Caffeine in preterm infants: where are we in 2020?

Laura Moschino; Sanja Zivanovic; Caroline Hartley; Daniele Trevisanuto; Eugenio Baraldi; Charles Christoph Roehr

doi:10.1183/23120541.00330-2019

Figures

Tables

Download figure
Open in new tab
Download powerpoint
FIGURE 1
Schematic of the known effects of caffeine citrate during early development on the brain, the lung and the cardiovascular system derived from animal and infant studies. The first column indicates effects 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 low birthweight; IPPV: intermittent positive pressure ventilation; PMA: post-menstrual age; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus.

Tables

Figures

TABLE 1

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

First author, year [ref.]	Study characteristics, regimen, limitations	Patient characteristics		Main significant findings
First author, year [ref.]	Study characteristics, regimen, limitations	Early caffeine	Late caffeine	Benefits of early caffeine	Drawbacks or no effect of early caffeine
Davis, 2010 [34]	Post hoc subgroup analysis of the CAP trial Caffeine citrate 20 mg·kg⁻¹ load ≤3 DoL versus >3 DoL Post hoc analysis for treatment indication, not as primary outcome			Larger reduction in days of respiratory support (p=0.02) Lower PMA at time of discontinuing PPV (mean difference 1.35 weeks (0.90–1.81) versus 0.55 weeks (−0.11–0.99))
Abbasi, 2010 (abstract) [65]	Retrospective cohort study Early caffeine (0–2 DoL) versus late caffeine (≥3 DoL) Retrospective, many data not available; Newcastle–Ottawa score for risk of bias 4	166 case/control pairs, BW 500–1250 g		Reduced odds of IVH (OR 0.37)
Patel, 2013 [61]	Retrospective cohort study Caffeine initial dose <3 DoL versus ≥3 DoL Retrospective, single-centre; indication for caffeine therapy unknown; no protocol on caffeine use	83 neonates BW 940 (730–1100) g GA 27.3 (25.6–28.7) weeks	57 neonates BW 910 (715–1035) g GA 26.6 (25.3–27.7) weeks	Decreased incidence of death or BPD (25.3% versus 52.6%) by a reduced rate of BPD (23.6% versus 50.9%) Reduced need for treatment of PDA (10.4% versus 36.4%) Lower duration of MV (6 versus 22 days)
Saeidi, 2014 (abstract) [69]	RCT Caffeine citrate 20 mg·kg⁻¹ load within first 3 DoL versus ≥3 DoL Single-centre; small sample size; many data not available	16 neonates BW 1123±244 g GA 29.5±2.0 weeks (BW and GA for all 36 included infants)	20 neonates	Marginal reduction in BPD and significant reduction in apnoea
Dobson, 2014 [32]	Retrospective analysis Caffeine initial dose <3 DoL versus ≥3 DoL Retrospective; variable indications for early caffeine use among centres (hypothetically: apnoea, prophylactically, weaning from MV and reduction in BPD); possible changes in clinical practice during the study period	14 535 neonates BW 1055 (630–1447) g GA 28.1 (25.0–31.0) weeks	14 535 neonates BW 1054 (590–1460) g GA 28 (24.0–32.0) weeks	Reduced risk of BPD by 7.6% (23.1% versus 30.7%); Reduction in MV days at 36 weeks PMA (median 11 versus 17 days) Reduction in PDA requiring treatment (12.3% versus 19%)	Higher odds of death (OR 1.23, 95% CI 1.05–1.43; 4.5% versus 3.7%)
Lodha, 2015 [57]	Retrospective cohort study (Canadian Neonatal Network) Caffeine initial dose <3 DoL versus ≥3 DoL Retrospective; variations and inconsistency in the protocol for early caffeine use at various centres and unknown indications for caffeine use; potential variations in maintenance dose of caffeine	3806 neonates BW 1070 (850–1310) g GA 28 (26–29) weeks	1295 neonates BW 1050 (790–1360) g GA 28 (26–30) weeks	Reduction in BPD or death (aOR 0.81), stemming on BPD (aOR 0.79) Reduced incidence of PDA (40.5% versus 46.2%) and of surgical treatment for PDA (13.3% versus 25%) Reduced duration of MV, HFV and CPAP on day 2; reduction in the use of postnatal steroids	No difference in mortality (aOR 0.98) No difference in NEC ≥stage 2, ROP ≥stage 3, severe neurological injury (presence of parenchymal echolucency, periventricular echogenicity or PVL)
