Caffeine Caffeine versusversus Aminophylline Aminophylline for the Prevention of Apnoea of for the Prevention of Apnoea of

PrematurityPrematurity

Natalie SchellackNatalie Schellack, Njie Eric, Menzi , Njie Eric, Menzi Gule, Nqobile Nxumalo, Nontobeko Gule, Nqobile Nxumalo, Nontobeko

Nkosi, Prof A Gous, Monika Nkosi, Prof A Gous, Monika Zweygarth & Dr MawelaZweygarth & Dr Mawela

BackgroundBackground

• 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

IntroductionIntroduction

• 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 1000g an incidence of 80%

– Less than 2500g an incidence of 25%Less than 2500g an incidence of 25%

What treatment is available…What treatment is available…

Methylxanthines

CaffeineCaffeine AminophyllineAminophylline

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

AsthmaAsthma

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

ApnoeaApnoea

Common Adverse EffectsCommon 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 objectivesAim 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 FlowStudy Flow:

PatientAdmitted toNeonatal ICU

Prevention of AOPRequired?

34 weeksYES or NO

NO,Continue with

standardtreatment

YES, Check clinical

eligibility and obtain

consent

Randomize toaminophylline orcaffeine; obtainbaseline data;

administer loadingdose

Monitoring untilend of study:

Outcomes mayinclude death,completion of

study orwithdrawal, or

patient discharged

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 LevelsPlasma Levels• Therapeutic drug monitoring:Therapeutic drug monitoring:

– Aminophylline/CaffeineAminophylline/Caffeine: : Blood for plasma levels drawn on Day 4Blood for plasma levels drawn on Day 42 hours after administering the drug:2 hours after administering the drug:

– Therapeutic rangeTherapeutic range: : 5-205-20µg per ml µg per ml

Day 1Day 1

LoadingLoadingDoseDose

Day 2Day 2

DoseDose

Day 3Day 3

DoseDose

Day 4Day 4

Dose & SerumDose & SerumLevel afterLevel after

2 hours2 hours

Results and Discussion (1)Results and Discussion (1)

31 Study Patients 31 Study Patients

15 Caffeine15 Caffeine 16 Aminophylline16 Aminophylline

Admitted to NICUAdmitted to NICU

Results and Discussion (2) Results and Discussion (2) DemographicsDemographics

Parameters Aminophylline(n=16)

Caffeine(n=15)

Gestational age (weeks)

Mean s: 30.9 3.3

Median: 31

31.5 1.7

32

Birth weight (g) Mean s: 1475 472

Median: 1400

1460 402

1600

Gender (F; M) 6; 10 7; 8

Apgar scores at 5 min Mean s: 7.1 2.9

Median: 8

5.9 3.1

7

Concurrent medicines Concurrent medicines (Anti-infectives, metoclopramide, others)(Anti-infectives, metoclopramide, others)

Admission reasons Prematurity, others Prematurity, others

No significant differences

0

5

10

15

20

25

0 2 4 6 8 10

Day on study drug

Am

inop

hyllin

e le

vels

(mcg

/mL)

0

5

10

15

20

25

0 5 10 15 20

Day on study drug

Caf

fein

e le

vels

(mcg

/mL)

Serum ConcentrationsSerum Concentrations

0.350.35

AminophyllineAminophylline CaffeineCaffeine

2222

Comparative parametersComparative parameters

Cardiovascular Pulse

MAP

Respiratory Respiration

Ventilatory Support

Saturation

Gastrointestinal Volume Aspirated

Nutritional Support

Other

Central Nervous System Irritability

Jitteriness

Cardiovascular ProfileCardiovascular Profile

120

130

140

150

160

170

180

0 5 10 15 20 25 30

Days on study drug

Med

ian

hear

t rat

e (b

eats

/min

)

Aminophylline Caffeine

Day 7: aminophylline: 159.9 (n=10) caffeine: 148.1 (n=13)

Day 9: aminophylline: 167.8 (n=7); caffeine: 146.4 (n=10)

Statistically significant(Wilcoxon two sample test)

Pulse RatePulse Rate

Cardiovascular Profile (2)Cardiovascular Profile (2) Mean Arterial PressureMean Arterial Pressure

30

35

40

45

50

55

60

65

70

0 5 10 15 20 25 30

Days on study drug

Med

ian

MAP

(mm

Hg)

