Uso Racional de la Cafeina: Porque,

cuando y cuanto
Eduardo Bancalari MD
University of Miami Miller School of Medicine
Concepcion 2016

Why do Premature Infants Have Apnea?

Immature rhythm generation: irregular and
periodic breathing
Decreased ventilatory response to CO2
Close eupneic and apneic CO2 thresholds
Paradoxical response to hypoxia?
Unstable collapsible upper airway
Unstable chest wall, distortion
Limited load compensation ability
Strong H. Breuer inhibitory reflex

Efficacy of caffeine in treatment of apnea in the low-birth-weight infant

Aranda, JV et al. J Pediatrics 1977; 90(3): 467-472

Caffeine for Apnea of Prematurity

(Relative Risk and 95% confidence interval)
Outcome: Failed treatment after 5-7 days
Erenberg 2000

Murat 1981

<

Total

0.01

0.1

Favors caffeine

10

Favors control

Adapted from: Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane
Database of Systematic Reviews 2001, Issue 3. Art No.: CD000140. DOI: 10.1002/14651858. CD 000140.

Prophylactic methylxanthines for

endotracheal extubation in preterm infants

David J Henderson-Smart1, Peter G Davis2Editorial Group: Cochrane

Neonatal Group, Published Online: 19 JAN 2011

Henderson-Smart DJ, Steer PA. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.:
CD000273. DOI: 10.1002/14651858.CD000273.pub2.

Henderson-Smart DJ, Steer PA. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.:
CD000273. DOI: 10.1002/14651858.CD000273.pub2.

J Perinatology 2009

Reproduced from Bauer J, Maier, K, Linderkamp O with permission from Pediatrics 2001, Vol. 107, Pg 662,
Copyright 2001 by the AAP

CaffeineTherapyforApneaofPrematurity

Schmidt,Betal.NEngl JMed2006;354:21122121.

Table1.EffectsofCaffeineonCirculatoryParametersinPretermInfants

Internal Carotid Artery (n = 15)

Mean (m /s)
Anterior Cerebral Artery (n = 15)
Mean (m / s)
Celiac Artery (n = 16)
Mean (m / s)
Superior Mesenteric Artery (n = 13)
Mean (m / s)
Left Ventricular Output
(mL / kg / min; n = 15)
Blood pressure (n = 16)
Mean (m / s)

Before

1 Hour

2 Hours

0.18 0.04

0.15 0.03

0.14 0.02

0.14 0.02

0.12 0.04

0.12 0.02

0.37 0.14

0.32 0.12

0.35 0.13

0.23 0.10

0.16 0.07

0.16 0.06

196 53

179 43

173 52

45 9

47 9

45 5

Oral caffeine loading dose of 25 mg / kg.

P < .05 paired t test. P < .005 paired t test.
Reproduced from Hoecker, C. et al. with permission from Pediatrics 2002, Vol. 109, Pg 785,
Copyright 2002 by the AAP

CAPTrial: Schmidt,Betal.NEngl JMed2006

2006infants500 1250gconsideredcandidatesfor
methylxanthinesduringthefirst10daysforapneaor
extubationwererandomlyassignedtocaffeineor
placebo

CAPTrial ShortTermOutcome
(20mgxkgloading+5 10mg/kgmaintenance)
Caffeine (n1006)

Placebo (n1000)

BWT

964

958

Death

5.2%

5.5%

NEC

6.3%

6.7%
OR

BPD 36 weeks

36.3%

46.9%

0.64 (0.52-0.78)

PDA drug therapy

29.3%

38.1%

0.67 (0.54-0.82)

PDA surgical closure

4.5%

12.6%

0.29 (0.20-0.43)

Brain injury by US

13%

14.3%

0.97 (0.74-1.28)

Weight gain 14 days

compared to placebo

-23g
Adapted from Schmidt B. NEJM 2006; 354(20): 2112-2121

CAPTrial LongTermOutcome
(20mgxkgloading+5 10mg/kgmaintenance)

Caffeine(n1006)

Placebo (n1000)