Taha, 2014 [66]	Retrospective data analysis (Alere Neonatal Database) Caffeine initial dose <3 DoL (0–2) versus ≥3 DoL (3–10) Retrospective; unknown indications for use of early caffeine	1986 neonates BW 938±201 g GA 27.5±2.0 weeks	965 neonates BW 899±216 g GA 27.2±2.1 weeks	Reduced incidence of BPD (36.1% versus 46.7%, OR 0.69) and rate of BPD or death (45.5% versus 54.9%, OR 0.77) Lower age at first extubation (7.1 versus 10.8 days), decreased duration of MV (16.7 versus 23.7 days) and PMA to room air (34.7 versus 35.6 days) Lower odds of severe IVH and PDA	Higher odds of NEC (OR 1.41)
Dekker, 2017 [12]	Unblinded RCT Caffeine in the delivery room versus caffeine in the NICU Small sample size; no placebo-controlled group	13 neonates BW 870 (767–1198) g GA 27 (26–28) weeks	10 neonates BW 960 (731–1450) g GA 28.5 (27–29) weeks	Increased minute volumes (189±74 versus 162±70 mL·kg⁻¹·min⁻¹) and tidal volumes (5.2, IQR 3.9–6.4 mL·kg⁻¹) versus 4.4, IQR 3.0–5.6 mL·kg⁻¹) at 7–9 min after birth	No differences in short-term clinical outcomes (intubation rates, surfactant administration) and IVH
Katheria, 2015 [40]	Pilot RCT Caffeine citrate 20 mg·kg⁻¹ load within the first 2 h of life versus at 12 h of life Small sample size underpowered to achieve differences in the outcome of reducing intubation	11 neonates BW 1007±169 g GA 27±0.9 weeks	10 neonates BW 1005±239 g GA 27±0.9 weeks	Reduced incidence of intubation in the first 12 h (27% versus 70%, p=0.08) Reduced vasopressor requirement in the first 24 h (0% versus 20%, p=0.21) Higher SVC flow (101±25 mL·kg⁻¹·min⁻¹ versus 77±24 mL·kg⁻¹·min⁻¹) and RVO (273±62 mL·kg⁻¹·min⁻¹ versus 219 ± 43 mL·kg⁻¹·min⁻¹)	Similar duration of oxygen treatment, MV, IVH, PDA requiring treatment
Park, 2015 [64]	Systematic review and meta-analysis Early caffeine (0–2 DoL) versus late caffeine (≥3 DoL) Only one RCT included; one retrospective study in the meta-analysis; no analysis on the effect of caffeine on apnoea as the studies did not report it as an outcome	30 974 neonates for primary outcomes	23 873 neonates for primary outcomes	Reduced mortality (3.8% versus 4.2%, OR 0.90), incidence of BPD (20% versus 34.6%, OR 0.5) and rate of BPD or death (23.7% versus 37.9%, OR 0.52) Reduced risk of IVH, PVL, ROP requiring photocoagulation, PDA requiring treatment	Risk of NEC and NEC requiring surgery not associated with the early use of caffeine (OR 0.97 and 1.06, respectively)
Kua, 2017 [67]	Systematic review and meta-analysis Early caffeine (initiated <3 DoL) in preterm infants No information on the indications for early versus late caffeine treatment from the studies; most of the RCTs had small sample size			Meta-analysis of cohort studies and RCTs: - Reduction of BPD 20–33% - 29% reduction in the incidence of PDA (cohort studies) - 59% decrease in the need for surgical closure of PDA (cohort studies) - Shorter duration of MV (WMD −7.5 days)	Increase in absolute risk of mortality with early caffeine therapy (4.7% versus 3.9%). No difference in rates of NEC, need for surfactant, home oxygen
Borszewska-Kornacka, 2017 [63]	Prospective cohort study Early (initial dose on DoL 1) and late (initial dose on DoL ≥2) caffeine therapy Possible differences in local practices between centres; no randomisation	143 neonates BW 1130 (895–1450) g GA 29 (27–30) weeks	143 neonates BW 1100 (850–1485) g GA 29 (27–30) weeks	Significant lower incidence of PDA (25% versus 37%, OR 0.56) Reduced incidence of IVH (42.1% versus 60.1%, OR 0.48) Reduced duration of MV (IQR 0–4 versus IQR 1–15.9)	No statistically significant difference in the incidence of BPD (36.4% versus 45.8%, p=0.31) and mortality rates (8.6% versus 8.5%, nonsignificiant)
Patel, 2017 [73]	Multicentre, observational cohort study Early caffeine (initiation on DoL 0) versus late caffeine (initiation on DoL 1–6) No adjustment for factors possibly associated with doctor's decision to start caffeine; highly selected infants excluding those with need of surfactant or lower Apgar score	4528 neonates BW <1500 g GA 29 (28–30) weeks	6605 neonates BW <1500 g GA 30 (29–31) weeks		Similar incidence of CPAP failure (22% versus 21%, OR 1.05) No difference in exposure to a max F_iO₂ >0.3 (27% versus 32%, OR 1.05) No difference in duration of CPAP therapy (3 versus 2 days, OR 1.02)

