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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 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

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
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
introduction
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 %
introduction 2
Introduction (2)
  • Apnoeic attacks also linked to birth weight:
    • Less than 1000g an incidence of 80%
    • Less than 2500g an incidence of 25%
what treatment is available
What treatment is available…

Methylxanthines

Caffeine

Aminophylline

Mechanism of action…

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

Asthma

mechanism of action 2
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

common adverse effects
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
aim and objectives
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
methodology 1
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
methodology 2
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

treatment protocol 1
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)
treatment protocol 2
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%)
plasma levels

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
results and discussion 1
Results and Discussion (1)

31 Study Patients

15 Caffeine

16 Aminophylline

Admitted to NICU

results and discussion 2 demographics
Results and Discussion (2) Demographics

No significant differences

serum concentrations
Serum Concentrations

22

0.35

Aminophylline

Caffeine

cardiovascular profile
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)

cardiovascular profile 2
Cardiovascular Profile (2)

Mean Arterial Pressure

No significant difference – Wilcoxon two sample test

respiratory system profile 1
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)

respiratory support
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%

respiratory system profile 3
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%
gastrointestinal system
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)
gastrointestinal system1
Gastrointestinal System

Nutritional Support (2)

gastrointestinal system2
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)

gastrointestinal system3
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
central nervous system
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
apnoeic attacks
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

apnoeic attacks 2
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)

conclusions
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.
acknowledgements
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