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Critical Appraisal High Dose Vs Low Dose Caffeine Citrate in Preterms

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Tauhid Bhuiyan

The document discusses two studies that compared high dose vs low dose caffeine citrate for treatment of apnea of prematurity. The 2015 study found: 1) High dose caffeine (40/20 mg/kg loading/maintenance) was not associated with higher rates of extubation failure or more frequent apnea episodes compared to low dose (20/10 mg/kg). 2) Both doses were well-tolerated with no significant differences in adverse effects. 3) The authors concluded higher doses may reduce extubation failure and apnea frequency without increased side effects. However, the study had a small sample size. An earlier 2004 study found similar results, with high dose (80/20 mg/kg loading

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Critical Appraisal: High Dose vs Low Dose Caffeine Citrate in Apnea of Prematurity (AOP) Tauhid Ahmed Bhuiyan, PharmD Pharmacy Practice Resident (R2) King Faisal Specialist Hospital & Research Center (KFSH&RC)
Definition & Terminology Gestational age (or menstrual age) First day of the last normal menstruation to day of delivery Chronological age (or postnatal age) time elapsed after birth Corrected age (or adjusted age) Prematurity: Gestational age <37 weeks Birth weight: Normal: 2500 g + Low: <2500 g Very low: <1500 g Blackmon LR et al. PEDIATRICS 2004; 114(5):1362-65
Apnea of Prematurity (AOP) Developmental disorder As a result of immature respiratory control mechanisms Depends on gestational age and birth weight In premature infants: Defined as, respiratory pauses >20 sec or pauses <20 sec accompanied by bradycardia (< 100 beats/min), central cyanosis, and/or O2 saturation < 90% Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Epidemiology Occur in almost all infants born at <29 weeks gestation or <1000 g 50 % of infants born between 30 to 32 weeks 7 % of infants born at 34 to 35 weeks gestation Apneic episodes might persist beyond term in infants born <28 weeks gestation Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Prognosis Death is rare Typically, apneic spells stops (in most cases) by the time infants reach 37 weeks gestation Intermittent hypoxemia deleterious neurodevelopmental outcomes & retinopathy of prematurity (ROP) Poor respiratory drive Prolongation of duration of mechanical ventilation Decrease chances of successful extubation Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Treatment of Choice Non-pharmacological: continuous positive airway pressure Pharmacological: methylxanthines aminophylline, theophylline, and caffeine Theophylline: narrow therapeutic window Caffeine: multiple trials validated the use proven short-term effectiveness of apnea episodes need for assisted ventilation up to 7 days of life Duration: postmenstrual age of 34-35 wks Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Caffeine Citrate Standard dose: 20 mg/kg loading followed by 5- 10 mg/kg/day Pros: higher therapeutic index, better enteral absorption, and longer half-life (neonates: 72-96 hours) Cons: tachycardia, jitteriness, and feeding intolerance in preterm infants Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Evidence On Use Cochrane review of 5 trials (N = 108 preterm) caffeine was as effective as theophylline Reducing apnea and extubation failure during the first week of life with lower adverse effects (e.g. tachycardia and feeding intolerance) Caffeine for Apnea of Prematurity (CAP) trial (caffeine vs placebo) Study population: 2006 preterm infants (gestational age: 27賊2 wks, weight: 964賊186g with AOP) Caffeine therapy was associated with reduction of the duration of positive pressure ventilation, duration of supplemental oxygen, rate of bronchopulmonary dysplasia (BPD) rate of severe ROP Follow-up study of infants in CAP trial: caffeine was associated with improvement in motor coordination and visual perception at age of 5 years Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Dosing: Variable Evidence Scanlon et al. (1992) Loading dose of 50 mg/kg caffeine citrate (25 mg/kg caffeine base) is more effective in reducing apneic episodes within 8 h than a caffeine loading dose of 25 mg/kg Two studies (2004,2011) revealed daily administration of 20 mg/kg caffeine citrate starting in the periextubation period was as well tolerated as the use of 5 mg/kg per day Steer et al. (2003) daily maintenance dose of 30 mg/kg caffeine can be used safely in preterm infants Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