CAP: Caffeine for Apnoea of Prematurity; DoL: day of life; PMA: post-menstrual age; PPV: positive pressure ventilation; BW: birthweight; IVH: intraventricular haemorrhage; GA: gestational age; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus; MV: mechanical ventilation; aOR: adjusted odds ratio; HFV: high-frequency ventilation; CPAP: continuous positive airway pressure; NEC: necrotising enterocolitis; ROP: retinopathy of prematurity; PVL: periventricular leukomalacia; NICU: neonatal intensive care unit; IQR: interquartile range; SVC: superior vena cava; RVO: right ventricular output; WMD: weighted mean difference; F_iO₂: fraction of inhaled oxygen.

TABLE 2

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

First author, year [ref.]	Study characteristics Patient characteristics Limitations	Regimen		Main significant findings
First author, year [ref.]		High caffeine dose	Standard/low caffeine dose	Benefits of high caffeine dose	Drawbacks or no effects of high caffeine dose
Romagnoli, 1992 [88]	Single-centre RCT 37 total neonates, 14 (controls) versus 13 versus 10 neonates, born <32 GW Single centre; small sample size; unclear risk of most biases with incomplete outcome data	Group I: LD 10 mg·kg⁻¹; MD 5 mg·kg⁻¹	Group II: LD 10 mg·kg⁻¹; MD 2.5 mg·kg⁻¹	Decrease in the number of apnoeic spells in both treated groups compared with a control group (p<0.01)	Significantly lower frequency of side-effects such as tachycardia (p<0.001) and gastrointestinal intolerance in the low-dose group (nonsignificant)
Scanlon, 1992 [80]	Single-centre RCT 44 total neonates, 14 versus 16 neonates (14 infants treated with theophylline), born <31 GW, with frequent apnoeic attacks (≥10 in 8 h or 4 in 1 h) Single centre; small sample size; unclear risk of most biases with incomplete outcome data	LD 50 mg·kg⁻¹; MD 12 mg·kg⁻¹	LD 25 mg·kg⁻¹; MD 6 mg·kg⁻¹	Number of apnoea events·day⁻¹ reduced by 1/3 within 24 h by standard dose treatment versus a reduction by >50% by the higher dose treatment within the same time period
Steer, 2003 [81]	Single-centre RCT 45 versus 40 versus 42 neonates <32 GW ventilated for >48 h Single centre; small sample size	High dose: LD 60 mg·kg⁻¹; MD 30 mg·kg⁻¹ Moderate dose: LD 30 mg·kg⁻¹; MD 15 mg·kg⁻¹	LD 6 mg·kg⁻¹; MD 3 mg·kg⁻¹	Reduction in documented apnoea episodes (p<0.02); Trend to decrease in failure of extubation in the two highest dose groups (24% versus 25% versus 45%, p=0.06)
Steer, 2004 [82]	Multicentre RCT Total of 234 neonates, 113 versus 121 neonates, born <30 GW ventilated for >48 h; Data on long-term neurodevelopment to be considered with caution due to 18% loss at follow-up and not being the primary outcome	MD 20 mg·kg⁻¹ before a planned extubation or 6 h within an unplanned extubation	MD 5 mg·kg⁻¹ before a planned extubation or 6 h within an unplanned extubation	Reduced rate of extubation failure (15.0% versus 29.8%, RR 0.51; NNT 7) Reduction in documented apnoea episodes (4 (1–12) versus 7 (2–22), p<0.01) ignificant difference in duration of MV in infants <28 GW (mean 14.4 days versus 22.1 days, p=0.01)	No difference in mortality, major morbidities, severe disability
