Caffeine is a proven medication used for the prevention and treatment of apnea in premature infants, offering both short- and long-term benefits. International guidelines provide a range of recommendations regarding the preterm population eligible for caffeine prophylaxis, including the timing, dosage, and duration of treatment. Our national guidelines, published prior to the most recent updates of the international guidelines, recommend the use of caffeine citrate starting from the first day after delivery for preterm infants with a gestational age of <28 weeks. For infants up to 32 weeks, if positive pressure ventilation is required, the decision should be made on an individual basis. This study aims to describe the variability in caffeine usage across neonatal intensive care units in our country.

An online survey was sent to neonatologist who are members of the Turkish Neonatology Society to describe the variability in caffeine usage in neonatal intensive care units in our country.

We collected responses from 74 units. Prophylactic caffeine usage was observed as; GA ≤276/7: 98.6%, GA 280/7-286/7: 89.0%, GA 290/7-296/7: 75.3%, GA 300/7-316/7: 53.4%. 62.2% of units reported administering loading dose within the first two hours. The initial maintenance dose was 5 mg/kg in 64.8% of units, 10 mg/kg in 32.4% of units, and intermediate dose in 5.3% of units. 47.3% of units reported no routine dose adjustment. The postmenstrual age that caffeine treatment was stopped was found to be 34 (min-max; 32-36) weeks for infants without apnea and respiratory support, 36 (min-max; 34-52) weeks for infants without apnea but any respiratory support. The time to discharge after treatment cessation was found as; 1-4 days: 37.8%, 5-7 days: 68.9%. Among the 56 units with multiple responsible physicians, 32.1% reported intra-unit variations.

The significant differences in caffeine usage characteristics between and within units highlight the need for clear recommendations provided by standardized guidelines.

Extubation failure (EF) is common in preterm neonates and may be associated with adverse outcomes.

To systematically review and meta-analyze the existing literature on predictors and outcomes of EF in preterm neonates.

MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase (OvidSP), CINAHL (EBSCOHost), and Cochrane Library (Wiley) from 1995 onward. The search strategy was developed by a reference librarian.

Experimental or observational studies reporting on predictors and/or outcomes related to EF (defined as reintubation within 7 days) in preterm neonates less than 37 weeks were eligible. Predictors included machine learning (ML) algorithms and lung ultrasound (LUS). Main outcome of interest was association of EF with mortality and/or bronchopulmonary dysplasia (BPD).

Studies identified by the search strategy were screened based on title and abstract. Data from included studies were extracted independently by 2 authors, along with adjudication of risk of bias. RevMan Web was used to conduct meta-analyses.

Out of 8336 studies screened, 120 were included. Neonates with lower gestational age at birth, birthweight, postmenstrual age, and weight at extubation were more likely to experience EF. Higher level of pre-extubation respiratory support, indicated by lower pre-extubation pH and higher pre-extubation mean airway pressure, fraction of inspired oxygen, and Pco2 were associated with EF risk. ML models showed variable accuracy and lower external validity. LUS may be a promising predictor, though scoring systems varied. EF was associated with higher odds of mortality and/or BPD (pooled odds ratio [OR], 4.7; 95% CI, 2.84-7.76) as well as the individual components of the composite: mortality (pooled OR, 3.87; 95% CI, 2.35-6.36) and BPD (pooled OR, 3.27; 95% CI, 2.54-4.21).

Associations were derived from unadjusted data, precluding a definitive causal relationship between EF and predictors/outcomes.

Lower gestational and chronological age and higher levels of pre-extubation ventilation support were associated with EF. ML models and LUS scores require further validation in larger studies. EF was associated with mortality and/or BPD.

Minimizing the duration of mechanical ventilation is one of the most important therapeutic goals during the care of preterm infants at neonatal intensive care units (NICUs). The rate of extubation failure among preterm infants is between 16% and 40% worldwide. Numerous studies have been conducted on the assessment of extubation suitability, the optimal choice of respiratory support around extubation, and the effectiveness of medical interventions. Since the Caffeine Therapy for Apnea of Prematurity (CAP) trial, caffeine has become one of the essential drugs at NICUs. However, the optimal dosage and timing for adequate effectiveness still need to be more conclusive. Previous studies suggest that higher doses of caffeine treatment increase the success rate of extubation. Therefore, we aim to determine whether using a single additional loading dose of caffeine citrate one hour prior to extubation impacts the success rate of extubation.

The study is an open-label, multicenter randomized clinical trial testing the effectiveness and safety of pre-extubational loading dose of caffeine citrate. Inclusion criteria will be infants born before the 32nd gestational week, before the first extubation attempt after at least 48 hours of mechanical ventilation, and a signed parental informed consent. A total of 226 patients will be randomly allocated to either the experimental or control group. The randomization will be stratified by gestational age and antenatal steroid prophylaxis. Preterm infants in the experimental group will receive an additional intravenous (IV) loading dose (20 mg/kg) of caffeine citrate one hour before the first planned extubation, in addition to the standard dosing regimen (20 mg/kg caffeine citrate IV on the first day of life and 5 to 10 mg/kg IV or orally caffeine citrate each consecutive day). Preterm infants in the control group will receive the standard dosing regimen. The primary outcome will be reintubation within 48 hours.

A pre-extubational loading dose of caffeine citrate can reduce extubation failure. Obtaining evidence on this feature has the potential to contribute to finding the optimal dosing regimen.

The study protocol was approved by the Hungarian Ethics Committee for Clinical Pharmacology of the Medical Research Council and National Institute of Pharmacy and Nutrition (OGYÉI/6838-11/2023). ClinicalTrials.gov identifier NCT06401083 Registered 06. May 2024.; EudraCT number: 2022-003202-77.

This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg-1) vs. high dose (>10 mg·kg-1 caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1-5 years), middle childhood (6-11 years) and adolescence (12-19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.

