminars in Fetal & Neonatal Medicine 22 (2017) 342e347 345

disordered breathing (SDB) at 5 and 12 years of age found that survey of 364 NICUs from four different countries found that 62% of
former premature babies were at increased risk for SDB; however, the units were using caffeine for prophylaxis [42]. Furthermore, in a
there was no effect of caffeine administration on sleeping behavior retrospective review of more than 51,000 infants born between
or SDB [39]. 1997 and 2010 in the Pediatrix group database, caffeine was found
to be used progressively earlier over time. Caffeine was started at a
6. Current practice of caffeine use mean age of 10 days in 1997 versus 4 days in 2010. In fact, the
majority of infants had caffeine started in the first 2 days of life [43].
Despite the well-documented benefits of caffeine administra- There are currently no randomized controlled trials evaluating
tion on short- and long-term neonatal outcomes, there continue to long-term safety or efficacy of prophylactic versus therapeutic use
be controversies in clinical practice with regards to dose, when to of caffeine. Current available data regarding optimum timing of
start and when to stop caffeine (Table 1). starting caffeine involve either retrospective studies or secondary
analysis of controlled trials. In the CAP trial, use of caffeine before 3
6.1. Dose of caffeine days of life, versus on or after three days, was associated with lower
postmenstrual age of last use of positive pressure ventilation and
Upon initial approval of caffeine by the US Food and Drug endotracheal intubation. However, there was no effect on the
Administration for the treatment of apnea of prematurity, the adjusted composite primary outcome of BPD/death, PDA, or ROP.
recommended dose was a bolus of 20 mg/kg/dose of caffeine citrate On the other hand, early use of caffeine, before 3 days versus on or
which is equivalent to 10 mg/kg/dose of caffeine base followed by a after 3 days of life, was associated with lower incidence of com-
daily maintenance dose of 5 mg/kg/day. The doses used in the CAP posite outcome of BPD or death in very low birth weight infants in
trial e the largest randomized controlled trial to date that looked at the Pediatrix retrospective review [43]. The difference in BPD
efficacy and safety e were a similar bolus dose and a maintenance incidence was 7.4% favoring early caffeine, and the effect was
dose of 5e10 mg/kg/day, based on response. consistent among all gestational age subgroups, whereas mortality
Multiple small studies have evaluated different dosing regi- was higher by 0.8% in the early caffeine group, especially in infants
mens. Mohammad et al. compared two doses of caffeine (loading/ aged <24 weeks. Additionally, early use of caffeine was associated
maintenance doses of 40/20 vs 20/10 mg/kg/dose) in 120 infants at with lower incidence of PDA requiring treatment, late onset sepsis,
an average gestational age of 29 weeks. Higher doses of caffeine and an average of 6 days less of mechanical ventilation, ROP
were associated with significant reduction in extubation failure in including severe ROP and IVH. It appeared that overall improve-
mechanically ventilated preterm infants (P < 0.05), the frequency of ment of outcomes coincided with switching to early caffeine use.
apnea (P < 0.001), and days of documented apnea (P < 0.001). On retrospective review of infants in the Canadian Network
However, high-dose caffeine was also associated with significant involving >5000 infants born before 31 weeks gestation between
increase in episodes of tachycardia (P < 0.05) without a significant 2010 and 2012, caffeine started in the first 2 days of life, as opposed
impact on physician decision to withhold caffeine [40]. There was to the third day of life or later, was associated with lower incidence
no difference between the two groups in the incidence of BPD, ROP, of the composite outcome of BPD or death and PDA, but not mor-
intraventricular hemorrhage (IVH), periventricular leukomalacia, tality, NEC or severe neurological injury [44]. In small pilot studies
or length of hospital stay. In another study that compared three randomizing infants to caffeine before 2 h of life versus at 12 h of
maintenance doses of caffeine of 3, 15 and 30 mg/kg/day in 127 life, early caffeine did not affect rate of intubation or vasopressor
infants at gestational age of 28 weeks, the incidence of extubation use, but was associated with improved blood pressure and systemic
failure did not differ among groups. However, infants in the two blood flow [45]. Currently, early use of caffeine seems to be safe and
higher-dose groups had statistically significantly less documented might contribute to earlier extubation and lower incidence of BPD.
apnea, increased heart rate, and more stable saturation profile [41]. However, long-term effectiveness and safety need further evalua-
Whereas caffeine doses higher than currently used have been tion. Randomized controlled studies are clearly needed to identify
associated with lower incidence and severity of apnea and ten- optimum timing for starting or stopping caffeine.
dency toward extubation success, lack of effect on long-term out-
comes, as well as lack of evidence for long-term safety, preclude its 6.3. When to stop treatment
use in clinical practice. Furthermore, previously stated evidence
from animal studies regarding possible mechanisms for toxicity of The optimal duration of caffeine treatment has not been sys-
higher doses raises concern regarding long-term safety. Currently tematically evaluated. In the CAP trial, as well as other studies, this
there is no evidence to support the use of caffeine in any doses was a clinical decision based on resolution of apnea. In a recent
other than were used in the CAP trial. report from 21 centers in Europe summarizing use of caffeine in
504 preterm infants, resolution of apnea was the reason for
6.2. When to start caffeine discontinuation of caffeine in 80% of infants [46]. The majority of
retrospective studies have indicated successful discontinuation of
Following the CAP trial, many centers around the world have caffeine at an average corrected gestational age of 34e35 weeks. As
started using caffeine routinely on admission to the NICU to “pre- incidence and severity of apnea decrease with advancing age, it is
vent BPD or improve neurodevelopmental outcomes.” A 2013 reasonable to attempt a trial of discontinuation of caffeine at 33e35

Table 1
Neonatal caffeine therapy: unresolved issues.

Pro Con

Optimal dosage Higher doses more strongly enhance respiratory neural Adenosine receptor subtype inhibition of inflammation is
output variable and dose dependent, raising safety concerns
When to start Early onset of therapy improves various morbidities Available data are largely based on associations rather than
on randomized trials
When to stop Prolonged therapy decreases duration of intermittent May prolong hospitalization and potentially increase home
hypoxic episodes monitor use
346 J.M. Abu-Shaweesh, R.J. Martin / Seminars in Fetal & Neonatal Medicine 22 (2017) 342e347

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caffeine exposure. Pediatr Res 2007;62:604e9.
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None declared. ceptors in brainstem and hypothalamic cardio-respiratory related nuclei of rat
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Funding sources high-dose caffeine therapy in preterm infants. Pediatr Res 2015;78:198e204.
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