Side Effects of Caffeine Given to Premature Babies

Caffeine in preterm infants: where are we in 2020?

, Sanja Zivanovic , Caroline Hartley , Daniele Trevisanuto , Eugenio Baraldi , Charles Christoph Roehr

ERJ Open Inquiry 2020 vi: 00330-2019; DOI: 10.1183/23120541.00330-2019

Abstract

The incidence of preterm birth is increasing, leading to a growing population with potential long-term pulmonary complications. Apnoea of prematurity (AOP) is i of the major challenges when treating preterm infants; information technology tin pb to respiratory failure and the demand for mechanical ventilation. Ventilating preterm infants can be associated with severe negative pulmonary and extrapulmonary outcomes, such equally bronchopulmonary dysplasia (BPD), astringent neurological impairment and death. Therefore, international guidelines favour non-invasive respiratory support. Strategies to improve the success charge per unit of non-invasive ventilation in preterm infants include pharmacological treatment of AOP. Amidst the unlike pharmacological options, caffeine citrate is the current drug of choice. Caffeine is effective in reducing AOP and mechanical ventilation and enhances extubation success; it decreases the take chances of BPD; and is associated with improved cerebral outcome at 2 years of age, and pulmonary function up to 11 years of historic period. The commonly prescribed dose (xx mg·kg⁻¹ loading dose, v–10 mg·kg⁻¹ per twenty-four hours maintenance dose) is considered safe and effective. However, to date there is no commonly agreed standardised protocol on the optimal dosing and timing of caffeine therapy. Furthermore, despite the wide pharmacological safety profile of caffeine, the role of therapeutic drug monitoring in caffeine-treated preterm infants is still debated. This land-of-the-art review summarises the current noesis of caff­eine therapy in preterm infants and highlights some of the unresolved questions of AOP. We speculate that with increased understanding of caffeine and its metabolism, a more than refined respiratory management of preterm infants is feasible, leading to an overall improvement in patient result.

Abstract

Caffeine is the current drug of selection to forestall and treat apnoea of prematurity. There is no agreed protocol on the optimal timing and dosage of caffeine therapy for preterm babies. Data on caffeine metabolism may optimise individualised therapy. http://flake.ly/2LMuJPY

Background

Preterm nascence represents a meaning healthcare burden and is among the leading causes of infant mortality and long-term morbidity [i]. Therefore, the prevention of morbidities related to prematurity is considered a central health priority [two, 3]. As the number of children surviving extremely preterm birth is likely to continue to rise over the coming years, an increment in children with respiratory complications is expected [ii, 4], especially those with chronic lung diseases such as bronchopulmonary dysplasia (BPD) [v–7]. To minimise lung injury and illnesses related to prematurity, neonatologists are focusing on non-invasive ventilation techniques from the very first minutes of life [8, nine]. Withal, non-invasive respiratory support is often ineffective, with a high failure charge per unit of up to 50% in very depression birthweight (VLBW) infants [10, xi], most commonly due to insufficient respiratory bulldoze. Thus, apnoea is one of the major well-recognised challenges of prematurity, and remains i of the main indications for invasive ventilation [12–14]. Since the 1970s, methylxanthines have been routinely prescribed in preterm infants to prevent apnoea of prematurity (AOP) and reduce the demand for invasive ventilatory back up [13]. Of the methylxanthines, caffeine is the drug of choice considering of its longer half-life, wider therapeutic range, toll-effectiveness and decreased need for drug-level monitoring compared to other methylxanthines, especially theophylline [xv].

Caffeine is one of the top five near prescribed treatments in neonatology [16]. Its stimulating event was originally recognised by the Ethiopians, only it was the Sufis who probably first used information technology expressly for its pharmacological effects, in the 15th century [17, 18]. Caffeine is a trimethylated xanthine with a similar molecular construction to adenosine. It acts as a nonspecific inhibitor of ii of the four known adenosine receptors, in particular A1 and A2A, located at multiple sites in the brain [19]. The furnishings of caffeine on the brain, the lung and the cardiovascular system are summarised in effigy 1 [12, 18–40]. The dosage used in the largest randomised controlled trial (RCT) conducted to date investigating caffeine in preterm infants, the Caffeine for Apnea of Prematurity (CAP) trial [33], is the most oftentimes quoted template for local caffeine therapy protocols. Nevertheless, despite its frequent employ in routine neonatal practice, there are currently no commonly agreed, standardised protocols on caffeine assistants, and there is a particular dearth of knowledge regarding the optimal timing and dosage in the most young preterm infants (<29 gestational weeks (GW)). Additionally, concerns have been raised about potential safety bug and adverse furnishings, some of which may relate to loftier caffeine dosages [19, 32]. These data suggest that the optimal dose and timing of caffeine must still be investigated and be chosen with caution when treating preterm infants. The aim of this review is to present the country-of-the-art of current utilize of caffeine citrate in preterm infants, with a focus on the known short- and long-term effects of the drug, reported data on timing, dosage and monitoring in club to trigger time to come research on this hot topic.

