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Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity

Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity. Natalie Schellack , Njie Eric, Menzi Gule, Nqobile Nxumalo, Nontobeko Nkosi, Prof A Gous, Monika Zweygarth & Dr Mawela. Background. Part of Masters Degree Pharmaceutical care rendered

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Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity

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  1. Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity Natalie Schellack, Njie Eric, Menzi Gule, Nqobile Nxumalo, Nontobeko Nkosi, Prof A Gous, Monika Zweygarth & Dr Mawela

  2. Background • Part of Masters Degree • Pharmaceutical care rendered • Aminophylline identified as a difficult drug • Caffeine introduced as an alternative • Study done to confirm safety and efficacy in this population

  3. Introduction • What do we know? • Apnoeic attacks ↔ Gestational age inverse correlation: • Less than 30 weeks most infants • 30-32 weeks an incidence of 50 % • 34-36 weeks an incidence of 10 %

  4. Introduction (2) • Apnoeic attacks also linked to birth weight: • Less than 1000g an incidence of 80% • Less than 2500g an incidence of 25%

  5. What treatment is available… Methylxanthines Caffeine Aminophylline Mechanism of action…

  6. Mechanism of action… • Inhibition of phosphodiesterase (PDE) isozymes • Antagonism of adenosine receptors • Inhibition of calcium influx • Enhancement of catecholamine secretion Asthma

  7. Mechanism of action (2) • Acts via adenosine antagonism to increase the sensitivity of respiratory centers to carbon dioxide, and to increase the contractility of respiratory muscles Apnoea

  8. Common Adverse Effects • Central nervous system side effects • Irritability • Jitteriness • Cardio-vascular system side effects • Tachycardia • Gastrointestinal side effects • Feeding intolerance • Respiratory system side effects • Tachypnoea

  9. Aim and objectives • Aim: To determine the comparative efficacy of aminophylline and caffeine in the prevention of apnoea in premature infants in the neonatal intensive care unit • Objectives: • To determine the safety profile of aminophylline versus caffeine in the prevention of apnoea of prematurity (AOP) • To determine the efficacy of aminophylline versus caffeine in the prevention of AOP

  10. Methodology (1) • Quantitative, open-label with an experimental design • Predetermined blocked-randomization schedule was used • Ethical approval was obtained from REPC • Informed consent obtained from caregivers

  11. Methodology (2) • Study Flow: Patient Admitted to Neonatal ICU Monitoring until end of study: Outcomes may include death, completion of study or withdrawal, or patient discharged Prevention of AOP Required?  34 weeks YES or NO YES, Check clinical eligibility and obtain consent Randomize to aminophylline or caffeine; obtain baseline data; administer loading dose NO, Continue with standard treatment

  12. Treatment Protocol (1) • Aminophylline (IV): • Loading dose: 6 mg per kg per IV injection • Maintenance dose: 2.5 mg per kg per dose (8 hourly) • Caffeine (oral): • Loading dose: 10 mg per kg per dose (total of 2.5 ml, one hour apart) • Maintenance dose: 2.5 mg per kg per dose (once a day)

  13. Treatment Protocol (2) • Dose adjustments: • Loading doses were calculated according to baseline body weight (weight at birth) • Neonates were weighed on a weekly basis, starting 7 days from baseline • Maintentance doses adjusted accordingly (once a week, if change in body weight 10%)

  14. Day 1 Loading Dose Day 2 Dose Day 3 Dose Day 4 Dose & Serum Level after 2 hours Plasma Levels • Therapeutic drug monitoring: • Aminophylline/Caffeine: Blood for plasma levels drawn on Day 42 hours after administering the drug: • Therapeutic range: 5-20µg per ml

  15. Results and Discussion (1) 31 Study Patients 15 Caffeine 16 Aminophylline Admitted to NICU

  16. Results and Discussion (2) Demographics No significant differences

  17. Serum Concentrations 22 0.35 Aminophylline Caffeine

  18. Comparative parameters

  19. Cardiovascular Profile Pulse Rate Statistically significant (Wilcoxon two sample test) Day 7: aminophylline: 159.9 (n=10) caffeine: 148.1 (n=13) Day 9: aminophylline: 167.8 (n=7); caffeine: 146.4 (n=10)

  20. Cardiovascular Profile (2) Mean Arterial Pressure No significant difference – Wilcoxon two sample test

  21. Respiratory System Profile (1) Respiratory Rate The median respiratory rate was significantly higher in the aminophylline group than in the caffeine group on five study days (Days 3, 4, 5, 7 and 8) (Wilcoxon two-sample test)

  22. Respiratory support Percentages of patient-days CPAP/SiPAP A 8.5% C 9.2% Room air Nasal cann. Methods of Ventilation A 81.3% C 80.2% A 8.9% C 9.5% IPPV A 1.3% C 1.2%

  23. Respiratory System Profile (3) Saturation • Saturation monitored 3 hourly • No statistical difference between the 2 groups in terms of the number of patients saturation levels below 92% or below 80%

  24. Gastrointestinal System Nutritional Support • Patient-days on the following were compared: • Breast feeding (BF) • Expressed breast milk feeding (EBM) • Formula Feeding (FM) • Nil per Os (NPO) • Total Parenteral Nutrition (TPN)

  25. Gastrointestinal System Nutritional Support (2)

  26. Gastrointestinal System Aspirates Aminophylline Caffeine Followed for 175 days Followed for 153 days 77% 73% Aspirates recorded for 136 days Aspirates recorded for 112 days Aspirates > 30% of intake: 9 days Aspirates > 30% of intake: 13 days 7% 6% Statistical difference for aspirates > 30% of intake: None (Chi square test)

  27. Gastrointestinal System Other • Diarrhoea: • 3 patients on aminophylline • 1 patient on caffeine • Bloody Aspirates: • Equal in both groups • Vomiting: • Two patients in each group, but for the aminophylline patients one day longer

  28. Central Nervous System • Side effects often noted with clinical toxicity due to supra-therapeutic levels; no supra-therapeutic levels recorded for the study • Parameters monitored: • Irritability • Jitteriness • None were observed in either of the treatment arms

  29. Apnoeic Attacks 4 patients suffered apnoeic attacks: Patient no.1 Female Arm:Caffeine Gestation: 29 weeks Birth weight: 1000 g Time to AOP: 2 weeks Outcome: Death Sample level: 18 mcg/ml Patient no.2 Male Arm:Aminophylline Gestation: 29 weeks Birth weight: 1300 g Time to AOP: 2 weeks Outcome: Death Sample level: 17.6 mcg/ml

  30. Apnoeic Attacks (2) 4 patients suffered apnoeic attacks: Patient no.3 Male Arm: Aminophylline Gestation:31 weeks Birth weight: 1250 g Time to AOP: 3 weeks Outcome: Transferred Sample level: 16.5 mcg/ml Patient no.4 Female Arm:Aminophylline Gestation: 32 weeks Birth weight: 1400 g Time to AOP: 2 weeks Outcome: Death Sample level: 0.35 mcg/ml (1)14.1 mcg/ml (2)

  31. Conclusions • Caffeine caused fewercardiovascular and respiratoryside effects. • Gastrointestinal side effects were comparable between oral caffeine and IV aminophylline. • Oral caffeine is more convenient to administer and may facilitate breastfeeding. • Oral caffeine is an effective alternative to aminophylline in preventing apnoeic attacks.

  32. Acknowledgements • Babies and their parents for participating in the study • Doctors and nurses in the NICU for their cooperation • Monika Zweygarth for assistance with the analysis of the data • Medical Research Council for financial support • Department of Pharmacy for logistical support

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