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Review
. 2023 Apr 11;4(4):CD013873.
doi: 10.1002/14651858.CD013873.pub2.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity

Matteo Bruschettini  1   2 , Petter Brattström  3 , Chiara Russo  4 , Wes Onland  5 , Peter G Davis  6   7   8 , Roger Soll  9
Affiliations
Review

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity

Matteo Bruschettini et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Authors' conclusions: 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.

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Conflict of interest statement

MB: no known conflicts of interest. MB is an Associate Editor with the Cochrane Neonatal Group but took no part in editorial acceptance or review of this manuscript.

PB: no known conflicts of interest.

CR: no known conflicts of interest.

WO: no known conflicts of interest.

PGD is co‐author of publications relevant to the interventions in the work; works as a neonatologist at The Royal Women's Hospital, Melbourne.

RFS is the Co‐ordinating Editor of the Cochrane Neonatal Review Group, President and Director of Clinical Trials of the Vermont Oxford Network, and a professor at the University of Vermont. RFS took no part in the editorial processes for this review.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 1: All‐cause mortality prior to hospital discharge
1.2
1.2. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 2: Major neurodevelopmental disability in children aged three to five years
1.3
1.3. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 3: Failure to extubate within one week of commencing treatment
1.4
1.4. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 4: Reintubation within one week of commencing treatment
1.5
1.5. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 5: Apnea: number of infants with at least one episode (defined as interruption of breathing for more than 20 seconds) after 24 hours from commencing treatment, in a 24‐hour period and over one week
1.6
1.6. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 6: Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of caffeine
1.7
1.7. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 7: Bronchopulmonary dysplasia/chronic lung disease: 28 days of oxygen exposure
1.8
1.8. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 8: Bronchopulmonary dysplasia/chronic lung disease at 36 weeks' postmenstrual age
1.9
1.9. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 9: Number of days using mechanical ventilation
1.10
1.10. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 10: Intraventricular hemorrhage, any grade
1.11
1.11. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 11: Intraventricular hemorrhage, grade 3 to 4
1.12
1.12. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 12: Cerebellar hemorrhage at brain ultrasound (yes/no)
1.13
1.13. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 13: Magnetic resonance imaging (MRI) abnormalities at term equivalent age (yes/no), defined as white matter lesions (i.e. cavitations [Rutherford 2010]) and punctate lesions (Cornette 2002); germinal matrix‐intraventricular hemorrhage (Parodi 2015); or cerebellar hemorrhage (Limperopoulos 2007)
1.14
1.14. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 14: Periventricular leukomalacia
1.15
1.15. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 15: Necrotizing enterocolitis (proven = Bell stage of 2 or greater) (Bell 1978)
1.16
1.16. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 16: Patent ductus arteriosus (PDA) requiring treatment (cyclo‐oxygenase inhibitors or surgical ligation)
1.17
1.17. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 17: Retinopathy of prematurity (ROP) (any ROP) (International Committee 2005)
1.18
1.18. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 18: Retinopathy of prematurity (ROP) (severe ROP [stage 3 or greater]) (International Committee 2005)
1.19
1.19. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 19: Seizures (clinically diagnosed; diagnosed by electroencephalography)
1.20
1.20. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 20: Developmental delay (Bayley Mental Developmental Index or Griffiths Mental Development Scale in children aged 18 to 24 months
1.21
1.21. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 21: Bayley‐III cognitive score in children at 18 to 24 months CA
1.22
1.22. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 22: Cerebral palsy in children aged 18 to 24 months
1.23
1.23. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 23: Blindness in children aged 18 to 24 months
1.24
1.24. Analysis
Comparison 1: High‐ versus standard‐dose strategies for any indication, Outcome 24: Deafness in children aged 18 to 24 months
2.1
2.1. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 1: All‐cause mortality prior to hospital discharge
2.2
2.2. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 2: Major neurodevelopmental disability in children aged three to five years
2.3
2.3. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 3: Failure to extubate within one week of commencing treatment
2.4
2.4. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 4: Apnea: number of infants with at least one episode (defined as interruption of breathing for more than 20 seconds) after 24 hours from commencing treatment, in a 24‐hour period and over one week
2.5
2.5. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 5: Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of caffeine
2.6
2.6. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 6: Bronchopulmonary dysplasia/chronic lung disease at 36 weeks' postmenstrual age