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Figure 1

Schematic of the known effects of caffeine citrate during early on development on the encephalon, the lung and the cardiovascular system derived from fauna and infant studies. The showtime cavalcade indicates furnishings on a molecular level, while the second column describes demonstrated caffeine effects in the context of the specific system. CO₂: carbon dioxide; TNF: tumour necrosis factor; ELBW: extremely depression birthweight; IPPV: intermittent positive pressure level ventilation; PMA: post-menstrual age; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus.

The effects of caffeine in preterm infants

Neurological effects

A number of studies have suggested that caffeine intake in preterm infants may have a neuroprotective event, although researches on animal models have shown contrasting results, probably impacted by the species examined, dose of caffeine used, neurodevelopmental stage at the time of assistants and duration of exposure (figure 1) [23, 41–43].

In preterm infants, enhanced cerebral cortical activeness, observed as increases in amplitude and periods of continuity on electroencephalography recordings, is seen inside 2 h of administration of caffeine [25, 26], suggesting an effect on neurological function. Furthermore, at 36 weeks post-menstrual age (PMA) infants treated with caffeine therapy had a college amplitude-integrated electroencephalography score compared to the control grouping (p<0.001), without an increase in seizure activeness [26]. The most comprehensive report to engagement exploring the long-term effects of caffeine in preterm infants is the CAP trial, whose main objective was to make up one's mind whether survival without neurodevelopmental disability at a corrected age of eighteen–21 months was contradistinct if AOP was treated with caffeine [33]. 2006 infants (birthweight 500–1250 g) were enrolled and randomly assigned to receive either caffeine (20 mg·kg⁻¹ intravenously as loading dose followed by a maintenance dose of 5 mg·kg^−ane per day) or placebo. The caffeine grouping had a reduced likelihood of expiry or clinical disability (twoscore.2% versus 46.ii%; p=0.008), together with a reduced incidence of cognitive palsy (4.4% versus 7.iii%; p=0.009) and of cognitive delay (33.viii% versus 38.3%; p=0.04) [27]. The results of the subsequent follow-up at 5 years of age showed no significant difference between caffeine treatment and placebo in the blended effect of death or disability (21.one% versus 24.8%; p=0.09) [28], but a significant improvement of gross motor role in the caffeine group (odds ratio adjusted for centre 0.64, p=0.006). The long-term follow-upwards at 11 years of age confirmed previous results of reduced risk of motor impairment (nineteen.7% versus 27.v%; p=0.009), with no significant departure in the rates of functional impairment (31.vii% versus 37.half-dozen%; p=0.07), academic performance and behavioural problems (10.9% versus 8.iii%; p=0.22) [29, 30].

Prolonged treatment with caffeine reduces hypoxaemia events in premature infants [44], the severity and elapsing of which are probably associated with agin neurodevelopmental outcomes [45, 46]. Overall neonatal caffeine therapy, at the doses used in the CAP trial, appears to be safe into heart-school age, with no adverse effects on general motor function, intelligence, attention and behaviour.

Caffeine for apnoea, ventilatory support and extubation

Methylxanthines take been used for >xl years in neonatal medicine to reduce the frequency of apnoea, but, apart from the CAP trial, studies and systematic reviews comparing caffeine versus placebo take mainly addressed short-term respiratory outcomes, such as apnoea prophylaxis (i review, two trials), apnoea handling (one review, 3 trials), extubation success (one review, two trials) and ventilator support (intermittent positive pressure level ventilation (IPPV) and/or mechanical ventilation) (5 trials), with a consequent uncertainty of the long-term benefit/gamble ratio of this therapy [15, 33, 47].

The Cochrane review published in 2010 [35], included, in add-on to the CAP trial, two studies evaluating the furnishings of prophylactic caffeine on brusque-term outcomes. The review concluded against the back up of the use of safe caffeine for preterm infants at risk of apnoea, but simply ane study reported apnoea (as defined by duration >20 southward with bradycardia <100 bpm or cyanosis) equally an issue in the results [48].

Withal, a single-centre RCT [49] on premature infants (birthweight <1200 g) demonstrated a reduction in apnoea episodes (as a breathing interruption for ≤20 s with bradycardia and/or cyanosis) in the caffeine-treated group compared to placebo (15.iv% versus 61.5%, 95% CI 0.097–0.647; p=0.001), with the more than immature infants having the greater do good of prophylactic caffeine on the incidence and severity of apnoea. The limitations of this report, which was published after the 2010 Cochrane review, are the monocentric setting, the small sample size (26 infants in the treatment grouping versus 26 in the placebo grouping) and the unprecise detection of apnoea (daily neonatal intensive care unit reports and monitor downloads). In full general, the definition of prophylactic caffeine in terms of hours of life at first administration can be debated, as it is supposed that apnoea events can occur from the offset 60 minutes of life, and studies comparing caffeine in the delivery room versus placebo to reduce the incidence of apnoea are lacking.

