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Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity Natalie Schellack, Njie Eric, Menzi Gule, Nqobile Nxumalo, Nontobeko Nkosi, Prof.

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Presentation on theme: "Caffeine versus Aminophylline for the Prevention of Apnoea of Prematurity Natalie Schellack, Njie Eric, Menzi Gule, Nqobile Nxumalo, Nontobeko Nkosi, Prof."— Presentation transcript:

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 – weeks an incidence of 50 % – 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 CaffeineAminophylline Mechanism of action…

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

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 Plasma Levels Therapeutic drug monitoring:Therapeutic drug monitoring: –Aminophylline/Caffeine: Blood for plasma levels drawn on Day 4 2 hours after administering the drug: –Therapeutic range: 5-20 µ g per ml Day 1 LoadingDose Day 2 Dose Day 3 Dose Day 4 Dose & Serum Level after 2 hours

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

16 Results and Discussion (2) Demographics ParametersAminophylline (n=16) Caffeine (n=15) Gestational age (weeks) Mean  s:30.9  3.3 Median:  Birth weight (g) Mean  s: 1475  472 Median:  Gender (F; M)6; 107; 8 Apgar scores at 5 min Mean  s:7.1  2.9 Median:  Concurrent medicines (Anti-infectives, metoclopramide, others) Admission reasonsPrematurity, others No significant differences

17 Serum Concentrations 0.35 AminophyllineCaffeine 22

18 Comparative parameters CardiovascularPulse MAP RespiratoryRespiration Ventilatory Support Saturation GastrointestinalVolume Aspirated Nutritional Support Other Central Nervous SystemIrritability Jitteriness

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

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

21 Respiratory System Profile (1) 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) Respiratory Rate Respiratory Rate

22 Respiratory support A8.5%C9.2% A1.3%C1.2% A81.3%C80.2% A8.9%C9.5% Methods of Ventilation CPAP/ SiPAP Room air IPPV Nasal cann. Percentages of patient-days

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

24 Patient-days on the following were compared: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) Gastrointestinal System Nutritional Support Nutritional Support

25 Gastrointestinal System Nutritional Support (2) Feeding Study drug BFEBM Breast milk FormulaNPOTPN Amino- phylline (n=16) 14(7%) 97 (51%) 111 (58%) 7(4%) 63 (33%) 11 (6%) Caffeine (n=15) 53 (25%) 68(32%) 121 (57%) 36 (17 %) 54 (26%) 0 (0%)

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

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

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 fewer cardiovascular and respiratory side 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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