MANUSCRIPT CITATION

Oliphant EA, McKinlay CJ, McNamara D, Cavadino A, Alsweiler JM. Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):106-113. doi: 10.1136/archdischild-2022-324010. Epub 2022 Aug 29. PMID: 36038256

Reviewed by

Ayat Mohamed, MBBS, MRCPCH
Paediatric trainee ST5
Department of Neonatology
Newcross Hospital
Wolverhampton, United Kingdom
Ayat.mohamed@nhs.net

Hassanein Moustafa, MBBCh, MSc (Paed), MRCPCH
Senior Clinical Fellow in neonates
Department of neonatology
New cross Hospital
Wolverhampton, United Kingdom
hassanein.moustafa@doctors.org.uk

TYPE OF INVESTIGATION

Treatment -Safety and Efficacy

QUESTION

(P) In late preterm infants born at 34 –36 weeks’ gestation (I) does giving enteral caffeine citrate at certain dose (C) compared to placebo (O) reduce intermittent hypoxia (T) if it is given daily for 2 weeks post-randomisation.

METHODS

• Design: Phase IIB, double-blind, five-arm, parallel, randomised controlled trial.
• Allocation: Late preterm infants born at 34+0–36+6 weeks’ gestation, recruited within 72 hours of birth.
• Blinding: double-blind, five-arm, parallel, randomised controlled trial.
• Follow-up period: 100% followed until term.
• Setting: NICUs and postnatal wards of two tertiary maternity hospitals in Auckland at New Zealand.
• Patients:
  • Inclusion criteria:  Infants born between 34+0 – 36+6 weeks’ gestational age
  • Exclusion criteria:

• • • Major congenital abnormality.
    • Minor congenital abnormality likely to affect respiration, growth or development.
    • Previous caffeine treatment
    • Renal or hepatic impairment
    • Tachyarrhythmia
    • Seizures

• Data collected included:

• • Intermittent hypoxaemia (IH) at term equivalent age
  • Salivary caffeine concentration
  • Breastmilk caffeine concentration
  • Growth
  • Tachycardia
  • Feed intolerance
  • Sleeping 

• Intervention:  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.
  • Outcomes:

• • • Primary outcome: 

• • • • Reduction of intermittent hypoxia episodes at 2 weeks’ post randomisation

• • • Secondary outcomes:

• • • • Neonatal growth
      • Tachycardia
      • Salivary caffeine concentration
• Analysis and Sample Size:

The Authors estimated mean (SD) rate of 6.9 (3.4) IH episodes per hours at 2 weeks postrandomisation based on their previous study findings. To detect a 50% reduction (3.5 episodes per hour) in any group versus placebo with 90% power, allowing for a 10% drop out and clustering of multiples (intraclass correlation coefficient 0.05) would require 24 infants in each group (total 120 infants), with two-sided α=0.05.

The previous trial was not powered to conduct comparisons between caffeine doses.

 This  current study was conducted between February 2019 and December 2020, in which 337 late preterm infants were eligible for recruitment in this trial, however only 132 babies were randomised and  allocated to one of five parallel groups (5, 10, 15 or 20 mg/kg/day of caffeine citrate or placebo) within 72 hours of birth using an internet randomisation service with varying block sizes and 1:1:1:1:1 allocation stratified by study site and gestational age at birth (34, 35 or 36 weeks). Participating infants received an enteral loading dose of study drug (10, 20, 30 or 40 mg/kg of caffeine citrate or placebo) followed by a daily dose (5, 10, 15 or 20 mg/kg of caffeine citrate or placebo) until term equivalent age. The primary outcome data were available for 107 babies. Statistical analysis was performed using generalised linear mixed models, adjusting for various factors, and treatment effects were expressed as mean difference, geometric mean ratio, or odds ratio with 95% confidence intervals. Secondary analyses included comparisons of caffeine groups combined against placebo, per-protocol analysis, sensitivity analysis, and exploratory analyses.

MAIN RESULTS

• Caffeine citrate reduced IH significantly in late preterm infants, with doses of 10 and 20 mg/kg/day compared to placebo at 2 weeks post randomisation with significantly higher mean SpO2, but no difference for the 2 or 15 mg/kg/d groups.
• Caffeine citrate groups who received high doses spent significantly more time with tachycardia compared with placebo group.
• Infants in the 10 and 15 mg/kg/day of caffeine citrate groups, compared with placebo, had significantly lower gastroesophageal reflux symptom scores.
• No difference between placebo and caffeine groups in the proportion of infants not regaining birth weight by 2 weeks, or in growth velocity for weight or length at any timepoint. However, Infants in the 20 mg/kg/day group, compared with placebo, had significantly lower length z-scores at 2 weeks and term equivalent age.
• Head circumference velocity was significantly lower in the 5 mg/kg/day group compared with placebo.