Another Cochrane review published in 2010 [15] evaluated the furnishings of methylxanthine treatment on the incidence of apnoea (American Academy of Pediatrics 2003 definition [50]) and included three trials on caffeine. The analysis of the two trials [51, 52] on caffeine, without considering the CAP trial, found significantly less treatment failure (relative risk 0.46, 95% CI 0.27–0.78, number needed to treat 3) equally defined by <50% reduction in apnoea, or employ of IPPV, or death during the report period (by v and 10 days from starting treatment).

Finally, the last Cochrane review of the series summarised the effects of condom methylxanthine treatment to amend the chances of successful extubation, with failed extubation defined within 1 week of commencing handling, if unable to wean from IPPV and extubate, or reintubation for IPPV, or need for use of continuous positive airways pressure (CPAP) [36]. Overall analysis of the 6 included trials showed that methylxanthine handling results in an accented reduction of 27% in the incidence of failed extubation. Even so, although all trials had the aim of improving the chances of successful extubation, protocols differed considerably, and only 2 trials compared caffeine versus placebo [33, 53].

The large CAP trial was included in each of the three Cochrane reviews, simply did not report on apnoea outcomes and extubation success, although recruited infants received caffeine for whatever i of the three indications (prophylaxis for apnoea (22%), handling of apnoea (xl%) or prophylaxis for extubation (38%)).

Nevertheless, the CAP trial clearly demonstrated that caffeine handling within the first x days of life determined a reduction in each of the three levels of respiratory support (need for endotracheal tube, any positive pressure ventilation (PPV), supplemental oxygen) of 1 week compared to placebo (p<0.001), with no difference according to the indication for starting treatment. Interestingly, the positive results on respiratory back up, together with the significantly reduced rate of BPD, surgical closure of patent ductus arteriosus (PDA) and of utilize of postnatal steroids, explained 55% of caffeine effect on the primary neurological outcomes at 18–21 months of age (with the most of import variable beingness earlier discontinuation of PPV), suggesting a direct neuroprotective result of the drug [33].

Every bit a consequence of these findings, caffeine is the drug of pick to reduce apnoea rates, need for IPPV, ventilatory support, extubation failure and PDA ligation in preterm infants. However, the role of caffeine on longer term clinical outcomes, such as apnoea incidence till 34 corrected gestational weeks, infant respiratory morbidity within the showtime year of age, need for oxygen treatment after discharge and lung function up until adult age needs to be farther investigated in accordingly designed RCTs.

BPD and long-term pulmonary outcomes

Caffeine is one of the few known drugs proven to reduce the risk of BPD at 36 weeks PMA. All the same, most of the studies evaluating this result have been limited in number, have used unlike definitions of BPD and have non reported longer-term pulmonary outcomes. The main data stalk from the results of the CAP trial. Other studies have compared different timing of caffeine treatment or different doses of the drug, and have been conducted mainly retrospectively.

In the Cochrane review on methylxanthines for extubation [36] two trials, the first comparing caffeine versus placebo [53] and the 2nd comparing caffeine, theophylline and placebo, reported rates of BPD divers equally oxygen supplementation at 28 days of life in the beginning, merely undefined in the 2d. Therefore, conclusions on this consequence could non be performed.

In the CAP trial [33], caffeine use led to a 36% subtract in BPD at 36 weeks PMA every bit defined by Due southhennan et al. [54], although the definition of BPD is continuously put into question and debate [55, 56]. Interestingly, the post hoc subgroup analysis of the CAP data showed an influence of postnatal age at onset of caffeine treatment on BPD reduction [34], and these findings were confirmed by subsequent accomplice studies (farther details in section on Benefits of early caffeine assistants) [32, 57]. Encouragingly, the upshot of caffeine therapy on BPD in the neonatal menstruum seems to have positive repercussions on later lung function besides, as demonstrated by the results of the follow-up at eleven years in Australian former CAP study participants. In this study, expiratory flows were improved by 0.fivesd in children randomised to caffeine (forced expiratory volume at 1 s mean z-score −i.00 versus −one.53, 95% CI 0.xiv–0.94; p=0.008), with 11% versus 28% with forced vital capacity values below the fifth centile [37]. Even so, when the respiratory outcomes were adapted for the higher incidence of BPD in the placebo group, the independent effect of caffeine was lost. As suggested in a comment by Jobe [58] subsequently the publishing of these results, caffeine is extremely useful in minimising apnoea of prematurity with associated improved lung and motor part at eleven years of age. Nevertheless, it is not a lung drug per se, as it minimises interventions for respiratory command abnormalities in the very preterm infant that result in lung injury persisting into childhood.

Overall, studies accept demonstrated that caffeine is effective in reducing BPD rates, especially when administered in the start 3 days of life (see later on). A follow-up of the CAP trial has shown a positive long-term upshot of caffeine on lung function. However, further trials are needed in order to describe more than conclusions on the long-term benefits of caffeine in terms of respiratory outcomes, and to target the appropriate population for early treatment.