Apnea and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in preterm neonates (pre-nates) with respiratory distress. Caffeine citrate (CC) is often prescribed for pre-nates in doses of 5-10 mg/kg in 24 h. This study aimed to evaluate the most effective dosage regimen (5 mg/kg/day vs >5-10 mg/kg/day) to prevent apnea and EF with minimal caffeine-associated potential side effects (CC-APSEs) in pre-nates. This one-year retrospective cohort study included all the eligible neonates admitted to NICU and received CC-therapy till 28 days of life (DOL) or discharge. Based on CC-daily dose formed LD-caffeine-group (5 mg/kg/day) and HD-caffeine-group (>5-10 mg/kg/day). Antenatal, prenatal, and postnatal characteristics, CC-regimen, comorbidities, and CC-APSEs were compared between the groups. Predictors of apnea and EF were analyzed through logistic regression. There were 181 and 72 neonates in the LD and HD-caffeine-groups respectively. In HD-caffeine-group daily CC-dose was 7 to 7.5 mg/kg/day in 93% of neonates and >7.5 to 10 mg/kg/day in only 7%. Significantly fewer neonates experienced apnea and EF in the HD-caffeine-group till 28DOL or discharge. This difference was even greater in the subgroup of ≤28 weeks GA (15.6% vs 40.0%; P < .01). In HD-caffeine-group the incidence of severe/moderate-BPD was significantly lower and the frequency of CC-APSEs was higher. Multivariate analysis showed that; the smaller the GA higher the risk of apnea (AOR = 0.510, 95% CI 0.483-0.999) and EF (AOR = 0.787, 95% CI 0.411-0.997). The HD-caffeine was inversely associated with developing apnea (AOR = 0.244, 95% CI 0.053-0.291) and EF (AOR = 0.103, 95% CI 0.098-2.976). IMV-duration before extubation (AOR = 2.229, 95% CI 1.672-2.498) and severe/moderate-BPD (AOR = 2.410, 95%CI 1.104-2.952) had a high risk of EF. Initiating early HD-caffeine may prevent apnea and extubation failure in preterm neonates. Optimization of caffeine initiation time and dosages can be a safe and feasible approach to decrease the burden of neonatal respiratory morbidities.

This multicenter retrospective study was conducted to explore the effects of different courses and durations of invasive mechanical ventilation (MV) on the respiratory outcomes of very low birth weight infants (VLBWI) in China. The population for this study consisted of infants with birth weight less than 1500 g needing at least 1 course of invasive MV and admitted to the neonatal intensive care units affiliated with the Chinese Neonatal Network within 6 h of life from January 1st, 2019 to December 31st, 2020. Univariate and multivariate logistic regression analyses were performed to evaluate associations between invasive MV and respiratory outcomes. Adjusted odds ratios (ORs) were computed with the effects of potential confounders. (1) Among the 3183 VLBWs with a history of at least one course of invasive MV, 3155 (99.1%) met inclusion criteria and were assessed for the primary outcome. Most infants received one course (76.8%) and a shorter duration of invasive MV (62.16% with ventilation for 7 days or less). (2) In terms of the incidence of all bronchopulmonary dysplasia (BPD) (mild, moderate, and severe BPD), there were no significant differences between different invasive MV courses [For 2 courses, adjusted OR = 1.11 (0.88, 1.39); For 3 courses or more, adjusted OR = 1.07 (0.72, 1.60)]. But, with the duration of invasive MV prolonging, the OR of BPD increased [8-21 days, adjusted OR = 1.98 (1.59, 2.45); 22-35 days, adjusted OR = 4.37 (3.17, 6.03); ≥ 36 days, adjusted OR = 18.44 (10.98, 30.99)]. Concerning severe BPD, the OR increased not only with the course of invasive MV but also with the duration of invasive MV [For 2 courses, adjusted OR = 2.17 (1.07, 4.40); For 3 courses or more, adjusted OR = 2.59 (1.02, 6.61). 8-21 days, adjusted OR = 8.42 (3.22, 22.01); 22-35 days, adjusted OR = 27.82 (9.08, 85.22); ≥ 36 days, adjusted OR = 616.45 (195.79, > 999.999)]. (3) When the interaction effect between invasive MV duration and invasive MV course was considered, it was found that there were no interactive effects in BPD and severe BPD. Greater than or equal to three courses would increase the chance of severe BPD, death, and the requirement of home oxygen therapy. Compared with distinct courses of invasive MV, a longer duration of invasive MV (> 7 days) has a greater effect on the risk of BPD, severe BPD, death, and the requirement of home oxygen therapy.

Very preterm infants often require respiratory support and are therefore exposed to an increased risk of chronic lung disease and later neurodevelopmental disability. Although methylxanthines are widely used to prevent and treat apnea associated with prematurity and to facilitate extubation, there is uncertainty about the benefits and harms of different types of methylxanthines.

To assess the effects of methylxanthines on the incidence of apnea, death, neurodevelopmental disability, and other longer-term outcomes in preterm infants (1) at risk for or with apnea, or (2) undergoing extubation.

We searched CENTRAL, MEDLINE, Embase, two other databases, and three trial registers (November 2022).

We included randomized trials in preterm infants, in which methylxanthines (aminophylline, caffeine, or theophylline) were compared to placebo or no treatment for any indication (i.e. prevention of apnea, treatment of apnea, or prevention of re-intubation).

We used standard Cochrane methods and GRADE to assess the certainty of evidence.