Gray, 2011 [89]	Multicentre RCT Total of 287 neonates, 120 versus 126 neonates, born <30 GW Some incomplete outcome data (e.g. age at starting treatment)	LD 80 mg·kg⁻¹; MD 20 mg·kg⁻¹	LD 20 mg·kg⁻¹; MD 5 mg·kg⁻¹	Significantly greater mean general quotient in the high-dose group (98.0±13.8 versus 93.6±16.5, p=0.048) Nonsignificant trend for benefit in the high-dose caffeine group for death or major disability (15.4% versus 24.2%; RR 0.75, 95% CI 0.49–1.14)	No difference in temperament and behaviour
Mohammed, 2015 [83]	Single-centre RCT 60 versus 60 neonates, born <32 GW Single centre; small sample size	LD 40 mg·kg⁻¹; MD 20 mg·kg⁻¹	LD 20 mg·kg⁻¹; MD 10 mg·kg⁻¹	Reduction in extubation failure (p<0.05) Reduction in frequency of apnoea (p<0.001)	Significant increase in episodes of tachycardia (p<0.05) No difference in the incidence of BPD No difference in the incidence of ROP, IVH, PVL or LOS
McPherson, 2015 [85]	Single-centre RCT Total of 74 neonates, 37 versus 37 neonates, born ≤30 GW Pilot study with small sample size only powered to detect differences in the primary outcome of microstructural brain development at term-equivalent age	LD 80 mg·kg⁻¹ over a 36-h period (40–20–10); MD 10 mg·kg⁻¹	LD 30 mg·kg⁻¹ over a 36-h period (20–10); MD 10 mg·kg⁻¹		Increased incidence of cerebellar haemorrhage in the high-dose group (36% versus 10%, p=0.03), more deviant neurological signs (p=0.04) at term-equivalent age No differences in diffusion measures at term-equivalent age and developmental outcomes at 2 years
Zhao, 2016 [90]	Single-centre RCT 164 total infants, 82 versus 82 neonates, born <32 GW Single-centre; possible selection, detection and reporting biases	LD 20 mg·kg⁻¹; MD 15 mg·kg⁻¹	LD 20 mg·kg⁻¹; MD 5 mg·kg⁻¹	Reduction in the frequency of apnoea (10 versus 18, p=0.009) Higher success rate of ventilator removal (85% versus 70%, p=0.015)	No significant difference in death during hospitalisation, CLD and duration of hospital stay No significant difference in tachycardia, irritability, difficulty in feeding, hyperglycaemia, hypertension, digestive disorders and electrolyte disturbances
Vliegenthart, 2018 [84]	Systematic review and meta-analysis including 6 RCTs with a total of 620 preterm infants; GA ≤32 GW Overall quality of the outcome measures (GRADE) considered low to very low due to imprecision and inconstancy of the effect estimates; small sample sizes of the included studies	LD 10–80 mg·kg⁻¹; MD 5–30 mg·kg⁻¹	LD 6–30 mg·kg⁻¹; MD 2.5–20 mg·kg⁻¹	In the subgroup analysis for therapy duration >14 days, significant reduction in the combined outcome of mortality or BPD at 36 weeks PMA (3 studies, 