Caffeine timing: early on versus late

Benefits of early caffeine administration

A post hoc subgroup analysis of results from the CAP trial suggested an influence of postnatal historic period at onset of caffeine treatment on BPD reduction, with a decrease in the rate of BPD by 52% in those with early treatment (1–3 days of life) in contrast with a reduction of only 23% if started after day 3 [34]. Since the publication of the results of the CAP trial caffeine has been administered closer and closer to birth, sometimes fifty-fifty in the delivery room [12]. The 2019 European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants and the recently published National Constitute for Health and Care Excellence recommendations on preterm infants emphasise the role of the timing of caffeine initiation, suggesting that before treatment is associated with increased benefit [59, 60]. Nonetheless, no formal guidance specifying the exact timing of therapy beginning has been provided so far.

A retrospective accomplice written report on 140 infants (birthweight <1250 g) by Patel et al. [61] in 2013 demonstrated that early caffeine initiation (<iii days of life) was associated with a reduced rate of decease or BPD, decreased requirement of PDA treatment and shorter duration of mechanical ventilation compared to subsequently caffeine initiation (≥3 days of life). Infants with birthweight <750 yard, considered to be at the highest risk for BPD or death, showed the strongest association between early caffeine initiation and decreased incidence of this combined outcome. These results were confirmed by two retrospective studies conducted in 2014. The beginning study included 29 070 VLBW infants [32], half of whom received early on caffeine treatment and were matched on baseline demographics to infants in the late caffeine group. Infants in the early on caffeine group had a reduced charge per unit of the blended event of death or BPD, less PDA requiring handling and fewer days of mechanical ventilation. Although infants built-in at <24 GW treated with early caffeine showed increased odds of death, this result was attributed to survival bias (need to survive to receive later caffeine), as many very preterm infants die in the starting time 48 h [32]. The second study by Fiftyodha et al. [57] from the Canadian Neonatal Network also showed decreased odds of death or BPD in the group treated with early caffeine (<2 days of life), with nigh of this effect stemming from the reduction of BPD. In add-on, they constitute a reduced incidence of PDA and duration of mechanical ventilations. Importantly, follow-up of 2108 infants in this study at 18–24 months corrected historic period demonstrated lower odds of neurodevelopmental impairment in the early on caffeine grouping [62].

Three prospective studies accept too suggested benefits of early caffeine administration. A small pilot double-blinded, randomised, placebo-controlled trial conducted in 2015 on 21 infants (<29 GW) randomised to early safe apply of caffeine (<2 h of age) or to subsequently caffeine initiation (at 12 h of historic period), reported improved claret pressure and systemic blood menstruum (significantly higher superior vena cava flow and correct ventricular output) in the early group, and a trend towards reduced rates of intubation past 12 h of historic period (27% versus lxx%; p=0.08), just no reduction in the number of days of mechanical ventilation [40]. More recently, a prospective cohort report on 986 infants (≤32 GW) with respiratory distress syndrome demonstrated that early on caffeine treatment (<24 h after nascence) compared to later treatment (≥two days) was associated with a significantly reduced need for invasive ventilation, total elapsing of mechanical ventilations and significantly lower odds of intraventricular haemorrhage (IVH) and PDA, but no difference in the incidence of BPD and mortality rates [63]. Finally, in a small accomplice randomised study, Dekker et al. [12] demonstrated benefits of caffeine administered in the delivery room on minute volumes and tidal volumes at 7–9 min after nascency compared to caffeine given after arrival in the neonatal intensive intendance unit of measurement.

3 systematic reviews and meta-analyses accept summarised the results of all the studies published and then far comparison early versus belatedly caffeine assistants. The starting time, conducted past Park et al. [64] in 2015 included VLBW infants (birthweight <1500 g) treated with early on utilise of caffeine (0–2 days of life) versus late use (≥three days of life). This meta-assay of 5 studies [32, 34, 61, 65, 66] concluded that early caffeine apply was associated with a decreased incidence of death, BPD and the composite measure of the ii, while the duration of mechanical ventilation was not significantly reduced. The second review and meta-assay by Kua and Lee [67], published in 2017, selected 14 studies in which early caffeine (<3 days of life) was compared with late caffeine, placebo or theophylline. The meta-assay of the five cohort studies [34, 57, 61, 65, 68] comparing early versus late caffeine showed reduced rates of BPD, PDA, PDA requiring surgical intervention, brain injury and duration of mechanical ventilation in the early on caffeine group, but an increased rate of death, which was non confirmed by the pooled analysis of two randomised control trials [34, 69]. A more than recent systematic review and meta-analysis past Pakvasa et al. [70] has explored the issue of both timing of caffeine initiation and dose of caffeine therapy on clinical outcomes (primary: BPD equally defined by each specific report or by the demand for oxygen at 36 weeks PMA; secondary: death, BPD or decease, PDA, necrotising enterocolitis, retinopathy of prematurity, duration of mechanical ventilation and neurodevelopmental impairment). The assay of the five included observational studies [32, 57, 61, 66, 71] demonstrated a decreased hazard of BPD with earlier initiation of caffeine (<three days of life), while only one RCT comparing early versus routine use of caffeine was identified, and therefore meta-assay could not be performed [34].