CONCLUSION

The authors conclude that caffeine citrate reduces intermittent hypoxia in late preterm infants, with doses of 10 and 20 mg/kg/day being effective. Side effects at these doses include tachycardia, and possibly associated with lower length z-scores. Lower head circumference velocity was reported in the 5mg/kg/day group. In both affected growth cases, a statistically significant difference occurred only in a single dose group and for a single parameter, and other related parameters failed to show the same changes; it thus appears unlikely that caffeine has a significant impact on overall neonatal growth. A longer, larger trial with neurodevelopmental impairment as the primary outcome is required to establish if the reduction in intermittent hypoxia will result in clinically significant improvements in neurodevelopment.

COMMENTARY

Caffeine citrate is considered to be the drug of choice of apnea of prematurity. Caffeine therapy reduces the incidence of intermittent hypoxaemia, duration of mechanical ventilation and lung damage in preterm babies who are born before 28 week gestation (1).

 

Intermittent hypoxemia is the brief and repetitive episodes of dropped haemoglobin oxygen saturation from the normal oxygenation state, which are followed by returning to normal oxygenation baseline state. Preterm babies are more likely to have more frequent episodes of Intermittent hypoxia until term-equivalent age with no clear potential clinical triggers of developing apnea (2). The frequent occurrence of these episodes of desaturations in preterm infants have been suggested to be associated with later poor neurodevelopmental outcomes (3).

 

Late preterm infants, who are born between 34 ^0/7 and 36 ^6/7 weeks gestational age, account for an important proportion of newborn babies requiring admission to the neonatal unit because of respiratory morbidity (4). Nearly one third (28.6%) of late preterm newborns were reported to have apnea of prematurity which was attributed to both lung and respiratory centre immaturity, and hence required treatment (5) Furthermore, a prospective cohort observational study showed that there is a great risk of having intermittent hypoxemia in late preterm babies (6). Therefore, preventing or reducing intermittent hypoxemia episodes in late preterm infants could be associated with improving the neurodevelopmental outcomes.

 

This study was published in a reputable journal and declared no conflict of interest. It started with a large sample size and clear primary and prespecified secondary outcomes. However, there was a high rate of withdrawal of significant number of eligible babies in the higher dose caffeine. This was because of poor tolerability and administration difficulty, which may be attributed to the bitter solution taste as caffeine was received orally, in addition to the difficulty to give big volume in higher doses. The optimal dosage of caffeine citrate for reducing intermittent hypoxia in late preterm infants was not clear. This study used different dosages, and it is important to determine the most effective dose without adverse effects. It might be worth conducting longer and larger trials using more palatable caffeine formulation to assess the efficacy and safety of caffeine therapy in high doses, in addition to recording concurrent use of other medication that may interact with caffeine citrate. This would be very beneficial alongside with comparing early prophylactic versus late caffeine therapy and duration of caffeine treatment in late preterm infants in order to come to a definitive conclusion regarding its routine use on this population.

REFERENCES

1. Chavez L, Bancalari E. Caffeine: Some of the Evidence behind Its Use and Abuse in the Preterm Infant. Neonatology. 2022;119(4):428-432.
2. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014;168(3):250-7.
3. Pillekamp F, Hermann C, Keller T, von Gontard A, Kribs A, Roth B. Factors influencing apnea and bradycardia of prematurity – implications for neurodevelopment. Neonatology. 2007;91(3):155-61.
4. Consortium on Safe Labor. Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, et al. Respiratory morbidity in late preterm births. JAMA 2010; 304:419–25.
5. Olivier F, Nadeau S, Caouette G, Piedboeuf B. Association between Apnea of Prematurity and Respiratory Distress Syndrome in Late Preterm Infants: An Observational Study. Front Pediatr. 2016 Sep 26;4:105.
6. Williams LZJ, McNamara D, Alsweiler JM. Intermittent Hypoxemia in Infants Born Late Preterm: A Prospective Cohort Observational Study. J Pediatr. 2019; 204:89-95.e1.