We included 18 studies (2705 infants), evaluating the use of methylxanthine in preterm infants for: any indication (one study); prevention of apnea (six studies); treatment of apnea (five studies); and to prevent re-intubation (six studies). Death or major neurodevelopmental disability (DMND) at 18 to 24 months. Only the Caffeine for Apnea of Prematurity (CAP) study (enrolling 2006 infants) reported on this outcome. Overall, caffeine probably reduced the risk of DMND in preterm infants treated with caffeine for any indication (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.78 to 0.97; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence). No other trials reported DMND. Results from the CAP trial regarding DMND at 18 to 24 months are less precise when analyzed based on treatment indication. Caffeine probably results in little or no difference in DMND in infants treated for prevention of apnea (RR 1.00, 95% CI 0.80 to 1.24; RD -0.00, 95% CI -0.10 to 0.09; 1 study, 423 infants; moderate-certainty evidence) and probably results in a slight reduction in DMND in infants treated for apnea of prematurity (RR 0.85, 95% CI 0.71 to 1.01; RD -0.06, 95% CI -0.13 to 0.00; NNTB 16, 95% CI 7 to > 1000; 1 study, 767 infants; moderate-certainty evidence) or to prevent re-intubation (RR 0.85, 95% CI 0.73 to 0.99; RD -0.08, 95% CI -0.15 to -0.00; NNTB 12, 95% CI 6 to >1000; 1 study, 676 infants; moderate-certainty evidence). Death. In the overall analysis of any methylxanthine treatment for any indication, methylxanthine used for any indication probably results in little or no difference in death at hospital discharge (RR 0.99, 95% CI 0.71 to 1.37; I2 = 0%; RD -0.00, 95% CI -0.02 to 0.02; I2 = 5%; 7 studies, 2289 infants; moderate-certainty evidence). Major neurodevelopmental disability at 18 to 24 months. In the CAP trial, caffeine probably reduced the risk of major neurodevelopmental disability at 18 to 24 months (RR 0.85, 95% CI 0.76 to 0.96; RD -0.06, 95% CI -0.10 to -0.02; NNTB 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence), including a reduction in the risk of cerebral palsy or gross motor disability (RR 0.60, 95% CI 0.41 to 0.88; RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100; 1 study, 1810 infants; moderate-certainty evidence) and a marginal reduction in the risk of developmental delay (RR 0.88, 95% CI 0.78 to 1.00; RD -0.05, 95% CI -0.09 to -0.00; NNTB 20, 95% CI 11 to > 1000; 1 study, 1725 infants; moderate-certainty evidence). Any apneic episodes, failed apnea reduction after two to seven days (< 50% reduction in apnea) (for infants treated with apnea), and need for positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication probably reduces the occurrence of any apneic episodes (RR 0.31, 95% CI 0.18 to 0.52; I2 = 47%; RD -0.38, 95% CI -0.51 to -0.25; I2 = 49%; NNTB 3, 95% CI 2 to 4; 4 studies, 167 infants; moderate-certainty evidence), failed apnea reduction after two to seven days (RR 0.48, 95% CI 0.33 to 0.70; I2 = 0%; RD -0.31, 95% CI -0.44 to -0.17; I2 = 53%; NNTB 3, 95% CI 2 to 6; 4 studies, 174 infants; moderate-certainty evidence), and may reduce receipt of positive-pressure ventilation after institution of treatment (RR 0.61, 95% CI 0.39 to 0.96; I2 = 0%; RD -0.06, 95% CI -0.11 to -0.01; I2 = 49%; NNTB 16, 95% CI 9 to 100; 9 studies, 373 infants; low-certainty evidence). Chronic lung disease. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age) (RR 0.78, 95% CI 0.70 to 0.86; I2 = 0%; RD -0.10, 95% CI -0.14 to -0.06; I2 = 0%; NNTB 10, 95% CI 7 to 16; 3 studies, 2090 infants; high-certainty evidence). Failure to extubate or the need for re-intubation within one week after initiation of therapy. Methylxanthine used for the prevention of re-intubation probably results in a large reduction in failed extubation compared with no treatment (RR 0.48, 95% CI 0.32 to 0.71; I2 = 0%; RD -0.27, 95% CI -0.39 to -0.15; I2 = 69%; NNTB 4, 95% CI 2 to 6; 6 studies, 197 infants; moderate-certainty evidence).

Caffeine probably reduces the risk of death, major neurodevelopmental disability at 18 to 24 months, and the composite outcome DMND at 18 to 24 months. Administration of any methylxanthine to preterm infants for any indication probably leads to a reduction in the risk of any apneic episodes, failed apnea reduction after two to seven days, cerebral palsy, developmental delay, and may reduce receipt of positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age).

This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical ventilation. Drugs used to promote respiratory drive, reduce the risk of apnoea, reduce lung inflammation and avoid bronchospasm are critically assessed. When available, Cochrane reviews and randomised trials are used as the primary sources of evidence. Methylxanthines, particularly caffeine, are well studied and there is accumulating evidence to guide clinicians on the timing and dosage that may be used. Efficacy and safety for doxapram, steroids, adrenaline and salbutamol are summarised. Management of term infants, extubation following surgery, accidental and complicated extubation and the use of cuffed endotracheal tubes are presented. Overall, caffeine is the only drug with a substantial evidence base, proven to increase the likelihood of successful extubation in preterm infants; no drugs are needed to facilitate extubation in most term infants. Future studies might further define the role of caffeine in late preterm infants and evaluate medications for post-extubation stridor, bronchospasm or apnoea not responsive to methylxanthines.

Scientific scrutiny has proved the safety and benefits of caffeine to treat apnoea of prematurity (AOP). However, there is no consensus on the effects of this treatment on sleep, especially considering the key role of adenosine and early brain development for sleep maturation. We systematically reviewed studies with sleep as a primary and/or secondary outcome or any mention of sleep parameters in the context of caffeine treatment for AOP.

We performed a systematic search of PubMed, Web of Science and the Virtual Health Library from inception to 7 September 2022 to identify studies investigating the short- and long-term effects of caffeine to treat AOP on sleep parameters. We used the PIC strategy considering preterm infants as the Population, caffeine for apnoea as the Intervention and no or other intervention other than caffeine as the Comparison. We registered the protocol on PROSPERO (CRD42021282536).

Of 4019 studies, we deemed 20, including randomised controlled trials and follow-up and observational studies, to be eligible for our systematic review. The analysed sleep parameters, the evaluation phase and the instruments for sleep assessment varied considerably among the studies. The main findings can be summarised as follows: (i) most of the eligible studies in this systematic review indicate that caffeine used to treat AOP seems to have no effect on key sleep parameters and (ii) the effects on sleep when caffeine is administered earlier, at higher doses or for longer periods than the most common protocol have not been investigated. There is a possible correlation between the caffeine concentration and period of exposure and negative sleep quality, but the sleep assessment protocols used in the included studies did not have high-quality standards and could not provide good evidence.

Sleep quality is an important determinant of health, and better investments in research with adequate sleep assessment tools are necessary to guarantee the ideal management of children who were born preterm.

Although invasive mechanical ventilation (IMV) has contributed to the survival of preterm infants with extremely low birth weight (ELBW), it is also associated with unsatisfactory clinical outcomes when used for prolonged periods. This study aimed to identify factors that may be decisive for extubation success in very low birth weight (VLBW) and extremely low birth weight (ELBW) preterm infants.

