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

Apnea of prematurity (AOP) is a common developmental complication in preterm infants, which may have different causes, mostly constituting two different types of AOP: a central apnea due to no or insufficient respiratory drive due to the immaturity of the brain stem, and an obstructive apnea due to obstruction of the infants’ (upper) airways. Based on these, there is also the potential for mixed apnea [1]. Other specific causes of neonatal apnea include tissue damage in the infant’s brain, respiratory disease, infection, gastrointestinal reflux, cardiac problems, and metabolic disorders [2]. If prolonged, this can lead to hypoxemia and reflex bradycardia, which may require active resuscitative efforts to reverse.

As respiratory stimulators, caffeine, theophylline, and aminophylline have been used for AOP for more than 40 years. Caffeine, a methylxanthine derivative, has been used in the neonatal intensive care unit (NICU) to treat AOP since the mid-seventies [3, 4]. The Caffeine for Apnea of Prematurity (CAP) trial reported that caffeine reduced duration of ventilation and oxygen dependency and improved disability and disability-free survival [5]. The CAP trial also showed a significant benefit in the caffeine group in terms of motor skills compared with the placebo group at the age of 11 years [6]. In the United States, more than 300,000 infants are born late preterm; among them, nearly 12% experience apnea before discharge [7]. In one study, the estimated inpatient hospital cost due to the delay in discharge was as high as US$2422 per patient [8].

Our preliminary literature search suggested that there are numerous systematic reviews (SRs) published for the purpose of providing evidence on the usefulness of caffeine for apnea. The high quantity and the variability in focus and structure of these SRs could potentially lead to limitations regarding easy access and interpretation of evidence, and therefore, these reviews often fail to efficiently support decision-making in healthcare. The systematic overview of SRs is a recent study design for the purpose of addressing the growing problem of information overload, enabling an approach to filter large volumes of evidence so as to enhance access to evidence and better inform healthcare decision-making [9].

In this systematic overview of SRs, we aimed to summarize the main reported outcomes of caffeine for apnea management in published SRs that considered all types of study designs.

The current review is a systematic overview that follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines (Appendix 1; see the Electronic Supplementary Material).

Our literature search yielded 979 studies, and after the removal of duplicates, 559 were assessed based on titles and abstracts. Studies that were relevant were subjected to full-text screening according to the pre-specified eligibility criteria. Finally, seven SRs with meta-analyses (SRMAs) were included in our overview (Fig. 1).

A total of 63,315 neonates were included among all studies that were considered in all seven SRMAs. The interventions studied in the included studies were caffeine (high maintenance dose, low maintenance dose, high loading and maintenance doses, low loading and maintenance doses, standard loading and maintenance doses), theophylline, doxapram, methylxanthine, and placebo. The SRMAs’ main characteristics are reported in Table 1.

Our review summarizes all the evidence in terms of SRMAs available for the treatment of apnea in infants. A total of seven SRMAs were published in the last 2 decades, including updates of three Cochrane reviews and one non-Cochrane review. All these SRMAs were based on RCTs, except one, which also included observational studies. SRMAs varied with respect to interventions, comparators, and outcomes.

Three of the included seven SRMAs sought to evaluate caffeine against a comparator. In one of the three, caffeine was compared to theophylline [14]. This review concluded that both caffeine and theophylline are found to have similar short-term outcomes in relation to rates of apnea and treatment failure. Theophylline, however, had some lesser therapeutic advantages than caffeine in relation to dose changes due to tachycardia and intolerance. These results are in agreement with more recent individual studies that were not included in the SRMA. A study conducted by Jeong et al. [19] also reported that caffeine is found to be efficacious in terms of short-term treatment outcomes and easier to administer compared to theophylline. These conclusions are also supported by a recently published RCT conducted by Zulqarnain et al. among 100 infants in Pakistan [20]. Another study conducted recently by Shivakumar et al. [21] compared caffeine with aminophylline and reported caffeine and aminophylline are equally effective.

Indeed, caffeine therapy is currently one of the most prescribed medications for treating AOP. It is the initial drug of choice among all methylxanthines because of its efficacy, better tolerability, wider therapeutic margin, and longer half-life [22]. Theophylline, another methylxanthine agent, is administered more than once a day and may cause adverse events that require closer serum level monitoring than caffeine, which is given only once a day, rarely causes toxic effects, and has a relatively wide therapeutic index [23].

In the remaining two studies that evaluated caffeine against comparators, caffeine was evaluated as part of a methylxanthine study group (including caffeine and theophylline): one compared against doxapram and one against a placebo or no treatment (control). Since the 1970s, methylxanthines have been used to stimulate breathing efforts to reduce apnea [24‐26], of which, theophylline and caffeine have been used.

The first use of doxapram was tested in 1985 [27] as an alternative to caffeine for breathing issues in neonates. Doxapram acts on both peripheral chemoreceptors and the central nervous system to improve breathing efforts. However, the use of doxapram is no longer recommended and has been reserved for neonates whom methylxanthine and continuous positive airways pressure (CPAP) strategies fail to control severe apneic events as it is associated with a decrease of cerebral blood flow [28, 29]. In one included SRMA [15], comparing doxapram to methylxanthines against the incidence rate of failed treatment within 48 h of the intravenous use of both therapies, a non-significant difference was concluded. Against control, in another included Cochran review [15], the methylxanthines were associated with a reduced rate of failure as well as the need for pressure ventilation. In this SRMA, the effect against mortality was analyzed, and no advantages in reducing early mortality were observed.

Important is that all comparative SRMAs of caffeine had high-quality methods and a low risk of bias.