The clinical benefits of beginning caffeine treatment before iii days of age has been summarised recently by Dobson and Hunt [72], showing the reduced incidence of BPD (with moderate quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation system), expiry or BPD, IVH, necrotising enterocolitis, need for treatment of PDA, retinopathy of prematurity and use of postnatal steroids (all of which with depression quality of show) with the early treatment.

Contrasting results on early caffeine administration

A retrospective assay conducted past Patel et al. [73] on VLBW infants (birthweight <1500 grand) receiving initial CPAP (on twenty-four hours of life 0) compared the effect of early on caffeine (day of life 0) versus routine caffeine (day of life ane–6). The results demonstrated no deviation in CPAP failure divers every bit invasive mechanical ventilation or surfactant therapy on day of life 1–6 (22% versus 21%, adapted odds ratio (aOR) 1.05), in exposure to a maximal inspiratory oxygen fraction >0.iii in the offset calendar week of life (27% versus 32%, aOR one.05) and in the full duration of CPAP therapy (median iii versus 2 days, aOR one.02). The authors hypothesised that mechanisms influencing CPAP failure might be unlike from those influencing the risk of BPD or elapsing of respiratory support.

In a contempo unmarried-centre double-blinded placebo-controlled trial [74], preterm infants (23–30 GW) requiring mechanical ventilations in the commencement five postnatal days were randomised to receive an early caffeine loading dose of 20 mg·kg⁻¹ followed by five mg·kg⁻¹ per mean solar day or placebo until considered gear up for extubation (the control group then received a pre-extubation bolus of caffeine, whereas the intervention group received a pre-extubation bolus of placebo). Caffeine handling did non reduce age of start successful extubation (>24 h) nor full elapsing of mechanical ventilation, incidence of BPD, severe BPD or the composites of BPD or death. Furthermore, a nonsignificant trend towards higher mortality in the early caffeine group led to a cautious decision to stop the trial (22% versus 12%; p=0.22). However, ane-3rd of the deaths in the caffeine group occurred after the showtime successful extubation, when both groups were receiving caffeine. Furthermore, a recent external assay of the study [75] highlights that, given the early termination of the trial, the differences in prognostic variables for mortality between groups (gender, Apgar score at 5 min and birthweight) and the imprecision in the estimates of the treatment issue of early caffeine on bloodshed, no confident conclusions can exist determined regarding the effect of early caffeine on mortality.

Currently at that place are 2 principal ongoing trials exploring the utilize of early on caffeine initiation (data sourced from ClinicalTrials.gov database (https://clinicaltrials.gov)). The commencement is a double-blind, randomised, placebo-controlled trial evaluating the need for endotracheal intubation within the first 12 h of life and the cardiac output in neonates born at <32 GW receiving caffeine either inside ii h after birth or at 12 h later on birth (clinicaltrials.gov identifier NCT0308647). The second is a randomised, double-blind controlled trial of extremely low birthweight newborns (birthweight ≤1000 g and <28 GW) aiming to evaluate the cumulative incidence of death and BPD between groups receiving caffeine (xx mg·kg⁻¹ i.five. bolus, so i.v. or by mouth 5 mg·kg⁻¹ daily for 14 days), or placebo (dextrose) inside 24 h of life and and then for the subsequent 14 days (clinicaltrials.gov identifier NCT02524249). The results of these trials will exist able to shed further light on the best timing for caffeine administration in lodge to potentially reduce these short- and long-term outcomes.

Table ane summarises the studies conducted to date in this area. Overall, caffeine administered inside the start three days of life seems to provide a reduction in BPD rates, PDA and IVH, just does not reduce the risk of CPAP and extubation failure. In addition, at that place are even so contrasting results of the event of early caffeine initiation on duration of mechanical ventilation and death. In that location is an urgent need for RCTs addressing this event, as nigh results stem from retrospective studies or trials with pocket-size sample sizes.

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TABLE i

Summary of retrospective studies, post hoc analyses, randomised controlled trials (RCTs) and systematic reviews and meta-analyses comparing early on versus late caffeine treatment in preterm infants

Caffeine dosage: high versus low/standard dose

Similar to timing of caffeine handling initiation, there is nonetheless doubtfulness regarding the optimal dose of caffeine in preterm infants. In 1977 Aranda et al. [76] administered 20 mg·kg⁻¹ i.5. caffeine citrate to 18 preterm infants followed past 5 or 10 mg·kg⁻¹ in one case or twice daily, demonstrating a reduction in mean frequency of apnoeic spells from 13.6 to 2.i per day (p<0.01). Subsequent studies investigating the relationship of dose and plasma concentrations of caffeine indicated a rapid ascent in minute ventilation followed past a plateau in the ventilatory response with increasing doses of the drug [77]. These observations, coupled with the unusual pharmacokinetic profile of caffeine, described later, led to the standard dose regimen that is widely used today: an i.five. loading dose of twenty mg·kg⁻¹ of caffeine citrate (10 mg·kg⁻¹ of caffeine base) followed past a maintenance dose of 5–ten mg·kg⁻¹ per solar day started 24 h afterwards the loading dose. This regimen was the one adopted in the CAP trial and recommended by the U.s.a. Nutrient and Drug Administration to treat apnoea of prematurity [78, 79].