The cohort study included preterm infants with gestational age (GA) <36 weeks, birth weight (BW) <1500 grams who underwent IMV, born between 2015 and 2018. The infants were allocated into two groups: extubation success (SG) or failure (FG). A stepwise logistic regression model was created to determine variables associated with successful extubation.

Eighty-three preterm infants were included. GA and post-extubation arterial partial pressure of carbon dioxide (PaCO2) were predictive of extubation success. Infants from FG had lower GA and BW, while those from SG had higher weight at extubation and lower post-extubation PaCO2.

Although we found post-extubation PaCO2 as an extubation success predictor, which is a variable representative of the moment after the primary outcome, this does not diminish its clinical relevance since extubation does not implicate in ET removal only; it also involves all the aspects that take place within a specified period (72 hours) after the planned event.

GA and post-extubation PaCO2 were predictors for extubation success in VLBW and ELBW preterm infants. Infants who experienced extubation failure had lower birth weight and higher FiO2 prior to extubation.

Very preterm infants often require respiratory support and are therefore exposed to an increased risk of bronchopulmonary dysplasia (chronic lung disease) and later neurodevelopmental disability. Caffeine is widely used to prevent and treat apnea (temporal cessation of breathing) associated with prematurity and facilitate extubation. Though widely recognized dosage regimes have been used for decades, higher doses have been suggested to further improve neonatal outcomes. However, observational studies suggest that higher doses may be associated with harm.

To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, or peri-extubation.

We searched CENTRAL, MEDLINE, Embase, CINAHL, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in May 2022. The reference lists of relevant articles were also checked to identify additional studies.

We included randomized (RCTs), quasi-RCTs and cluster-RCTs, comparing high-dose to standard-dose strategies in preterm infants. High-dose strategies were defined as a high-loading dose (more than 20 mg of caffeine citrate/kg) or a high-maintenance dose (more than 10 mg of caffeine citrate/kg/day). Standard-dose strategies were defined as a standard-loading dose (20 mg or less of caffeine citrate/kg) or a standard-maintenance dose (10 mg or less of caffeine citrate/kg/day). We specified three additional comparisons according to the indication for commencing caffeine: 1) prevention trials, i.e. preterm infants born at less than 34 weeks' gestation, who are at risk for apnea; 2) treatment trials, i.e. preterm infants born at less than 37 weeks' gestation, with signs of apnea; 3) extubation trials: preterm infants born at less than 34 weeks' gestation, prior to planned extubation.

We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data.  MAIN RESULTS: We included seven trials enrolling 894 very preterm infants (reported in Comparison 1, i.e. any indication). Two studies included infants for apnea prevention (Comparison 2), four studies for apnea treatment (Comparison 3) and two for extubation management (Comparison 4); in one study, indication for caffeine administration was both apnea treatment and extubation management (reported in Comparison 1, Comparison 3 and Comparison 4). In the high-dose groups, loading and maintenance caffeine doses ranged from 30 mg/kg to 80 mg/kg, and 12 mg/kg to 30 mg/kg, respectively; in the standard-dose groups, loading and maintenance caffeine doses ranged from 6 mg/kg to 25 mg/kg, and 3 mg/kg to 10 mg/kg, respectively. Two studies had three study groups: infants were randomized in three different doses (two of them matched our definition of high dose and one matched our definition of standard dose); high-dose caffeine and standard-dose caffeine were compared to theophylline administration (the latter is included in a separate review). Six of the seven included studies compared high-loading and high-maintenance dose to standard-loading and standard-maintenance dose, whereas in one study standard-loading dose and high-maintenance dose was compared to standard-loading dose and standard-maintenance dose. High-dose caffeine strategies (administration for any indication) may have little or no effect on mortality prior to hospital discharge (risk ratio (RR) 0.86, 95% confidence of interval (CI) 0.53 to 1.38; risk difference (RD) -0.01, 95% CI -0.05 to 0.03; I² for RR and RD = 0%; 5 studies, 723 participants; low-certainty evidence). Only one study enrolling 74 infants reported major neurodevelopmental disability in children aged three to five years (RR 0.79, 95% CI 0.51 to 1.24; RD -0.15, 95% CI -0.42 to 0.13; 46 participants; very low-certainty evidence). No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. Five studies reported bronchopulmonary dysplasia at 36 weeks' postmenstrual age (RR 0.75, 95% CI 0.60 to 0.94; RD -0.08, 95% CI -0.15 to -0.02; number needed to benefit (NNTB) = 13; I² for RR and RD = 0%; 723 participants; moderate-certainty evidence). High-dose caffeine strategies may have little or no effect on side effects (RR 1.66, 95% CI 0.86 to 3.23; RD 0.03, 95% CI -0.01 to 0.07; I² for RR and RD = 0%; 5 studies, 593 participants; low-certainty evidence). The evidence is very uncertain for duration of hospital stay (data reported in three studies could not be pooled in meta-analysis because outcomes were expressed as medians and interquartile ranges) and seizures (RR 1.42, 95% CI 0.79 to 2.53; RD 0.14, 95% CI -0.09 to 0.36; 1 study, 74 participants; very low-certainty evidence). We identified three ongoing trials conducted in China, Egypt, and New Zealand.

High-dose caffeine strategies in preterm infants may have little or no effect on reducing mortality prior to hospital discharge or side effects. We are very uncertain whether high-dose caffeine strategies improves major neurodevelopmental disability, duration of hospital stay or seizures. No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. High-dose caffeine strategies probably reduce the rate of bronchopulmonary dysplasia. Recently completed and future trials should report long-term neurodevelopmental outcome of children exposed to different caffeine dosing strategies in the neonatal period. Data from extremely preterm infants are needed, as this population is exposed to the highest risk for mortality and morbidity. However, caution is required when administering high doses in the first hours of life, when the risk for intracranial bleeding is highest. Observational studies might provide useful information regarding potential harms of the highest doses.

To establish the most effective and best tolerated dose of caffeine citrate for the prevention of intermittent hypoxaemia (IH) in late preterm infants.

Phase IIB, double-blind, five-arm, parallel, randomised controlled trial.

