1. Overview of the included studies, ordered by indication.
| High‐dose versus standard‐dose strategies | |||||||||
| Study ID | Enrollment period | Country | GA (weeks) | Sample size | Age at study entry | High dose | Standard dose | Indication | Subgroup by dose |
| McPherson 2015 | 2008 to 2010 |
US | Mean (SD): 25.8 (2.0) high dose Mean (SD): 26.5 (1.9) standard dose. |
74 | Within 24 h | LD 40 mg/kg + 20 mg/kg after 12 h; MD 10 mg/kg at 24 and 36 h; then every 24 hs |
LD 20 mg/kg MD 10 mg/kg |
Apnea prevention | High LD versus standard LD |
| Mohd 2021 | 2019 to 2020 | Malaysia | Median (IQR): 30 (2.7) high dose Median (IQR): 29.8 (3.3) standard dose |
78 | Median 2 weeks | LD 40 mg/kg MD 20 mg/kg |
LD 20 mg/kg MD 10 mg/kg |
Apnea prevention | High LD versus standard LD |
| Scanlon 1992 | Not reported | UK | Mean (SD): 28.2 (1.1) high dose Mean (SD): 28.7 (1.2) standard dose |
44 | Mean 6 days | LD 50 mg/kg MD 12 mg/kg |
LD 25mg/kg MD 6 mg/kg |
Apnea treatment | High LD versus standard LD |
| Zhao 2016a | 2013 to 2014 | China | Mean (SD): 29.8 (3.4) high dose Mean (SD): 29.9 (2.7) standard dose |
164 | Mean 4 days | LD 20 mg/kg MD 15 mg/kg |
LD 20 mg/kg MD 5 mg/kg |
Apnea treatment | Standard LD in both groups |
| Mohammed 2015 | 2011 to 2012 | Egypt | Mean (SD): 29.4 (2.0) high dose Mean (SD): 29.8 (1.9) standard dose |
120 | Mean 3 days | LD 40 mg/kg MD 20 mg/kg |
LD 20 mg/kg MD 10 mg/kg |
Apnea treatment | High LD versus standard LD |
| Steer 2004 | 1996 to 1999 |
Australia | Mean (SD): 27.3 (1.4) high dose Mean (SD): 27.5 (1.4) standard dose |
287 | Median 4 days, within 12 days | LD 80 mg/kg MD 20 mg/kg |
LD 20 mg/kg MD 5 mg/kg |
Apnea treatment and extubation management |
High LD versus standard LD |
| Steer 2003b | 1993 to 1995 |
Australia | Mean (SD): 27.8 (1.9) high dose 1 Mean (SD): 28.4 (1.7) high dose 2 Mean (SD): 28 (1.8) standard dose |
127 | Mean 4 days | LD 60 mg/kg or 30 mg/kg; MD 30 mg/kg or 15 mg/kg |
LD 6 mg/kg MD 3 mg/kg |
Extubation management | High LD versus standard LD |
GA: gestational age; IQR: interquartile range; LD: loading dose; MD: maintenance dose; SD: standard deviation
Footnotes aIn all studies infants were randomized to high‐loading and high‐maintenance or standard‐loading and standard‐maintenance dose except Zhao 2016, where infants were randomized to standard‐loading and high‐maintenance or standard‐loading and standard‐maintenance dose. bIn Steer 2003, infants were randomized in three groups: two of them match our definition of high dose and one standard dose. Outcome data are reported according to the footnotes in comparisons 1 and 3 (e.g. Analysis 1.1).
Definition of the doses
- High‐loading dose: more than 25 mg of caffeine citrate/kg
- Standard‐loading dose: 25 mg or less of caffeine citrate/kg
- High‐maintenance dose: more than 10 mg of caffeine citrate/kg/day
- Standard‐maintenance dose: 10 mg or less of caffeine citrate/kg/day