In 1992 an RCT was published comparison two different regimens of caffeine with theophylline in a group of preterm infants (gestational historic period <31 GW), showing a loading dose of fifty mg·kg⁻¹ caffeine citrate to be more effective in reducing apnoeic episodes within 8 h after assistants than a loading dose of 25 mg·kg⁻¹, with no particular side-furnishings [80]. In 2003, a randomised double-blind clinical trial of three dosing regimens of caffeine citrate for periextubation management of ventilated preterm infants (<32 GW) demonstrated that the college daily maintenance doses (of 15 and thirty mg·kg⁻ⁱ per day) significantly reduced documented apnoea, but with no statistically significant difference in the incidence of extubation failure [81]. However, in a subsequent multicentre double-bullheaded RCT the same authors found that a dose of 20 mg·kg⁻¹ given 24 h before a planned extubation or within six h of an unplanned extubation in infants <30 GW reduced the rate of extubation failure within 48 h compared to a low maintenance dose of v mg·kg⁻¹, with no effect on infant mortality and major neonatal morbidities in the showtime year of life. Furthermore, a significant reduction in duration of mechanical ventilations was shown in infants <28 GW receiving the high dose regimen [82]. Confirming these results, an RCT demonstrated that the utilize of high loading and maintenance doses of caffeine citrate (loading/maintenance doses of 40/20 versus 20/10 mg·kg^−ane) was associated with a significant decrease in extubation failure in preterm infants <32 GW and a decreased frequency of apnoea, with no differences in the incidence of major disabilities, but with more episodes of tachycardia [83].

Three systematic reviews and meta-analyses accept summarised the results of RCTs assessing the efficacy and safety of college dosage regimens of caffeine in preterm infants. A review by 5liegenthart et al. [84] identified six RCTs (620 patients, <32 GW) with considerable variation in loading and maintenance doses, besides as duration of therapy between allocation arms. The meta-assay of data showed a potential benefit of a higher caffeine dosing regimen on the combined result of decease or BPD and on BPD alone at 36 weeks PMA when therapy was given for >14 days. Meta-analysis for apnoea frequency could not be performed due to variation in definitions. One study reported an increased chance of cerebellar bleeding (CBH) with higher doses of caffeine [85]. Yet, this study was powered only to detect differences in the primary effect of microstructural brain development at term-equivalent age, and long-term neurodevelopment is a better effect compared to single cerebellar lesions or other short-term neurological effects. In addition, a contempo retrospective written report of 218 preterm infants <28 GW divided into two groups to receive either a median loading dose of the drug of 80 mg·kg⁻¹ or of 20 mg·kg⁻¹ within the first 36 h of historic period, has shown no difference in the incidence of neonatal morbidities, including CBH, between the 2 groups (two.5% versus 1.seven%) [86]. A second review and meta-assay published by Brattström et al. [87] comparison a high versus low dose of caffeine [88, 90–] identified six RCTs (total of 816 infants, <32 GW), with loading and maintenance doses varying betwixt xx and 80 mg·kg⁻ⁱ per day and iii–20 mg·kg⁻¹ per day, respectively, and diverse times of starting handling. The use of high dose had no impact on bloodshed, but showed a reduction of BPD [91] with a adventure ratio of 0.76 (0.sixty–0.96), very similar to Vliegenthart's calculation [92]. Furthermore, it resulted in fewer cases of extubation failure and apnoea and a shorter elapsing of mechanical ventilations, despite higher rates of tachycardia.

The last systematic review and meta-analysis past Pakvasa et al. [70] included three RCTs comparing high-dose caffeine with the standard dose [82, 83, 85], showing a decreased hazard of BPD in the outset grouping. In improver, the meta-analysis of three studies demonstrated an increased efficacy of loftier-dose caffeine in reducing AOP [81–83].

One boosted review and meta-analysis published in 2018 [92] has evaluated efficacy and safety of different maintenance doses of caffeine citrate to care for AOP. The review included 13 RCTs, of which five were written in English language. It concluded that the high-dose grouping (maintenance doses of x–twenty mg·kg^−one) exhibited greater constructive treatment rate (defined equally successful extubation within 72 h afterward handling onset, fewer than iii apnoea episodes per day, and no significant abnormalities in respiratory rhythm), success rate for ventilator removal, lower extubation failure rate, frequency of apnoea, apnoea duration and rate of BPD.

The bear witness so far (summarised in tabular array two) suggests that higher doses of caffeine treatment may exist more than effective in reducing apnoea rates and extubation failure, besides every bit BPD at 36 weeks PMA. Yet, future RCTs of high versus low/standard dose of caffeine with larger sample sizes are needed to improve allocation darkening and result reporting. Chiefly, lack of data on long-term outcomes and condom limits the use of caffeine regimens other than those used in the CAP trial in standard neonatal care.