428 patients) (TRR 0.76, 95% CI 0.59–0.98) and in BPD rates alone (TRR 0.72, 95% CI 0.54–0.97) Reduction in extubation failure (TRR 0.51, 95% CI 0.37–0.70)	No difference in mortality at discharge or at 12 months Increased risk of tachycardia in the HD group (RR 3.39, 95% CI 1.50–7.64) No difference in NEC, SIP, ROP, IVH, hyperglycaemia. Considerations: no meta-analysis on differences in apnoea frequency due to diverse definition of the outcome No meta-analysis on duration of respiratory support due to data reported in IQR Inadequate power to detect small but clinical relevant differences Considerable differences in administered caffeine doses between studies
Brattström, 2019 [87]	Systematic review and meta-analysis including 6 RCTs with a total of 816 preterm infants (GA ≤32 GW); LD 20–80 mg·kg⁻¹; MD 3–20 mg·kg⁻¹ Low quality of evidence mainly due to imprecision of the estimates, few events, small sample sizes and the wide confidence intervals of the meta-analysis	LD >20 mg·kg⁻¹; MD >10 mg·kg⁻¹	Doses lower than the high-caffeine group	Reduction in BPD at 36 weeks PMA (RR 0.76, 95% CI 0.60–0.96) Fewer cases of extubation failure (as defined by study authors, RR 0.51, 95% CI 0.36–0.71) and apnoeas (mean difference −5.68, −6.15—5.22), and shorter duration of MV (mean difference −1.69, −2.13—1.25) in the HD group	No difference in mortality (RR 0.85, 95% CI 0.53–1.38) No difference in IVH ≥3 (RR 1.41, 95% CI 0.71–2.79)
Chen, 2018 [92]	Systematic review and meta-analysis including 13 RCTs with 1515 infants, GA <32 GW Variable maintenance doses within the high- and low-dose range; only few trials assessing outcomes such as extubation failure, frequency of apnoea, apnoea duration; most studies in Chinese with low quality	Variable LD MD 10–20 mg·kg⁻¹	Variable LD MD 5–10 mg·kg⁻¹	Higher efficacy rate in the HD group (RR 1.37, 95% CI 1.18–1.45) Higher success rate of ventilator removal (3 studies, RR 1.74, 95% CI 1.04–2.90) Lower extubation failure rate in the HD group (3 studies, RR 0.5, 95% CI 0.35–0.71) Lower frequency of apnoea and shorter apnoea duration in the HD group (MD −1.55, 95% CI −2.72–−0.39 and MD −4.85, 95% CI −8.29–−1.40) Lower incidence of BPD in the HD group (RR 0.79, 95% CI 0.68–0.91)	Higher incidence of tachycardia in the HD group (RR 2.02, 95% CI 1.30–3.12)

GW: gestational weeks; LD: loading dose; MD: maintenance dose; RR: risk ratio; NNT: number needed to treat; MV: mechanical ventilation; BPD: bronchopulmonary dysplasia; ROP: retinopathy of prematurity; IVH: intraventricular haemorrhage; PVL: periventricular leukomalacia; LOS: late-onset sepsis; CLD: chronic lung disease; GRADE: Grading of Recommendations Assessment, Development and Evaluation; PMA: post-menstrual age; TRR: typical risk ratio; HD: high dose; NEC: necrotising enterocolitis; SIP: spontaneous intestinal perforation; IQR: interquartile range; GA: gestational age.