Neonatal units and postnatal wards of two tertiary maternity hospitals in New Zealand.

Late preterm infants born at 34+0-36+6 weeks' gestation, recruited within 72 hours of birth.

Infants were randomly assigned to receive a loading dose (10, 20, 30 or 40 mg/kg) followed by 5, 10, 15 or 20 mg/kg/day equivolume enteral caffeine citrate or placebo daily until term corrected age.

IH (events/hour with oxygen saturation concentration ≥10% below baseline for ≤2 min), 2 weeks postrandomisation.

132 infants with mean (SD) birth weight 2561 (481) g and gestational age 35.7 (0.8) weeks were randomised (24-28 per group). Caffeine reduced the rate of IH at 2 weeks postrandomisation (geometric mean (GM): 4.6, 4.6, 2.0, 3.8 and 1.7 events/hour for placebo, 5, 10, 15 and 20 mg/kg/day, respectively), with differences statistically significant for 10 mg/kg/day (GM ratio (95% CI] 0.39 (0.20 to 0.76]; p=0.006) and 20 mg/kg/day (GM ratio (95% CI] 0.33 (0.17 to 0.68]; p=0.003) compared with placebo. The 20 mg/kg/day dose increased mean (SD) pulse oximetry oxygen saturation (SpO2) (97.2 (1.0) vs placebo 96.0 (0.8); p<0.001), and reduced median (IQR) percentage of time SpO2 <90% (0.5 (0.2-0.8) vs 1.1 (0.6-2.4); p<0.001) at 2 weeks, without significant adverse effects on growth velocity or sleeping.

Caffeine reduces IH in late preterm infants at 2 weeks of age, with 20 mg/kg/day being the most effective dose.

ACTRN12618001745235.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that occurs during the neonatal period and is commonly associated with prematurity. This condition results in a severe economic burden on society and the families involved. Caffeine is used not only for the treatment of apnea in prematurity, but also for the prevention of BPD. There are multiple clinical benefits of caffeine treatment, including improved extubation success, a reduced duration of mechanical ventilation, improved lung function, and a reduction of patent ductus arteriosus requiring treatment. These clinical benefits of caffeine for the treatment of BPD are supported by both clinical trials and evidence from animal models. However, the mechanism by which caffeine protects against BPD remains unclear. Here, we review the clinical value of caffeine in the prevention of BPD and its potential mechanisms of action, including anti-inflammatory, antioxidant, antifibrotic, and antiapoptotic properties, the regulation of angiogenesis, and diuretic effects. Our aim is to provide a new theoretical basis for the clinical treatment of BPD.

To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment.

A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group.

Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05).

This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.

Central apnea is a major cause of death in neonates with trisomy 18 (T18) and is likely due to immaturity of the respiratory drive, similar to the pathological mechanism in apnea of prematurity. Although caffeine has long been used for apnea of prematurity, its use has not yet been reported for infants with T18. Here we describe an infant with T18 receiving comfort-focused care and palliative transport home. Of utmost importance to her family was enabling the patient to spend time at home before her death. However, immediately before transport, she developed severe central apnea, raising concern that she may not survive the transfer. Caffeine was trialed in the hopes of reducing central apnea events. Its use was successful and facilitated safe transport, allowing the patient to uneventfully transition home, where she spent several meaningful weeks with her family before her death.

Caffeine citrate is the drug of choice for the pharmacological treatment of apnea of prematurity. Factors such as maturity and genetic variation contribute to the interindividual variability in the clinical response to caffeine therapy in preterm infants, making the optimal dose administered controversial. Moreover, the necessity for therapeutic drug monitoring (TDM) of caffeine is still worth discussing due to the need to achieve the desired target concentrations as well as concerns about the safety of higher doses. Therefore, we reviewed the pharmacokinetic profile of caffeine in preterm infants, evidence of the safety and efficacy of different doses of caffeine, therapeutic concentration ranges of caffeine and impact of genetic variability on caffeine therapy. Whereas the safety and efficacy of standard-dose caffeine have been demonstrated, evidence for the safety of higher administered doses is insufficient. Thus, preterm infants who lack clinical response to standard-dose caffeine therapy are of interest for TDM when dose optimization is performed. Polymorphisms in pharmacodynamics-related genes, but not in pharmacokinetics-related genes, have a significant impact on the interindividual variability in clinical response to caffeine therapy. For preterm infants lacking clinical response, how to develop individualized medication regimens for caffeine remains to be explored.

Caffeine is the most commonly used methyl xanthine for the prevention of apnoea in prematurity, but the ideal dose was uncertain, until now. This study compared two doses of caffeine for the prevention of apnoea in prematurity. A clinical trial was conducted on 78 preterm infants ≤32 weeks in Neonatal Intensive Care Unit. They were randomly allocated to receive the intervention (loading 40 mg/kg/day and maintenance of 20 mg/kg/day) or the control (loading 20 mg/kg/day and maintenance of 10 mg/kg/day) dose of caffeine. The primary outcome of the study was the frequency and total days of apnoea per duration of treatment for both groups. The frequency of apnoea ranged from zero to fourteen in the intervention group and zero to twelve in the control group. There was no statistically significant difference between the groups, with a p-value of 0.839. The number of days of apnoea was also similar between both groups, with a p-value of 0.928. There was also no significant difference in adverse events between both regimens. This study did not support the use of higher doses of caffeine as a prevention for apnoea in prematurity.

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.

The plasma elimination half-life of caffeine in the newborn is approximately 100 h. Caffeine is rapidly absorbed with complete bioavailability following oral dosing. Switching between parenteral and oral administration requires no dose adjustments. Caffeine has wide interindividual pharmacodynamic variability and a wide therapeutic index in preterm newborns. Thresholds of measurable efficacy on respiratory drive have been documented at plasma levels around 2 mg/L. At these low levels, caffeine competitively inhibits adenosine receptors (A1 and A2A). The toxicity threshold is ill-defined and possibly as high as 60 mg/L which can be lethal in adults. High doses of caffeine may produce better control of apnea. However, at high systemic drug concentrations, the pharmacodynamic actions of caffeine become more complex and worrisome. They include inhibition of GABA receptors and cholinergic receptors in addition to adenosine receptor inhibition, intracellular calcium mobilization and actions on adrenergic, dopaminergic and phosphodiesterase systems. The role of pharmacogenomic factors as determinants of neonatal pharmacologic response and clinical effects remains to be explored.

