Early Caffeine Use in Very Low Birth Weight Infants and Neonatal Outcomes: A Systematic Review and Meta-Analysis

Park, Hye Won; Lim, Gina; Chung, Sung-Hoon; Chung, Sochung; Kim, Kyo Sun; Kim, Soo-Nyung

doi:10.3346/jkms.2015.30.12.1828

Cited by 53 publications

(59 citation statements)

References 34 publications

(107 reference statements)

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“…This is in agreement with results from the Caffeine for Apnea of Prematurity (CAP) study which showed that early caffeine was associated with a 37% reduction in BPD compared to a 13% reduction when treated later with caffeine . Findings from this study also concur with a recent publication which reported early caffeine was associated with improvements in BPD, PDA, brain injury and ROP, with no increased risk of NEC .…”

Section: Discussionsupporting

confidence: 91%

Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates

Kua

Lee

2016

Brit J Clinical Pharma

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AIMSThis study evaluated the therapeutic outcomes of early versus late caffeine therapy in preterm neonates. METHODSWe performed a systematic literature search in PubMed, Embase, CINAHL and CENTRAL from inception to 30 June 2016 to identify studies investigating the use of early caffeine therapy (initiated at less than 3 days of life) in preterm infants. Effect estimates were combined using random-effects meta-analysis. The primary outcomes for this study were bronchopulmonary dysplasia and mortality. RESULTSThe initial search found 4066 citations, of which 14 studies enrolling a total of 64 438 participants were included. The time of initiation of early caffeine therapy varied from the first 2 h to 3 days postnatal. Early caffeine therapy reduced the risk of bronchopulmonary dysplasia in both cohort studies (RR: 0.80, 95% CI: 0.66 to 0.96) and randomized controlled trials (RR: 0.67, 95% CI: 0.56 to 0.81). In cohort studies, neonates treated early with caffeine also showed decreased risks of patent ductus arteriosus, brain injury, retinopathy of prematurity and postnatal steroid use. However, the mortality rate was increased. CONCLUSIONSThe findings suggest that early caffeine therapy is associated with reduced incidence of bronchopulmonary dysplasia and may help decrease the burden of morbidities in preterm infants. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Caffeine therapy is commonly used to treat apnoea of prematurity and facilitate extubation in neonates. It is shown to reduce the rates of bronchopulmonary dysplasia, severe retinopathy of prematurity, cerebral palsy and cognitive delay.• Recent publications suggests that early initiation of caffeine may have incremental benefits on neonatal outcomes. British Journal of Clinical Pharmacology WHAT THIS STUDY ADDS• This systematic review found that early caffeine therapy (initiated <3 days of life) was associated with a significant reduction in the incidence of bronchopulmonary dysplasia compared with late caffeine therapy. Tables of Links

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Section: Discussionsupporting

confidence: 91%

Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates

Kua

Lee

2016

Brit J Clinical Pharma

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“…Other retrospective studies and especially the prospective studies comparing the outcomes associated with early vs. late caffeine therapy did not find an increased incidence of death, but did confirm the association of decreased morbidities with early caffeine therapy. 85,86,88,89 The results of the CAP Trial combined with these retrospective cohort and prospective studies provided moderate quality evidence for the beneficial effects of early initiation of caffeine therapy in VLBW infants. A subsequent randomized pilot study in 21 infants born <29 weeks' gestation evaluated the use of even earlier prophylactic caffeine citrate (20 mg/kg) started at <2 h of age compared to initiation at 12 h. 90 There was a trend toward reduced intubation rates in the early caffeine group, but this did not reach statistical significance (27% vs. 70%, p = 0.08).…”

Section: Timing Of Caffeine Initiation: Benefits Of Early Treatmentmentioning

confidence: 99%

“…91 In summary, studies of initiation of caffeine treatment at <3 days of life have generally shown positive benefits. 88,89 One recent study, however, did raise significant concerns about very early, high-dose caffeine, and is discussed in the next section. 92…”

Section: Timing Of Caffeine Initiation: Benefits Of Early Treatmentmentioning

confidence: 99%

Caffeine: an evidence-based success story in VLBW pharmacotherapy

Dobson

Hunt

2018

Pediatr Res

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Apnea of prematurity (AOP) is a common and pervasive problem in very low birth weight infants. Methylxanthines were reported >40 years ago to be an effective therapy and, by the early 2000s, caffeine had become the preferred methylxanthine because of its wide therapeutic index, excellent bioavailability, and longer half-life. A clinical trial to address unresolved questions and toxicity concerns, completed in 2004, confirmed significant benefits of caffeine therapy, including shorter duration of intubation and respiratory support, reduced incidence of chronic lung disease, decreased need for treatment of patent ductus arteriosus, reduced severity of retinopathy of prematurity, and improved motor and visual function. Cohort studies have now further delineated the benefits of initiation of therapy before 3 days postnatal age, and of higher maintenance doses to achieve incremental beneficial effects. This review summarizes the pivotal and in particular the most recent studies that have established the safety and efficacy of caffeine therapy for AOP and other respiratory and neurodevelopmental outcomes. Caffeine has a very favorable benefit-to-risk ratio, and has become one of the most prescribed and cost-effective pharmacotherapies in the NICU.

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“…Of note, caffeine treatment has been associated with reduced incidences of BPD [41] and the prevention of hyperoxia-mediated pulmonary inflammation and lung injury [42, 43]. Although caffeine has been demonstrated anti-inflammatory [44] and antifibrotic effects [45, 46], its potential impact on airway remodeling has not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

Fehrholz¹,

Glaser²,

Speer³

et al. 2017

Respir Res

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BackgroundAlthough caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells.MethodsThe human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition.ResultsTreatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p < 0.0001) and IMR-90 cells (p < 0.01). Upon simultaneous exposure to caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p < 0.0001). Of note, 24 h exposure to caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover, caffeine increased TNF-α mRNA in H441 cells (6.5 ± 2.2-fold, p < 0.05) which has been described as potent inhibitor of CTGF expression.ConclusionsIn addition to well-known anti-inflammatory features, glucocorticoids may have adverse effects on long-term remodeling by TGF-β1-independent induction of CTGF in lung cells. Simultaneous treatment with caffeine may attenuate glucocorticoid-induced expression of CTGF, thereby promoting restoration of lung homeostasis.

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Early Caffeine Use in Very Low Birth Weight Infants and Neonatal Outcomes: A Systematic Review and Meta-Analysis

Cited by 53 publications

References 34 publications

Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates

Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates

Caffeine: an evidence-based success story in VLBW pharmacotherapy

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

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