2.7
2.7. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 7: Number of days using mechanical ventilation
2.8
2.8. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 8: Intraventricular hemorrhage, any grade
2.9
2.9. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 9: Intraventricular hemorrhage, grade 3 to 4
2.10
2.10. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 10: Cerebellar hemorrhage at brain ultrasound (yes/no)
2.11
2.11. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 11: Magnetic resonance imaging (MRI) abnormalities at term equivalent age (yes/no), defined as white matter lesions (i.e. cavitations [Rutherford 2010]) and punctate lesions (Cornette 2002); germinal matrix‐intraventricular hemorrhage (Parodi 2015); or cerebellar hemorrhage (Limperopoulos 2007)
2.12
2.12. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 12: Periventricular leukomalacia
2.13
2.13. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 13: Necrotizing enterocolitis (proven = Bell stage of 2 or greater) (Bell 1978)
2.14
2.14. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 14: Patent ductus arteriosus (PDA) requiring treatment (cyclo‐oxygenase inhibitors or surgical ligation)
2.15
2.15. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 15: Retinopathy of prematurity (ROP) (any ROP) (International Committee 2005)
2.16
2.16. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 16: Retinopathy of prematurity (ROP) (severe ROP [stage 3 or greater]) (International Committee 2005)
2.17
2.17. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 17: Seizures (clinically diagnosed; diagnosed by electroencephalography)
2.18
2.18. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 18: Developmental delay (Bayley Mental Developmental Index or Griffiths Mental Development Scale in children aged 18 to 24 months
2.19
2.19. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 19: Bayley‐III cognitive score in children at 18 to 24 montsh CA
2.20
2.20. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 20: Cerebral palsy in children aged 18 to 24 months
2.21
2.21. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 21: Blindness in children aged 18 to 24 months
2.22
2.22. Analysis
Comparison 2: High‐ versus standard‐dose strategies for prevention of apnea, Outcome 22: Deafness in children aged 18 to 24 months
3.1
3.1. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 1: All‐cause mortality prior to hospital discharge
3.2
3.2. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 2: Failure to extubate within one week of commencing treatment
3.3
3.3. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 3: Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of caffeine
3.4
3.4. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 4: Bronchopulmonary dysplasia/chronic lung disease at 36 weeks' postmenstrual age
3.5
3.5. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 5: Intraventricular hemorrhage, any grade
3.6
3.6. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 6: Intraventricular hemorrhage, grade 3 to 4
3.7
3.7. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 7: Periventricular leukomalacia
3.8
3.8. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 8: Necrotizing enterocolitis (proven = Bell stage of 2 or greater) (Bell 1978)
3.9
3.9. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 9: Retinopathy of prematurity (ROP) (any ROP) (International Committee 2005)
3.10
3.10. Analysis
Comparison 3: High‐ versus standard‐dose strategies for treatment of apnea, Outcome 10: Retinopathy of prematurity (ROP) (severe ROP [stage 3 or greater]) (International Committee 2005)
4.1
4.1. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 1: All‐cause mortality prior to hospital discharge
4.2
4.2. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 2: Failure to extubate within one week of commencing treatment
4.3
4.3. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 3: Reintubation within one week of commencing treatment
4.4
4.4. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 4: Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of caffeine
4.5
4.5. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 5: Bronchopulmonary dysplasia/chronic lung disease: 28 days of oxygen exposure
4.6
4.6. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 6: Bronchopulmonary dysplasia/chronic lung disease at 36 weeks' postmenstrual age
4.7
4.7. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 7: Number of days using mechanical ventilation
4.8
4.8. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 8: Intraventricular hemorrhage, any grade
4.9
4.9. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 9: Intraventricular hemorrhage, grade 3 to 4
4.10
4.10. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 10: Necrotizing enterocolitis (proven = Bell stage of 2 or greater) (Bell 1978)
4.11
4.11. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 11: Patent ductus arteriosus (PDA) requiring treatment (cyclo‐oxygenase inhibitors or surgical ligation)
4.12
4.12. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 12: Retinopathy of prematurity (ROP) (any ROP) (International Committee 2005)
4.13
4.13. Analysis
Comparison 4: High‐ versus standard‐dose strategies for the prevention of re‐intubation, Outcome 13: Retinopathy of prematurity (ROP) (severe ROP [stage 3 or greater]) (International Committee 2005)
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Update of

References

References to studies included in this review

McPherson 2015 {published data only}
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NCT04144712 {published data only}
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