Improving the adverse neurodevelopmental outcomes associated with prematurity is a priority. In the large international Caffeine for Apnea of Prematurity trial, caffeine improved survival without neurodevelopmental disability at 18 months and demonstrated long term safety up to 11 years. Caffeine is an adenosine receptor antagonist with effects on the brain, lung and other systems. The benefits of caffeine may be primary neuroprotection or reduction of risk factors for impairment, especially bronchopulmonary dysplasia. The effects of caffeine vary with age and dose. Animal data show risks of loss of neuronal protection from hypoxia. Treatment with earlier and higher dose caffeine may be beneficial but concerns remain.

Caffeine is an effective treatment for apnea of prematurity and has several important benefits, including decreasing respiratory morbidity and motor impairment. In this article, we focus on the dose of caffeine. We review the evidence regarding the efficacy and safety of standard caffeine dosing and alternative dosing approaches, including the use of high dose caffeine and routine dose adjustments for age. Current evidence suggests high dose caffeine may provide additional benefit in reducing the risk of bronchopulmonary dysplasia and extubation failure, but may also increase the risk of cerebellar hemorrhage and seizures. Increasing the standard caffeine citrate dose every 1-2 weeks to a goal dose of 8 mg per kilogram every 24 h may help maintain therapeutic effect. We conclude by highlighting the need for additional trials before high dose caffeine is routinely used.

Infants born late preterm (34+0 to 36+6 weeks' gestational age) have frequent episodes of intermittent hypoxaemia compared with term infants. Caffeine citrate reduces apnoea and intermittent hypoxaemia and improves long-term neurodevelopmental outcomes in infants born very preterm and may have similar effects in late preterm infants. Clearance of caffeine citrate increases with gestational age and late preterm infants are likely to need a higher dose than very preterm infants. Our aim is to determine the most effective and best-tolerated dose of caffeine citrate to reduce transient intermittent hypoxaemia events in late preterm infants.

A phase IIB, double-blind, five-arm, parallel, randomised controlled trial to compare the effect of four doses of oral caffeine citrate versus placebo on the frequency of intermittent hypoxaemia. Late preterm infants will be enrolled within 72 hours of birth and randomised to receive 5, 10, 15 or 20 mg/kg/day caffeine citrate or matching placebo daily until term corrected age. The frequency of intermittent hypoxaemia (events/hour where oxygen saturation concentration is ≥10% below baseline for ≤2 min) will be assessed with overnight oximetry at baseline, 2 weeks after randomisation (primary outcome) and at term corrected age. Growth will be measured at these timepoints, and effects on feeding and sleeping will be assessed by parental report. Data will be analysed using generalised linear mixed models.

This trial has been approved by the Health and Disability Ethics Committees of New Zealand (reference 18/NTA/129) and the local institutional research review committees. Findings will be disseminated to peer-reviewed journals to clinicians and researchers at local and international conferences and to the public. The findings of the trial will inform the design of a large multicentre trial of prophylactic caffeine in late preterm infants, by indicating the most appropriate dose to use and providing information on feasibility.

ACTRN12618001745235; Pre-results.

Caffeine citrate is used to prevent apnea in premature infants and help in extubation of invasive ventilation, but the optimal dose remains undetermined.

Neonates born at less than 30 weeks gestation who had received invasive ventilation for at least 48 hours and a loading dose of 20 mg/kg caffeine citrate were randomly assigned into high (10 mg/kg daily) or low (5 mg/kg daily) maintenance dose groups. The drug was discontinued if no apnea occurred for 7 consecutive days.

A total of 111 infants were assigned into the high (54) or low (57) dose groups. Extubation failure (16.7% vs 36.8%), age of extubation (8.2 ± 2.1 vs 10.7 ± 2.3 day), duration of invasive ventilation (7.2 ± 2.1 vs 8.5 ± 2.4 day), duration of ventilation before extubation (8.0 ± 1.8 vs 10.1 ± 1.9 day), and number of days of apnea (1.8 ± 1.3 vs 3.2 ± 1.1 day) were significantly lower in the high dose group than the low dose group. Difference in time until failure (6.7 ± 1.7d vs 7.0 ± 1.9d) and duration of nasal continuous positive airway pressure(7.8 ± 1.8 vs 8.0 ± 2.2 day) were not significant. Furthermore, no significant differences in the incidence of tachycardia (9.3% vs 12.3%), abdominal distension (16.7% vs 12.3%), feeding intolerance (3.7% vs 5.3%), or irritability (7.4% vs 5.3%) were observed between groups.

A higher maintenance dose of caffeine citrate reduced the incidence of extubation failure and apnea of prematurity without increasing the occurrence of adverse reactions.

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.

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.

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.

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.

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 different potential regimens, including in relation to safety.

To compare the efficacy of domestic and imported caffeine citrate in the treatment of apnea in preterm infants.

A total of 98 preterm infants with a gestational age of 28 - <34 weeks between April 2018 and December 2019 were enrolled. They were randomly administered with domestic (n=48) or imported caffeine citrate (n=50) within 6 hours after birth. The therapeutic effects, complications, adverse effects and clinical outcomes were compared between the two groups.

There were no significant differences in the incidence of apnea within 7 days after birth, daily frequency of apnea, the time of apnea disappearance, the failure rate of intubation-surfactant-extubation strategy, the time of non-invasive assisted ventilation, the duration of oxygen therapy, the duration of caffeine citrate therapy, the length of hospital stay, blood gas analysis results, liver and kidney function testing results between the two groups (P>0.05). There were no significant differences in the incidence of complications and the mortality rate between the two groups (P>0.05). There was no significant difference in the incidence of adverse effects between the two groups (P>0.05).

The efficacy and safety of domestic caffeine citrate in the treatment of apnea are similar to those of imported caffeine citrate in preterm infants.