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Table 2

Summary of retrospective studies, mail hoc analyses, randomised controlled trials (RCTs) and systematic reviews and meta-analyses comparison high versus depression/standard doses of caffeine citrate in preterm infants

Caffeine pharmacokinetics

Caffeine metabolism and pharmacokinetics

Nigh of the studies investigating the metabolism of caffeine in premature newborns were conducted between the 1970s and the 1990s past Aranda and co-workers [93, 94]. Using high-performance liquid chromatography (HPLC), these authors were able to show a strict correlation between administered dose of drug and plasma level [77], as well as between plasma and cerebrospinal fluid levels [95]. The route of caffeine assistants does not affect its pharmacokinetics, as in that location is almost complete bioavailability after its oral or i.v. administration. Oral caffeine citrate is apace and completely absorbed by the gastrointestinal tract, as there is nearly no kickoff-pass metabolism, with the peak plasma concentration often reached in <1 h [96].

Caffeine metabolism occurs in the liver, mainly by CYP1A2, with a subsequent North-demethylation at positions 1, three and 7 and hydroxylation at position 8. In preterm neonates, ∼86% of caffeine citrate is excreted unchanged in the urine [97], every bit the processes of caffeine metabolism maturates progressively through fourth dimension (N7-demethylation at the postal service-natal age of ∼4 months [98], acetylation past N-acetyltransferase (NAT2) completely developed past 1 twelvemonth of postnatal historic period [99] and 8-hydroxylation action starting equally early equally 1 month of age [100]). Thus, the maturity of the hepatic enzymes, dependent mainly by the postnatal historic period regardless of birthweight and gestational age, affects the plasma half-life of the drug [98, 101].

Due to this difference in metabolism, and to the slow urinary excretion of unmetabolised drug at the earlier gestational ages, the serum half-life of caffeine in infants ranges from forty to 230 h (>17-fold greater than that in adults), decreasing with the advance of PMA to ∼2–iv h by 6–8 months [102]. Of note, considering of the long half-life, caffeine may persist in an infant's plasma for some days subsequently cessation of therapy [102, 103].

Elimination of caffeine occurs mainly by renal excretion in the get-go weeks of life, which is slower in premature and term neonates compared with older children and adults, because of immaturity of renal functions [96]. Clearance of caffeine in neonates is influenced past gestational historic period, postconceptional historic period, parenteral diet and comorbidities [96, 99, 100, 103, 104], with values ranging from 0.08  to 0.13 mL·kg⁻¹·min⁻¹ compared to that of adults and older children of 1.5 and 4.4 mL·kg^−ane·min⁻¹, respectively [100, 105].

These data highlight that extremely premature infants do non behave equally "fiddling adults" with respect to caffeine pharmacokinetics, every bit caffeine metabolism and urinary elimination are strongly adamant by the maturity of liver enzymes and renal role, which are influenced by gestational and postnatal historic period and by the presence of morbidities affecting these organs.

Therapeutic drug monitoring

Caffeine dosing and therapeutic drug monitoring (TDM) vary from practice to practice. Caffeine has a wider therapeutic range than theophylline, therefore the role of TDM for the control of therapeutic ranges of caffeine has often been challenged [106]. A therapeutic level of caffeine is considered between v and 25 mg·Fifty⁻¹ (or µg·mL^−one), while toxic levels are reached with >40–fifty mg·50⁻¹ [107, 108]. An observational study by Natarajan et al. [109] in neonates built-in between 23 and 32 GW found that caffeine citrate doses of 2.5–10.9 mg·kg⁻¹ (median 5 mg·kg^−ane), obtained plasma levels ranging betwixt v.1 and 20 mg·50⁻¹ in 94.eight% of cases (inside the normal therapeutic ranges), independent of gestation, thus indicating against the necessity of TDM. Yet, in the subgroup of infants in whom caffeine plasma concentrations were obtained for lack of clinical efficacy, iii-quarters of the levels were within the normal range (15 mg·50⁻¹), which suggests that higher doses and plasma concentrations may be required for optimal efficacy in some preterm neonates. In addition, the numbers of infants with renal or hepatic dysfunction in the study were small at the time of caffeine level, and no information on relation to efficacy with regard to apnoea was reported. Importantly, another study demonstrated that a standardised regimen leads to a high variation of serum levels of caffeine metabolites in infants <33 GW, with no correlation betwixt episodes of apnoea and caffeine serum concentrations in the post-extubation menses [110]. Therefore, caffeine TDM may help dose individualisation in order to minimise the incidence of toxic agin furnishings, optimise efficacy and the performance of diagnostic tests, especially for patients who are unresponsive to therapy (quantum apnoea, bradycardia or desaturations without other obvious illness-related aetiologies) [106, 111, 112]. In addition, a retrospective chart review of infants built-in ≤29 GW demonstrated that those with an average caffeine concentration >fourteen.5 μg·mL^−ane had lower incidence of chronic lung disease and PDA, lesser number of days on ventilator and oxygen, less need for diuretics and lower length of stay and total hospital charges (all p<0.05) [113]. If these findings are confirmed prospectively, it could become useful to introduce TDM in routine practice.

