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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)

Critical Appraisal High Dose Vs Low Dose Caffeine Citrate in Preterms

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Critical Appraisal: High Dose vs Low Dose Caffeine Citrate

in Apnea of Prematurity (AOP)

Tauhid Ahmed Bhuiyan, PharmDPharmacy 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 O 2 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±2 wks,

weight: 964±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 yearsMohammed 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 Dose2015

2004

Major DifferencesSteer 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/kgStudy duration: 31 months

Randomized, double-blinded, prospective trial, in EgyptDosing regimen (per day): • High dose: 40 mg/kg loading,

followed by 20 mg/kg• Low dose: 20 mg/kg loading,

followed by 10 mg/kgStudy 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/s00431-015-2494-8Steer P. et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F499–F503

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 infants; durations of mechanical ventilation, CPAP, and oxygen therapy

• Length of hospital stay• Neonatal mortality• Chronic lung disease (defined as the need for oxygen treatment at 36

weeks’ postmenstrual age, according to the National Institute of Child Health and Human Development diagnostic criteria

• Necrotizing enterocolitis (any stage, according to modified Bell classification)

• Intraventricular hemorrhage (IVH)• Periventricular leukomalacia• ROP • caffeine side effects (tachycardia, hypertension, and feeding intolerance)

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, Mann–Whitney 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 M

oham

med

S. e

t al.

(201

5)

Stee

r P. e

t al.

(200

4)

Kaplan-Meier for Secondary Outcomes M

oham

med

S. e

t al.

(201

5)

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?????”