Caffeine is one of the most commonly utilized medications in the NICU. In preterm infants, short-term and long-term pulmonary and neurodevelopmental benefits of therapy are well documented in the literature. While robust evidence supports the use of standard doses of caffeine for apnea of prematurity or to facilitate successful extubation, much remains unknown regarding the boundaries of efficacy and safety for this common therapeutic agent. Escalating dosing regimens seem to provide additional benefit in select infants, but grave toxicity has also been documented with early utilization of high-dose caffeine. Conflicting data exist surrounding the ideal timing of initiation of therapy. Even the widely adhered to discontinuation point has been challenged by data supporting continued use. Until robust data definitively support change, practice should align with current evidence defining clear, safe, and efficacious dosing and timing of caffeine therapy.

Administration of caffeine citrate can facilitate extubation. Our aim was to determine whether a loading dose of caffeine citrate given to ventilated, preterm infants affected the diaphragm electrical activity.

Infants <34 weeks of gestational age were recruited if requiring mechanical ventilation and prescribed a loading dose of caffeine citrate. Surface electrodes recorded the electrical activity of the diaphragm (dEMG) before and after administration of intravenous caffeine citrate. The mean amplitude of the EMG (dEMG) trace and the mean area under the EMG curve (aEMGc) were calculated.

Thirty-two infants were assessed with a median gestational age of 29 (27-31) weeks. The dEMG amplitude increased, peaking at 25 min post administration (p = 0.006), and the increase in aEMGc (p = 0.004) peaked at 30 min; the differences were not significant after 60 min. At 20 min, there was an increase in minute volume (p = 0.034) and a reduction in the peak inspiratory pressure (p = 0.049).

We have demonstrated a transient increase in both electrical activity of the diaphragm and respiratory function following an intravenous loading dose of caffeine citrate.

Background: Caffeine is routinely used in preterm infants for apnea of prematurity. Preterm infants are usually monitored for 5 days after discontinuation of caffeine to assess for possible recurrence of apnea. Our objective was to determine if the serum concentration of caffeine decreases to a subtherapeutic level 5 days after its discontinuation.Methods: This is a retrospective analysis of caffeine levels after the drug was discontinued in preterm neonates (birth weight ≤1500 g) born between January 2010 and June 2017. The primary outcome was the proportion of infants with therapeutic levels of caffeine 5 days after the drug was stopped.Results: Caffeine levels were measured in 353 samples from 280 infants (birth weight 1246 ± 390 g and gestational age 29.2 ± 2.4 weeks) after discontinuation of the drug. Five and more days after discontinuation of caffeine, 29.3% (82/280) of the infants had caffeine levels ≥5 mg/L. Approximately 41% (75/181) of the caffeine levels measured between 5 and 7 days and 18% (17/95) between 8 and 10 days were ≥5 mg/L. A caffeine dose of >5 mg/kg/day when discontinued was associated with the caffeine level of ≥5 mg/L (OR 2.3, 95% CI 1.28-4.13, p = .005).Conclusions: Preterm infants treated with caffeine frequently had therapeutic levels of caffeine 5-10 days after discontinuation of the drug. The infants receiving higher doses were more likely to have a therapeutic level of caffeine 5 days after stopping the medication. Preterm infants should be monitored for recurrence of apnea for more than 5 days after stopping caffeine or levels should be monitored prior to discharge.

To study the efficacy and safety of caffeine used in the early (≤72 hours after birth) and late (>72 hours after birth) stage in preterm infants with a gestational age of ≤31 weeks.

A retrospective analysis was performed for 640 preterm infants (with a gestational age of ≤31 weeks) who were admitted to the neonatal intensive care unit of eight hospitals in Jiangsu Province, China. Of the 640 preterm infants, 510 were given caffeine in the early stage (≤72 hours after birth; early use group) and 130 were given caffeine in the late stage (>72 hours after birth; late use group). The clinical data were compared between the two groups.

There were no significant differences in birth weight, Apgar score, sex, gestational age, and age on admission between the two groups (P>0.05). Compared with the late use group, the early use group had a significantly younger age at the beginning and withdrawal of caffeine treatment (P<0.05) and a significantly shorter duration of caffeine treatment (P<0.05). There was no significant difference in respiratory support on admission between the two groups (P>0.05). Compared with the late use group, the early use group had significantly lower incidence rate of apnea (P<0.05) and significantly shorter oxygen supply time and length of hospital stay (P<0.05). There were no significant differences between the two groups in the incidence rates of neonatal intracranial hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and patent ductus arteriosus at discharge and NBNA score at the corrected gestational age of 40 weeks (P>0.05). However, significant differences were found in the incidence of bronchopulmonary dysplasia and the rate of home oxygen therapy, but there was no significant difference in the mortality rate between the two groups (P>0.05).

Early use of caffeine can shorten the duration of caffeine treatment, oxygen supply time, and length of hospital stay, with little adverse effect, in preterm infants with a gestational age of ≤31 weeks.

The incidence of preterm birth is increasing, leading to a growing population with potential long-term pulmonary complications. Apnoea of prematurity (AOP) is one of the major challenges when treating preterm infants; it can lead to respiratory failure and the need for mechanical ventilation. Ventilating preterm infants can be associated with severe negative pulmonary and extrapulmonary outcomes, such as bronchopulmonary dysplasia (BPD), severe neurological impairment and death. Therefore, international guidelines favour non-invasive respiratory support. Strategies to improve the success rate of non-invasive ventilation in preterm infants include pharmacological treatment of AOP. Among the different 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 risk of BPD; and is associated with improved cognitive outcome at 2 years of age, and pulmonary function up to 11 years of age. The commonly prescribed dose (20 mg·kg-1 loading dose, 5-10 mg·kg-1 per day 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 state-of-the-art review summarises the current knowledge of caff-eine 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 refined respiratory management of preterm infants is feasible, leading to an overall improvement in patient outcome.

To examine neonatal morbidities, including the incidence of cerebellar haemorrhage (CBH), and neurodevelopmental outcomes following the administration of high loading dose caffeine citrate compared to standard loading dose caffeine citrate.

This was a retrospective study of 218 preterm infants <28 weeks' gestation who received a loading dose of caffeine citrate within the first 36 h of life at the Mater Mothers' Hospital over a 3-year period (2011-2013). Two groups were compared, with 158 neonates in the high-dose cohort receiving a median dose of caffeine citrate of 80 mg/kg and 60 neonates in the standard dose cohort receiving a median dose of 20 mg/kg. Routine cranial ultrasound, including mastoid views, was performed during the neonatal period. At 2 years of age, infants presented for follow-up and were assessed with the Neurosensory Motor Developmental Assessment (NSMDA) and the Bayley Scales of Infant and Toddler Development-III (Bayley-III).