One SRMA compared early to late administration of caffeine, and the outcomes were in favor of early administration in relation to mortality, BPD rate, PVL, ROP requiring laser photocoagulation, PDA requiring treatment, and BPD or death. Early administration, however, did significantly reduce the duration of MV. This SRMA, however, had a critically low level of quality and it was associated with an unclear risk of bias.

Three of the included SRMAs compared different dose regimens of caffeine, i.e., high versus lower dose. According to the “Consensus Guidelines for Management of Apnea of Prematurity UCSF (NC)2” (Northern CA Neonatology Consortium) [30], the loading dose should be 20 mg/kg intravenously (IV) and the maximum maintenance dose could be 10 mg/kg IV or orally (PO). All three SRMAs defined the low maintenance dosage in similar ranges: 5–10 mg/kg/day [11], ≤ 10 mg/kg/day [17], and 2.5–10 mg/kg/day [16]. The SRMAs, however, defined the high maintenance dosage and the loading dose differently: 10–20 mg/kg/day [11], > 10 mg/kg/day [17], and 5–30 mg/kg/day [16], and no limit of dose [11], > 20 mg/kg [16], and 10–80 mg/kg [17], respectively. In any case, higher doses of caffeine were associated with greater effectiveness against most outcomes, including success rate, apnea rate and duration, BPD rate, duration of MV, extubation failure BPD or death, and ventilator removal. The SRMAs of the different dose regimens of caffeine were of low to moderate quality and are associated with low, unclear, and high levels of bias.

Therapeutic drug monitoring (TDM) is frequently measured when administering methylxanthine medications; it helps clinicians adjust the dosing amount and duration of methylxanthines to ensure drug concentrations stay within the therapeutic range, potentially avoiding supra-therapeutic toxicity and subtherapeutic treatment failure [31]. None of the SRMAs collected data with regard to the peak and trough levels of caffeine or methylxanthine. Although the current SR confirms that caffeine is preferred over theophylline for the management of AOP, the clinical utility of routine TDM remains controversial [32]. While measuring serum levels is required in neonates managed with theophylline, due to a smaller margin of safety and greater variability of absorption, caffeine levels are only monitored in cases where signs of toxicity are suspected [31]. Natarajan et al [31], in their observational study of 101 preterm neonates with a median gestation of 28 weeks, reported that caffeine doses ranging from 2.5 to 10.9 mg/kg resulted in plasma concentrations that ranged from 3 to 23.8 mg/L and showed that 94.8% of concentrations fell within the normal reference range of 5.1–20 mg/L. Another prospective study showed that the serum concentrations by 14 days of life of 154 preterm neonates with a mean gestation of 29 weeks, who were given a 20 or 25 mg/kg caffeine loading dose followed by 6 mg/kg/day maintenance dosage, were no longer dependent on gestational age, weight, or postnatal age, suggesting that routine measurement of serum caffeine concentrations in preterm infants is not likely to be necessary [33]. In relation to caffeine toxicity, which is less likely to occur with caffeine standard doses than with other medications in the same class, an RCT reported that the need for TDM in infants with levels within the normal therapeutic range of 5.5–23.7 mg/L is unlikely. However, in cases in which toxicity is suspected or when a clinical response is absent, TDM may be required [34].

Despite some SRMAs demonstrating the benefits of caffeine in reducing the duration of MV, none of them reported whether caffeine reduces the need for CPAP, which is a substitute for invasive ventilation that does not need an endotracheal tube and is a preferred mode of ventilation for clinicians, avoiding neonate discomfort. Based on other literature, however, and although caffeine has been suggested to be beneficial for improving respiratory function via enhancing CPAP success [35], recent evidence demonstrated that early administration of caffeine (first 3 days of life) does not provide a reduction in the risk of CPAP and extubation failure [36].

Adverse events with caffeine use were only a focus in the SRMAs that evaluated the different administration regimens [12, 13, 17, 18]. With critically low-level quality and an unclear risk of bias, the early administration of caffeine was associated with fewer adverse events and a lower risk for NEC complications as compared to late administration [13]. With moderate quality and a low to high risk of bias, the higher caffeine doses were found to be associated with a higher rate of tachycardia [12, 18]. With a low to moderate quality level and an unclear to high risk of bias, there was no difference between the high and low doses of caffeine with respect to adverse events [12, 17, 18]. The adverse events of interest in comparative regimen studies included PVL, ROP, PDA, IVH, NEC, spontaneous intestinal perforation, and hyperglycemia.

Only one publication, by Chen et al., reported a greater number of IVH cases with high doses of caffeine (n = 422) [12]. While no specific risk factor behind this has been indicated, it is reported in the literature that neonates who received high doses of caffeine therapy tended to have a higher incidence of seizures as compared to those receiving standard doses (58% vs. 40%), with a seizure burden in the high-dose group ranging between 0 and 2174 s, versus 0 and 240 s in the low-dose group [37]. Given this, and the fact that no data on the neonates’ seizure status were reported in the Chen et al. study, an association between the occurrence of seizures and the increased number of IVH cases cannot be excluded.

The overview has some limitations. Searching with additional index terms to those in the study or additional combinations of them is always possible and may generate additional studies. In addition, the fact that a primary article could have been included in more than one SRMA may contribute to double counting of data within reported meta-analyses. No exploration of such overlaps took place in this study.

The overview of SRMAs indicates via limited quantity, but high quality of evidence that caffeine is efficacious and safe to administer to reduce apnea and stimulate breathing in infants. However, owing to the limited quantity and quality of relevant evidence, no robust conclusions can be made with regard to the comparative effectiveness and safety of different timings and doses of caffeine administration. Larger and long-term trials are needed to confirm the different aspects of caffeine use in neonatal apnea, particularly the ideal regimen to use.