High Dose Vs. Low Dose 2015 2004
Major Differences Steer P et al. (2004) Mohammed S et al. (2015) Study Design Multicenter (4 centers, Australia), randomized, double-blinded Dosing regimen (per day): High dose: 80 mg/kg loading, followed by 20 mg/kg Low dose: 20 mg/kg loading, followed by 5 mg/kg Study duration: 31 months Randomized, double-blinded, prospective trial, in Egypt Dosing regimen (per day): High dose: 40 mg/kg loading, followed by 20 mg/kg Low dose: 20 mg/kg loading, followed by 10 mg/kg Study duration: 12 months Sample Size/Pop- ulation N= 234 preterm infants, gestational age <30 weeks, ventilated for >48 hours N= 120 preterm infants, gestational age <32 weeks, exhibited AOP within the first 10 days of life Major Exclusions Major congenital abnormality, sepsis (confirmed by blood culture), major neurological condition, grade 3 or 4 intraventricular hemorrhage, previous methylxanthine treatment Major congenital malformations and chromosomal anomalies Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8 Steer P. et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F499F503
Mohammed S. et al. Study objective: Feasibility of using high-dose, compared to low-dose, of caffeine citrate for prevention of extubation failure and treatment of apnea in preterm infants Endpoints: Primary: extubation failure in mechanically ventilated infants (need of re-intubation within 72 h of extubation from mechanical ventilation) Secondary: Frequency (per the whole duration of caffeine therapy) and documented days of apnea as recognized by daily tracing of monitor review performed by co-authors Need for mechanical ventilation (for the purpose of AOP) in on ventilated
Randomization Internet-based random table technique A designated pharmacist was responsible for the randomization of selected infants and the preparation of caffeine dose Blinding: the investigators, nursing staff, and family Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Study Procedure Two treatment arm: Low dose group: 20 mg/kg/day loading, followed by 10 mg/kg/day High dose group: 40 mg/kg loading, followed by 20 mg/kg Equivalent caffeine base: 2:1 Oxygen saturation, heart rate, and respiratory rate were continuously monitored (Tachycardia: >180 beats/min) Blood pressure was checked twice daily (High: BP > 95th percentile) Frequency of apnea and bradycardia were taken from the monitor and validated by attending qualified nurses Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Statistical Analysis Inferential statistics: Student t test, MannWhitney U test, Chi-square test or Fisher exact test (if necessary), or Kolmogorov Smirnov test P < 0.05; considered to be statistically significant All statistical analysis was done on an intention- to-treat base Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Results
Study Profile Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Baseline demographics: Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Primary Outcomes MohammedS.etal.(2015) SteerP.etal.(2004)
Kaplan-Meier for Secondary Outcomes MohammedS.etal.(2015)
Adverse Effects (Impact on Neonatal Outcome) Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Adverse Effects (Side Effects of Caffeine) Mohammed S. et al. (2015) Steer P. et al. (2004)
Authors Conclusion The use of higher, than current standard, dose of caffeine may decrease the chance of extubation failure in mechanically ventilated preterm infants and the frequency of apnea in preterm infants without significant side effects Consistent with earlier study Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
Study Limitations Smaller sample size than previous study that validated same results No power calculation to detect difference of clinical and statistical significance Lack of long-term follow-up of neonatal outcome
Long-Term Follow-up (Steer P. et al.) Outcomes at 12 months corrected for prematurity
Practice in KFMC
Question of the day: Are we willing to change our practice?????

