Caffeine for the Treatment of Apnea in the Neonatal Intensive Care Unit: A Systematic Overview of Meta-Analyses

Abstract

Background Caffeine is a common treatment for neonatal intensive care management of the developmental complication of apnea of prematurity in preterm infants. There are several systematic reviews (SRs) on the performance of caffeine in the treatment of apnea. The evidence provided by those, however, is depressed by an information overload due to high heterogeneity in the characteristics as well as the quality of these SRs. Objective The aim was to provide a systematic overview of SRs on the use of caffeine for the management of neonatal apnea. Such overviews are a recent method used to assess and filter top evidence among SRs, enabling enhanced access to targeted information of interest. Methods A comprehensive literature search was conducted via EMBASE, Cochrane Database of Systematic Reviews (CDSR), and PubMed since inception to January 2020. Two reviewers independently conducted study selection and data extraction, and assessed the quality of methods and the risk of bias in included SRs based on A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) and Risk of Bias in Systematic Reviews (ROBIS) tools. Extracted data related to study type, characteristics, patients, intervention, comparator, regimen, and outcome measures. Results Seven SRs with meta-analyses (SRMAs) were included in the current overview, involving a total of 63,315 neonates. SRMAs included randomized clinical and observational studies, with various types of patients, comparators, and outcomes. The quality of SRMAs ranged from critically low (n = 1), low (n = 1), moderate (n = 2), to high (n = 3), and the risk of bias was unclear (n = 2), low (n = 4), and high (n = 1). The effectiveness of caffeine with regard to treatment success and the rate of apnea was not significantly different from that of theophylline or doxapram in two SRMAs. Against control, in one SRMA, while caffeine reduced the rate of failure as well as the need for pressure ventilation, it did not significantly reduce mortality. This comparative effectiveness of caffeine was based on high-quality SRMAs with a low risk of bias. The effectiveness against apnea seems to be enhanced via the administration of early (0-2 days) or high doses of caffeine in one and three SRMAs, respectively. This, nevertheless, was based on lower-quality SRMAs with a higher risk of bias. Safety outcomes were mostly based on comparative SRMAs of different drug regimens, whereby, less tachycardia and lower risk for complications were reported with lower and earlier caffeine administrations, respectively. The evidence behind this, however, was limited in quantity and quality. Conclusion While limited in quantity, there is evidence of non-inferior effectiveness of caffeine against other methylxanthines or doxapram for the management of apnea in neonates. Owing to the limited quality, however, limited evidence exists in support of an optimal administration regimen for caffeine. Further controlled studies are, therefore, needed to confirm the comparative usefulness of caffeine as well as to assess its diff...

Effect of prophylactic caffeine in the treatment of apnea in very low birth weight infants: a meta-analysis

“…The preferred methylxanthine for this indication due to its broad therapeutic window and a prolonged serum half-life is caffeine citrate [3]. This finding has been validated in several independent experiments, leading to the widespread use of caffeine as the first-line AOP treatment [4].…”

Is Early Preventive Caffeine Safe and Effective in Premature Neonates? A Clinical Trial

“…According to our recent search (in Medline, PubMed, Ovid, the Cochran Library, Google, and Google Scholar); the previous systematic reviews of Henderson-Smart and De Paoli [ 22 ], Park et al [ 23 ], and Kua and Lee [ 24 ]; and the recent systematic reviews of Alhersh et al [ 25 ] and Moschino et al [ 26 ], most of the studies about early caffeine administration in preterm infants are retrospective cohort studies like Patel et al [ 27 ], Lodha et al [ 15 ], Taha et al [ 20 ], Feng et al [ 28 ], Bhatt-Mehta et al [ 29 ], Mürner-Lavanchy et al [ 30 ], and Shenk et al [ 31 ], or prospective cohort studies like Borszewska-Kornacka et al [ 32 ] and Du et al [ 33 ].…”

Five-year outcomes of premature infants randomized to high or standard loading dose caffeine

“…Follow-up of this cohort to early school age was vital due to the disproportionate rate of cerebellar hemorrhage in infants randomized to early, high-dose caffeine in the initial trial and ongoing research regarding the optimal dose and timing of caffeine. 21 , 22 Existing studies have shown that children born prematurely with severe cerebellar hemorrhage before term-equivalent age have a higher likelihood of longer-term neurologic abnormalities, including hypertonia and hyerreflexia, and that cerebellar hemorrhage is associated with adverse neurodevelopmental outcomes. 23 , 24 Previous work in this cohort has shown that infants who received high-dose caffeine exhibited increased tone and more deviant neurologic signs on standardized neurobehavioral assessment at term-equivalent age, 7 a finding that we attributed to the increased incidence of cerebellar hemorrhage in the high-dose group.…”