BWT

937g

932g

Death

5.2%

5.5%

Died or Developmental 40.2%

delay

46.2%

0.008

Cerebral palsy

4.4%

7.3%

0.009

Cognitive delay

33.8%

38.3%

0.04

Schmidt B. NEJM 2007; 357: 1893-1902

Ped Research 2011

Outcome

Caffeine

Placebo

OR(95%CI)

Deathordisability

22%

25%

0.8(0.71.0)

Death

6.4%6.5%

1.0(0.71.4)

GMFCFlevel>1

2.4%3.8%0.6(0.41.1)

ScaleIQ<70

4.9%

5.1%

1.0(0.61.6)

Disablingbehavior

5.4%

7.1%

0.8(0.51.2)

CaffeineforApneaofPrematurityTrial:BenefitsMayVaryinSubgroups

DavisPGetal.JPediatr 2010;156:382387.

TrendsinCaffeineUseandAssociationbetweenClinicalOutcomes
andTimingofTherapyinVeryLowBirthWeightInfants

DobsonNRetal.JPediatr 2014;164:992998.

Earlycaffeinetherapyandclinicaloutcomes
Neonataloutcomes bytimingofcaffeineinitiation
Outcomes

Earlycaffeine Latecaffeine
(<DOL3)
(DOL3)

Oddsratio
(95%CI)

Adjustedodds
ratio
(95%CI)

Pvalue

Primaryoutcome
DeathorBPD

21(25%)

30(53%)

0.31(0.150.63)

0.26(0.090.70)

<0.01

5(6%)

3(5%)

1.15(0.265.03)

1.47(0.307.26)

0.640

17(24%)

27(51%)

0.30(0.140.64)

0.33(0.110.98)

0.04

PDArequiringtreatment

8(10%)

20(36%)

0.20(0.080.51)

0.28(0.100.73)

0.01

Pharmacologiconly

7(9%)

15(27%)

Surgical

1(1%)

5(9%)

22

Death
BPD
Secondaryoutcomes

Durationofventilation(mediandays)
PatelRMetal.JPerinatol 2013;33:134140.

<0.01

TrendsinCaffeineUseandAssociationbetweenClinicalOutcomes
andTimingofTherapyinVeryLowBirthWeightInfants
TableIV. Clinicaloutcomes
PSmatchedpatients
Earlycaffeine
(n=14535)

Latecaffeine
(n=14535)

OR(99%CI)

Pvalue

BPDordeath

3681(27.6)

4591(34.0)

0.74(0.690.80)

<.001

BPDinsurvivors

3070(23.1)

4154(30.7)

0.68(0.630.73)

<.001

659(4.5)

542(3.7)

1.23(1.051.43)

<.001

TreatmentofPDA

1794(12.3)

2765(19.0)

0.60(0.550.65)

<.001

Lateonsetsepsis

3083(21.2)

3559(24.5)

0.81(0.760.88)

<.001

11(0,48)

17(0,64)

3(112)

6(025)

DOL7

6.3(25.1,12.9)

3.5(23.6,17.0)

<.001

DOL14

5.6(5.1,17.1)

6.5(5.0,18.9)

<.001

DOL28

13.6(4.8,23.6)

13.7(4.3,24.4)

.40

Outcomes
Primaryoutcomes,n(%)

Death
Secondaryoutcomes,n(%)

DurationofMV,d
Mean(5th95thpercentile)
Median(IQR)

<.001

Weightgain, g/d,mean(5th,95th percentile)

DobsonNRetal.JPediatr 2014;164:992998.

Randomization

CAFFEINE GROUP

CONTROL GROUP
Equivalent volume
normal saline
bolus

Caffeine bolus 20
mg/kg
Maintenance
caffeine 5 mg/kg

Maintenance
volume placebo

Routine ventilator management until decision to extubate

Pre-extubation
caffeine bolus 20
mg/kg

Pre-extubation
placebo bolus
EXTUBATE
Re-intubated
< 24 hrs

EXTUBATE
Remains
extubated 24 hrs

Re-intubated
< 24 hrs

STUDY INTERVENTION ENDS

Continue open label caffeine as per clinical team
Amaro et al SPR 2016

Highdosecaffeinecitrateforextubationofpreterminfants:
arandomised controlledtrial
Table2.Analysisof trialdata
20mg/kg
(n=113)
Extubationfailure

5mg/kg
(n=121)

RR(95% CI)

pValue

0.51(0.31to0.85)

<0.01

17(15%)

36(29.8%)

10

29

Durationofmechanicalventilation(days)

7.4(3.316.5)

9.0(0.577)

0.38

DurationofNCPAP(days)

10.1(2.321.2)

9.8(4.320.1)

0.56

Documentedapnoea

4(112)

7(222)

<0.01

Documentedapnoea (days)

0.6(0.12.1)

1.3(0.34.3)

0.02

Reventilated

Steer,Petal.ArchDisChildFetalNeonatalEd2004;89:F499F503.