Caffeine levels can exist measured in plasma, saliva or urine by enzyme immunoassay technique, which is simple, user-friendly and rapid, or using HPLC, which is the virtually accurate technique for caffeine TDM in the clinical setting [114, 115]. In recent years, minimally invasive techniques have been proposed for the detection of caffeine levels, with promising results. In 2013, Patel et al. [116] used dried claret spots (DBS) to measure caffeine dosage with liquid chromatography triple quadrupole mass spectrometry from 67 preterm infants at random time intervals post-obit either oral or i.v. doses. The study showed a adept agreement between pharmacokinetic parameters estimated using DBS samples and historical caffeine pharmacokinetic parameters based on plasma samples.

In 2016, Bruschettini et al. [117] confirmed the importance of limiting the size of blood samples to avert anaemia due to blood sampling for TDM in preterm infants and highlighted the advantages of DBS over conventional sampling techniques. To overcome the problem of haematocrit, culling strategies based on new microfluidic sampling procedures or volumetric microsampling devices have been described and proved to be a reliable sampling approach for caffeine [118, 119]; yet, the drawback is the use of expensive devices for routine TDM analyses or for pharmacokinetic studies. To overcome the problem of blood sample size, invasiveness and cost, in 2017, Chaabane et al. [120] determined caffeine concentrations in both saliva and serum of preterm infants (mean gestational age 32.2±0.7 weeks), showing a proportional increase in both saliva and serum caffeine concentration to the administered dose, with the saliva caffeine concentrations strongly correlating with those from serum.

Despite different studies exploring the all-time minimally invasive and price-effective methods to monitor therapeutic ranges of caffeine in clinical exercise, few have tried to develop a pharmacokinetic model to adjust caffeine dosage and none has investigated the relationship between caffeine biofluid levels in the showtime weeks of life and clinical outcomes, such as apnoea frequency [121, 122]. Interestingly, in 2017 Moch et al. [122] developed simulation models of caffeine concentrations, proposing the need of adjusting the maintenance doses through time in preterm neonates, with the administration of six mg·kg⁻¹·solar day⁻¹ in the 2d calendar week of life, vii mg·kg^−ane·day⁻¹ in weeks iii–iv and eight mg·kg⁻¹·day^−one in weeks v–viii.

Further studies are needed to determine whether caffeine dosage tin can exist optimised for the individual patient through TDM in particular situations. Drug levels could be performed minimising the drawn blood volume (for instance with DBS) or, fifty-fifty better, non-invasively (for example in urine or saliva samples). Prospective pharmacokinetic studies of caffeine with relation to both clinical outcomes (apnoea episodes, extubation failure, respiratory support at 36 weeks PMA, respiratory morbidity in the outset yr of life), and adverse events (tachycardia, hypoglycaemia, seizures, weight loss, neurodevelopment at two and 5 years) should be conducted in gild to identify the appropriate dosage of the drug.

Conclusions

In preterm infants, caffeine is effective in reducing apnoea frequency, the need for IPPV and mechanical ventilation, every bit well as enhancing the success of extubation. In add-on, caffeine-treated newborns have lower rates of BPD, IVH and PDA, with positive long-term outcomes on pulmonary role and neurodevelopment. Despite the longstanding employ of caffeine in the neonatal intensive intendance units, controversies regarding the optimal timing and dosage of caffeine therapy still remain [123], equally the majority of data on long-term outcomes and safety stalk from one randomised placebo-controlled trial [33]. Furthermore, the role of therapeutic drug monitoring needs to be addressed. The paucity of data on caffeine metabolism related to clinical outcomes in extremely preterm neonates highlights the importance of further research in this field in guild to ameliorate refine the respiratory management of these subjects.

Footnotes

• Support statement: The authors gratefully acknowledge that Fifty. Moschino is the recipient of the European Respiratory Society Short-term Enquiry Fellowship 2017, and C. Hartley received grants from The Wellcome Trust and the Imperial Order during the writing of the manuscript.

• Disharmonize of interest: Fifty. Moschino reports an ERS Short-Term Research Fellowship 2017 during the writing of this article.

• Conflict of interest: S. Zivanovic has zippo to disclose.

• Conflict of interest: C. Hartley reports grants from The Wellcome Trust and the Majestic Club during the writing of this article.

• Disharmonize of interest: D. Trevisanuto has nothing to disclose.

• Disharmonize of interest: E. Baraldi has nothing to disclose.

• Disharmonize of involvement: C.C. Roehr reports that donations for processing laboratory samples were received from Chiesi Pharmaceuticals (Parma, Italian republic) for conducting an investigator-initiated written report on caffeine metabolism in newborn infants. None of the content of this review relates to the company, their donation or the product they distribute. The company has not been involved in the writing of the review.

• Received November 28, 2019.
• Accepted Dec 4, 2019.

• Copyright ©ERS 2020

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Source: https://openres.ersjournals.com/content/6/1/00330-2019