Evidence-based management of apnea of prematurity: Is caffeine the - - PowerPoint PPT Presentation

Evidence-based management

• f apnea of prematurity:

Is caffeine the magic bullet?

Barbara Schmidt, MD, MSc, CM

• R. Alvaro J Dix N Granke M Lacy D Moddemann

R Sauve A Synnes P Anderson K Callanan D Dewey H Halliday H Lagercrantz T Mulder R Regev B Schmidt W Tin

B Adams K Barrington P Davis A Golan E Goldsch E Herlenius C Mayes A Ohlsson K Sankaran A Solimano

S Arnon M Clarke L Doyle AM Hamiltion A Juster-Reicher B Lemyre K O’Brien G Reynolds A Schulze H Walti H-U Bucher L Costantini A Golan R Haslam M Khairy H MacLean G Opie R Roberts E Shinwell A van Wassenaer

Caffeine for Apnea of Prematurity (CAP) Trial

CAP Trial Timeline

1998 Formulation of study question 1999-2004 Enrolment of > 2000 infants 2006 Short-term outcomes 2007 Primary outcome at 18 months 2008 Inaugural Trial of the Year Award 2012 Outcomes at 5 years 2017 Outcomes at 11 years

ORIGINAL STUDY QUESTION

Among infants with BW 500-1250 g who are at risk of apnea of prematurity, does the use of caffeine compared with placebo increase the risk of death or neurosensory disability at a corrected age of 18 months

P I C O T

Canada/US n=1052 Australia n=520 Europe n=434

PATIENT ACCRUAL

BPD Severe ROP Brain injury NEC PDA drug Tx PDA surgery

Short Term Outcomes of the Caffeine Trial

Outcome

Caffeine Placebo Odds Ratio n/N n/N (95% CI)

0.2 0.5 1 2 5 Favours Caffeine Favours Placebo

350/963 49/965 126/967 63/1006 293/1001 45/1001 447/954 75/955* 138/966 67/1000 381/999 126/999

NEJM 2006;354:2112 and *2007;357:1893

18-Months Outcomes of the Caffeine Trial

Outcome

0.2 0.5 1 2 5 Favours Caffeine Favours Placebo

Death or disability Death Cerebral Palsy Cognitive delay Hearing loss Blindness

Caffeine Placebo Odds Ratio n/N n/N (95% CI)

377/937 62/974 40/909 293/867 17/909 6/911 431/932 63/970 66/901 329/858 22/905 8/905

N Engl J Med 2007;357:1893

2008 SCT/Imp /ImpACT ACT CLINI INICAL CAL TRIAL AL OF THE YEAR R A W ARD

Long Term Effects of Caffeine for Apnea of Prematurity Trial

PI: Barbara Schmidt, MD, MSc

In recognition of a landmark randomized clinical trial to improve the lives of premature infants.

Eleanor McFadden, MA Steven Goodman, MD, PhD President, Society for Clinical Trials Project ImpACT

Death or Disability at 5 Years Caffeine Placebo

200 of 807 24.8%

OR = 0.82 95% CI 0.65-1.03 p = 0.09

176 of 833 21.1%

Gross Motor Function (GMFCS)

Level Caffeine Placebo P-value Normal 91% 86%

0.006

1 7.0% 10.1% 2 0.7% 1.0% 3 0.6% 0.6% 4 0.5% 1.3% 5 0.5% 0.8%

Rates of DCD at 5 Years Caffeine Placebo

106 of 698 15.2%

OR = 0.70 95% CI 0.51-0.95 p =.024

83 of 735 11.3%

Among English or French speaking CAP trial participants, does neonatal caffeine therapy compared with placebo decrease the risk of functional impairment at age 11 years?

P I C O T

Study Question

Primary Outcome at 11 Years

Functional impairment-at least 1 of:

• Poor academic performance
• Motor Impairment
• Behavior Problem

Tests: Wide Range Achievement Test-4 Movement ABC-2 Child Behavior Checklist - Parent

1202 CAP children were eligible

602 caffeine 600 placebo Composite Primary Outcome 457 (76%) 463 (77%)

Outcomes of 11 Year Cohort at 18 Mo Caffeine Placebo P-value

Disability 29.7% 36.4% 0.03 CP 3.8% 7.0% 0.03 MDI < 85 27.8% 31.3% 0.25 MDI < 70 9.7% 12.3% 0.22

Functional Impairment at 11 Years

Caffeine Placebo

174 of 463 37.6%

OR = 0.78 95% CI 0.59-1.02 p = 0.07

145 of 457 31.7%

Types of Impairments

Caffeine Placebo P-value

Academic 14.4% 13.2% 0.58 Motor 19.7% 27.5% 0.009 Behavior 10.9% 8.3% 0.22

Types of Impairments

Caffeine Placebo P-value

Academic 14.4% 13.2% 0.58 Motor 19.7% 27.5% 0.009 Behavior 10.9% 8.3% 0.22

Number Needed to Treat: 13 (95% CI, 8 to 42)

Conclusion I

Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor and behavioral impairments at age 11 years. However,

Conclusion II

Caffeine therapy reduced the risk

• f motor impairment 11 years later.

At the doses used in the CAP trial, neonatal caffeine therapy is effective and safe into middle school age.

Last Use of Respiratory Support*

Caffeine Placebo P value

Intubation Any pos. pressure Oxygen

29.1 30.0 <0.0001 31.0 32.0 <0.0001 33.6 35.1 <0.0001

* Median Postmenstrual Age

Explaining the benefit of caffeine

PMA at last use of any positive airway pressure (mean, 31.4 weeks caffeine; 32.8 weeks placebo) explained 53% (95% CI, 22-100%)

• f the benefit of caffeine on motor

impairment 11 years later.

Explaining the benefit of caffeine

“Caffeine likely is not a direct brain

• r a lung drug but rather a drug

that decreases adverse effects of interventions to treat apnea”. Alan Jobe, AJRCCM 2017

PEDIATRICS 2016: 137;e20

AAP Conclusion

Caffeine citrate is a safe and effective treatment of apnea of prematurity when administered at

• 20 mg/kg loading dose
• 5 to 10 mg/kg per day

maintenance

Beware of risky treatment creep

• 1. Indication: Apnea of prematurity
• 2. Dose: More is not always better
• 3. Timing: How early is too early?

In the CAP trial, the median age at start of drug therapy was 3 days.

CAP Children + Families Neonatal Trials Group McMaster University Investigators + staff in Canada Australia United Kingdom Sweden Canadian Institutes of Health Research (CIHR)