Highdosecaffeinecitrateforextubationofpreterminfants:
arandomised controlledtrial
Table3.Adverseeffects
20mg/kg
(n=113)

5mg/kg
(n=121)

Tachycardia

Jitteriness

Totalinwhomcaffeinewaswithheld

9(8)

5(4)

0.24

Feedintolerance

40(35)

37(31)

0.44

Weightgain(g/kg/day)

12.2(6.515.2)

12.6(9.215.2)

0.35

Timetoregainbirthweight(days)

14.8(5.3)

12.9(5.0)

<0.01

Steer,Petal.ArchDisChildFetalNeonatalEd2004;89:F499F503.

pValue

Highdosecaffeinecitrateforextubationofpreterminfants:
arandomised controlledtrial
Table4.Majormorbidityanddeath
20mg/kg
(n=113)

5mg/kg
(n=121)

Proveninfection

52(46)

60(50)

Necrotisingenterocolitis

5(4)

21(23)

34(33)

0.68(0.43to1.09)

0.11

0.42(0.11to1.52)

0.22

Chroniclungdisease,28days

64(66)

80(74)

0.89(0.74to1.07)

0.22

Chroniclungdisease,36weeks

33(34)

51(48)

0.72(0.51to1.01)

0.06

RR(95% CI)
0.93(0.71to1.21)

pValue
0.59

Intraventricularhaemorrhage
Grades3or4
Retinopathyofprematurity
Stage3and4

Steer,Petal.ArchDisChildFetalNeonatalEd2004;89:F499F503.

0.11

Highdosecaffeinecitrateforextubationofpreterminfants:
arandomised controlledtrial
Table5.Outcomesat12monthscorrected forprematurity
20mg/kg
(n=87)

5mg/kg
(n= 86)

n=80

n=78

Generalquotient(GQ)

96.6(13.2)

92.2(17.3)

Majordisability

14

0.42(0.17to1.05)

0.05

Deathordisability

13

22

0.58(0.32to1.08)

0.08

Developmentalassessment

Steer,Petal.ArchDisChildFetalNeonatalEd2004;89:F499F503.

RR(95% CI)

pValue

0.08

CaffeineCitrateTreatmentforExtremelyPrematureInfantswithApnea:
PopulationPharmacokinetics,AbsoluteBioavailability,andImplicationsfor
TherapeuticDrugMonitoring

Charles,BGetal.Ther DrugMonit 2008;30:709716.

Caffeineinducesalveolarapoptosisinthehyperoxia
exposeddevelopingmouselung

Dayanim Setal.Pediatr Res2014;75:395402.

CorrelationbetweenSerumCaffeineLevelsandChanges
inCytokineinaCohortofPretermInfants

Changeinplasmacytokineconcentrationsandserumcaffeinelevels
after1weekoftreatment
ChavezValdezRetal.JPediatr 2011;158:5754.

Ped Research 2015

Methods: 74 preterm infants (30 wk GA)

Randomly assigned to either a high (80 mg/kg i.v.) or
standard (20 mg/kg i.v.) loading dose of caffeine citrate first
24 h of life, followed by 5mg/kg in both groups.
MRI and neurobehavioral testing at term equivalent age and
at 2 y of age.

Mc Pherson C et al, Ped Research 2015

Many unanswered questions

Limited information on mechanisms of action
of caffeine
Effectiveness to prevent hypoxic spells not
established
Best dose to achieve optimal results not known
No prospective studies on effect of caffeine on
BPD or PDA as primary outcomes
Effectiveness and safety of early and prolonged
administration of caffeine not established