More Related Content

Critical Appraisal High Dose Vs Low Dose Caffeine Citrate in Preterms

  • 1. Critical Appraisal: High Dose vs Low Dose Caffeine Citrate in Apnea of Prematurity (AOP) Tauhid Ahmed Bhuiyan, PharmD Pharmacy Practice Resident (R2) King Faisal Specialist Hospital & Research Center (KFSH&RC)
  • 2. Definition & Terminology Gestational age (or menstrual age) First day of the last normal menstruation to day of delivery Chronological age (or postnatal age) time elapsed after birth Corrected age (or adjusted age) Prematurity: Gestational age <37 weeks Birth weight: Normal: 2500 g + Low: <2500 g Very low: <1500 g Blackmon LR et al. PEDIATRICS 2004; 114(5):1362-65
  • 3. Apnea of Prematurity (AOP) Developmental disorder As a result of immature respiratory control mechanisms Depends on gestational age and birth weight In premature infants: Defined as, respiratory pauses >20 sec or pauses <20 sec accompanied by bradycardia (< 100 beats/min), central cyanosis, and/or O2 saturation < 90% Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 4. Epidemiology Occur in almost all infants born at <29 weeks gestation or <1000 g 50 % of infants born between 30 to 32 weeks 7 % of infants born at 34 to 35 weeks gestation Apneic episodes might persist beyond term in infants born <28 weeks gestation Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 5. Prognosis Death is rare Typically, apneic spells stops (in most cases) by the time infants reach 37 weeks gestation Intermittent hypoxemia deleterious neurodevelopmental outcomes & retinopathy of prematurity (ROP) Poor respiratory drive Prolongation of duration of mechanical ventilation Decrease chances of successful extubation Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 6. Treatment of Choice Non-pharmacological: continuous positive airway pressure Pharmacological: methylxanthines aminophylline, theophylline, and caffeine Theophylline: narrow therapeutic window Caffeine: multiple trials validated the use proven short-term effectiveness of apnea episodes need for assisted ventilation up to 7 days of life Duration: postmenstrual age of 34-35 wks Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 7. Caffeine Citrate Standard dose: 20 mg/kg loading followed by 5- 10 mg/kg/day Pros: higher therapeutic index, better enteral absorption, and longer half-life (neonates: 72-96 hours) Cons: tachycardia, jitteriness, and feeding intolerance in preterm infants Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 8. Evidence On Use Cochrane review of 5 trials (N = 108 preterm) caffeine was as effective as theophylline Reducing apnea and extubation failure during the first week of life with lower adverse effects (e.g. tachycardia and feeding intolerance) Caffeine for Apnea of Prematurity (CAP) trial (caffeine vs placebo) Study population: 2006 preterm infants (gestational age: 27賊2 wks, weight: 964賊186g with AOP) Caffeine therapy was associated with reduction of the duration of positive pressure ventilation, duration of supplemental oxygen, rate of bronchopulmonary dysplasia (BPD) rate of severe ROP Follow-up study of infants in CAP trial: caffeine was associated with improvement in motor coordination and visual perception at age of 5 years Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 9. Dosing: Variable Evidence Scanlon et al. (1992) Loading dose of 50 mg/kg caffeine citrate (25 mg/kg caffeine base) is more effective in reducing apneic episodes within 8 h than a caffeine loading dose of 25 mg/kg Two studies (2004,2011) revealed daily administration of 20 mg/kg caffeine citrate starting in the periextubation period was as well tolerated as the use of 5 mg/kg per day Steer et al. (2003) daily maintenance dose of 30 mg/kg caffeine can be used safely in preterm infants Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 10. High Dose Vs. Low Dose 2015 2004
  • 11. Major Differences Steer P et al. (2004) Mohammed S et al. (2015) Study Design Multicenter (4 centers, Australia), randomized, double-blinded Dosing regimen (per day): High dose: 80 mg/kg loading, followed by 20 mg/kg Low dose: 20 mg/kg loading, followed by 5 mg/kg Study duration: 31 months Randomized, double-blinded, prospective trial, in Egypt Dosing regimen (per day): High dose: 40 mg/kg loading, followed by 20 mg/kg Low dose: 20 mg/kg loading, followed by 10 mg/kg Study duration: 12 months Sample Size/Pop- ulation N= 234 preterm infants, gestational age <30 weeks, ventilated for >48 hours N= 120 preterm infants, gestational age <32 weeks, exhibited AOP within the first 10 days of life Major Exclusions Major congenital abnormality, sepsis (confirmed by blood culture), major neurological condition, grade 3 or 4 intraventricular hemorrhage, previous methylxanthine treatment Major congenital malformations and chromosomal anomalies Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8 Steer P. et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F499F503
  • 12. Mohammed S. et al. Study objective: Feasibility of using high-dose, compared to low-dose, of caffeine citrate for prevention of extubation failure and treatment of apnea in preterm infants Endpoints: Primary: extubation failure in mechanically ventilated infants (need of re-intubation within 72 h of extubation from mechanical ventilation) Secondary: Frequency (per the whole duration of caffeine therapy) and documented days of apnea as recognized by daily tracing of monitor review performed by co-authors Need for mechanical ventilation (for the purpose of AOP) in on ventilated
  • 13. Randomization Internet-based random table technique A designated pharmacist was responsible for the randomization of selected infants and the preparation of caffeine dose Blinding: the investigators, nursing staff, and family Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 14. Study Procedure Two treatment arm: Low dose group: 20 mg/kg/day loading, followed by 10 mg/kg/day High dose group: 40 mg/kg loading, followed by 20 mg/kg Equivalent caffeine base: 2:1 Oxygen saturation, heart rate, and respiratory rate were continuously monitored (Tachycardia: >180 beats/min) Blood pressure was checked twice daily (High: BP > 95th percentile) Frequency of apnea and bradycardia were taken from the monitor and validated by attending qualified nurses Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 15. Statistical Analysis Inferential statistics: Student t test, MannWhitney U test, Chi-square test or Fisher exact test (if necessary), or Kolmogorov Smirnov test P < 0.05; considered to be statistically significant All statistical analysis was done on an intention- to-treat base Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 17. Study Profile Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 18. Baseline demographics: Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 21. Adverse Effects (Impact on Neonatal Outcome) Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 22. Adverse Effects (Side Effects of Caffeine) Mohammed S. et al. (2015) Steer P. et al. (2004)
  • 23. Authors Conclusion The use of higher, than current standard, dose of caffeine may decrease the chance of extubation failure in mechanically ventilated preterm infants and the frequency of apnea in preterm infants without significant side effects Consistent with earlier study Mohammed S et al. Eur J Pediatr 2015; DOI 10.1007/s00431-015-2494-8
  • 24. Study Limitations Smaller sample size than previous study that validated same results No power calculation to detect difference of clinical and statistical significance Lack of long-term follow-up of neonatal outcome
  • 25. Long-Term Follow-up (Steer P. et al.) Outcomes at 12 months corrected for prematurity
  • 27. Question of the day: Are we willing to change our practice?????