Aminophylline Caffeine

No significant difference – Wilcoxon two sample testNo significant difference – Wilcoxon two sample test

Respiratory System Profile (1)Respiratory System Profile (1)

50

55

60

65

70

75

0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930

Days on study drug

Med

ian

resp

irat

ion

rate

(b

reat

hs/m

in)Aminophylline Caffeine

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 RateRespiratory Rate

Respiratory supportRespiratory support

AA8.5%8.5%

CC9.2%9.2%

AA1.3%1.3%

CC1.2%1.2%

AA81.3%81.3%

CC80.2%80.2%

AA8.9%8.9%

CC9.5%9.5%

Methods of Methods of VentilationVentilation

CPAP/SiPAP

Room air

IPPV

Nasal cann.

Percentages of patient-daysPercentages of patient-days

Respiratory System Profile (3)Respiratory System Profile (3)SaturationSaturation

•Saturation Saturation monitored 3 hourlymonitored 3 hourly •No statistical differenceNo statistical difference between the 2 groups in terms of between the 2 groups in terms of the number of patients the number of patients saturation levels saturation levels below 92% or below 92% or below 80%below 80%

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

Gastrointestinal SystemGastrointestinal System Nutritional SupportNutritional Support

Gastrointestinal SystemGastrointestinal SystemNutritional Support (2)Nutritional Support (2)

FeedingFeeding

Study drugStudy drug

BFBF EBMEBM Breast Breast milkmilk

FormulaFormula NPONPO TPNTPN

Amino-Amino-phylline phylline (n=16)(n=16)

1414(7%)(7%)

97 97 (51%)(51%)

111111(58%)(58%)

7 7 (4%)(4%)

63 63 (33%)(33%)

11 11 (6%)(6%)

Caffeine Caffeine (n=15)(n=15)

53 53 (25%)(25%)

6868(32%)(32%)

121121(57%)(57%)

36 36 (17 %)(17 %)

54 54 (26%)(26%)

0 0 (0%)(0%)

Gastrointestinal SystemGastrointestinal System AspiratesAspirates

Followed for 153 daysFollowed for 153 daysFollowed for 175 daysFollowed for 175 days

Aspirates recorded for 112 daysAspirates recorded for 112 daysAspirates recorded for 136 daysAspirates recorded for 136 days

Aspirates > 30% of intake: Aspirates > 30% of intake: 9 days9 days

Aspirates > 30% of intake:Aspirates > 30% of intake: 13 days 13 days

Statistical difference for aspirates > 30% of intake:Statistical difference for aspirates > 30% of intake:NoneNone

(Chi square test)(Chi square test)

AminophyllineAminophylline CaffeineCaffeine

73%73%

6%6%

77%77%

7%7%

Gastrointestinal SystemGastrointestinal System

• Diarrhoea:Diarrhoea:– 3 patients on aminophylline3 patients on aminophylline– 1 patient on caffeine1 patient on caffeine

• Bloody Aspirates:Bloody Aspirates:– Equal in both groupsEqual in both groups

• Vomiting:Vomiting:– Two patients in each group, but for the Two patients in each group, but for the

aminophylline patients one day longeraminophylline patients one day longer

OtherOther

Central Nervous SystemCentral 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 AttacksApnoeic Attacks4 patients suffered apnoeic attacks:

Patient no.1Patient no.1Female

Arm: CaffeineGestation: 29 weeksBirth weight: 1000 gTime to AOP: 2 weeksOutcome: DeathSample level: 18 mcg/ml

Patient no.2Patient no.2Male

Arm: AminophyllineGestation: 29 weeksBirth weight: 1300 gTime to AOP: 2 weeksOutcome: Death Sample level: 17.6 mcg/ml

Apnoeic Attacks (2)Apnoeic Attacks (2)4 patients suffered apnoeic attacks:

Patient no.3Patient no.3Male

Arm: AminophyllineGestation: 31 weeksBirth weight: 1250 gTime to AOP: 3 weeksOutcome: TransferredSample level: 16.5 mcg/ml

Patient no.4Patient no.4Female

Arm: AminophyllineGestation: 32 weeksBirth weight: 1400 gTime to AOP: 2 weeksOutcome: Death Sample level: 0.35 mcg/ml (1)

14.1 mcg/ml (2)

ConclusionsConclusions• 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.

AcknowledgementsAcknowledgements

• 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