There was no difference in the incidence of neonatal morbidities, including CBH, between the two groups. The incidence of CBH in the high-dose group was 2.5% compared to 1.7% in the standard-dose group. There was no difference in the neurodevelopmental follow-up scores as evaluated with the NSMDA and the Bayley-III.

The use of early high loading dose caffeine citrate in extremely preterm infants was not shown to be associated with CBH or abnormal long-term neurodevelopmental outcomes. The overall incidence of CBH, however, was much lower than in studies using magnetic resonance imaging techniques. It is suggested that a large randomised clinical trial is needed to determine the optimal dose of caffeine citrate when given early to very preterm infants.

Caffeine is the most widely used drug by both adults and children worldwide due to its ability to promote alertness and elevate moods. It is effective in the management of apnea of prematurity in premature infants. Caffeine for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia in very-low-birth-weight infants and improves survival without neurodevelopmental disability at 18-21 months. Follow-up studies of the infants in the Caffeine for Apnea of Prematurity trial highlight the long-term safety of caffeine in these infants, especially relating to motor, behavioral, and intelligence skills. However, in animal models, exposure to caffeine during pregnancy and lactation adversely affects neuronal development and adult behavior of their offspring. Prenatal caffeine predisposes to intrauterine growth restriction and small growth for gestational age at birth. However, in-utero exposure to caffeine is also associated with excess growth, obesity, and cardio-metabolic changes in children. Caffeine therapy is a significant advance in newborn care, conferring immediate benefits in preterm neonates. Studies should help define the appropriate therapeutic window for caffeine treatment along with with the mechanisms relating to its beneficial effects on the brain and the lung. The long-term consequences of caffeine in adults born preterm are being studied and may depend on the ability of caffeine to modulate both the expression and the maturation of adenosine receptors in infants treated with caffeine.

Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28-33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V-VI projection neurons (p = 0.02), Tbr1-positive layers V-VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II-IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.

To study the clinical effect and safety of different maintenance doses of caffeine citrate in the treatment of apnea in very low birth weight preterm infants.

A total of 78 very low birth weight preterm infants with primary apnea were enrolled who were admitted from January 2016 to January 2018. They were randomly divided into high-dose caffeine group with 38 children and low-dose caffeine group with 40 children. Both groups received a loading dose of 20 mg/kg caffeine citrate, and 24 hours later, the children in the high-dose caffeine group were given a maintenance dose of 10 mg/kg, and those in the low-dose caffeine group were given a maintenance dose of 5 mg/kg. The two groups were compared in terms of response rate and incidence rate of adverse events.

The high-dose caffeine group had a significantly higher response rate than the low-dose caffeine group (71% vs 48%; P<0.05). Compared with the low-dose caffeine group, the high-dose caffeine group had significantly shorter duration of apnea and time of caffeine treatment (P<0.05). There were no significant differences between the two groups in length of hospital stay and incidence rates of tachycardia, feeding intolerance, bronchopulmonary dysplasia, necrotizing enterocolitis, and intracranial hemorrhage (P>0.05). There was no significant difference in the mortality rate between the two groups (P>0.05).

Higher maintenance dose of caffeine citrate has a better clinical effect than lower maintenance dose of caffeine citrate in the treatment of apnea in very low birth weight preterm infants, without increasing the incidence rates of adverse drug reactions and serious complications in preterm infants.

To study the clinical effect and safety of different maintenance doses of caffeine citrate in the treatment of apnea in very low birth weight preterm infants.

A total of 78 very low birth weight preterm infants with primary apnea were enrolled who were admitted from January 2016 to January 2018. They were randomly divided into high-dose caffeine group with 38 children and low-dose caffeine group with 40 children. Both groups received a loading dose of 20 mg/kg caffeine citrate, and 24 hours later, the children in the high-dose caffeine group were given a maintenance dose of 10 mg/kg, and those in the low-dose caffeine group were given a maintenance dose of 5 mg/kg. The two groups were compared in terms of response rate and incidence rate of adverse events.

The high-dose caffeine group had a significantly higher response rate than the low-dose caffeine group (71% vs 48%; P<0.05). Compared with the low-dose caffeine group, the high-dose caffeine group had significantly shorter duration of apnea and time of caffeine treatment (P<0.05). There were no significant differences between the two groups in length of hospital stay and incidence rates of tachycardia, feeding intolerance, bronchopulmonary dysplasia, necrotizing enterocolitis, and intracranial hemorrhage (P>0.05). There was no significant difference in the mortality rate between the two groups (P>0.05).

Higher maintenance dose of caffeine citrate has a better clinical effect than lower maintenance dose of caffeine citrate in the treatment of apnea in very low birth weight preterm infants, without increasing the incidence rates of adverse drug reactions and serious complications in preterm infants.

Though caffeine is a consolidated treatment in preterm infants, the efficacy and safety of a higher dose have not been systematically appraised.

A systematic review was conducted to compare high (loading dose >20 mg/kg and maintenance >10 mg/kg/day) versus low dose of caffeine. MEDLINE, EMBASE, Central and conference proceedings for randomised controlled trials (RCTs) and quasi-RCTs were searched. Two authors independently screened the records, extracted the data and assessed the risk of bias.

As only six RCTs enrolling a total of 816 preterm infants were included, the required information size was not reached. The loading and maintenance doses varied between 20 and 80 mg/kg/day and 3 and 20 mg/kg/day, respectively. The use of high dose had no impact on mortality (RR: 0.85; 95% CI: 0.53-1.38; RCTs = 4). However, it resulted in fewer cases of extubation failure, apnoeas and bronchopulmonary dysplasia (RR: 0.76; 95% CI: 0.60-0.96; studies = 4) and shorter duration of mechanical ventilation. The quality of the evidence was low due to imprecision of the estimates.

Due to imprecision, it is not possible to determine whether high-dose caffeine is more effective and safe than a low dose. High dose might improve short-term respiratory function and reduce bronchopulmonary dysplasia.