An Update on Caffeine Therapy

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Clemence Bridges
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University of Alabama at Birmingham Department of

1 An Update on Caffeine Therapy Emory University School of Medicine Atlanta, GA Wally Carlo, MD University of Alabama at Birmingham Department of Pediatrics Division of Neonatology

2 Objectives Learn which neonates may benefit from methylxanthines therapy Learn the short and long-term effect of methylxanthine therapy in neonates Review the evidence for early and high dose treatment with methylxanthines

3 Is severe apnea a problem in preemies despite the currently recommended doses of methylxanthines? Is severe apnea a problem in INTUBATED preemies despite currently recommended doses of methylxanthines?

4 Pharmacokinetics of Theophylline and Caffeine Theophylline Caffeine Half life (hr) Range (hr) Loading dose (mg/kg) Maintenance (mg/kg) 1 q 8 hr 2.5 q 24 hr *Active base But there are substantial interindividual variability in PK, and monitoring plasma levels is recommended. Lopes and Aranda. Pharmacologic Treatment of Neonatal Apnea. Yaffe and Aranda (eds) 2005

5 Effect of Theophylline on Apnea with Orally Administered Theophylline Apnea/day Apnea Requiring Ventilation (N) Pre Theophylline Post Theophylline 0 Pre Theophylline Post Theophylline Uauy et al. Pediatrics 55:595, 1975

6 Effect of Caffeine on Apnea Apnea/Day p< Aranda et al. J Pediatr 90:467, Pre Caffeine With Caffeine

7 Effectiveness of Theophylline vs Caffeine Apnea Frequency 100/min Theophylline Caffeine Days

8 Methylxanthine Treatment for Apnea of Prematurity Outcome Any methylxanthine vs control Apnea Use of mechanical ventilation Theophylline vs control Apnea Use of mechanical ventilation Caffeine vs control Apnea Use of mechanical ventilation RR (95% Cl) Modified from Henderson-Smart DJ and Steer P. Cochrane Collaboration 2001.

9 Caffeine vs. Theophyline Advantages of caffeine: Longer half life, less frequency dosing (q 24 hr) Less side effects (tachycardia, feeding intolerance) Advantages of theophylline: More bronchodilator effect

10 Meta-analysis Caffeine vs. Theophylline in Preterm Apnea Tachycardia/feed intol 3% in caffeine vs 31% in theophylline (p<0.05) Apnea at days (range ) less apnea per day in theophylline group (p<0.05) Steer and Henderson-Smart. Cochrane 2003

11 Possible Mechanisms of Action of Methylxanthines in Neonates with Apnea 1. Increased respiratory center drive 2. Improved respiratory muscle contractions 3. Preferential activation of upper respiratory muscles 4. Decreased pulmonary resistance 5. Blockade of adenosine (a respiratory inhibitory neurotransmitter) 6. Diuresis

12 MINUTE VENTILAITON (ml/min/kg) INFANTS WITHOUT APNEA P A CO 2 (mmhg) INFANTS WITH APNEA DIFFERENCE IN SLOPE P<0.001 Modified from Gerhardt T, et al. Pediatrics 74:58, 1984

13 CO 2 Threshold (mmhg) CO 2 Threshold for Various Respiratory Muscles DIA PCA AN GG Carlo and DiFiore. J Appl Physiol 68:1041, 1990

14 Resolving RDS Predisposed to Apnea Apnea duration (sec/hr) p <.05 NS NS Day 1 Day 3 Day 7 Carlo et al. Am Rev Resp Dis 126:103, 1982 RDS Non RDS

15 Thus, infants will have an increased predisposition to apnea as: 1. RDS is resolving 2. PCO 2 decreases

16 Methylxanthine Effect on Extubation Failure RR Methylxanthine Control (95% CI) Viscardi /14 10/11 0.4(0.2,0.8)* Greenough /18 8/20 0.3(0.1,1.1) Barrington /10 2/10 1.5(0.3,7.1) Durand /23 15/28 0.4(0.2,1.1) Muro /12 6/6 0.3(0.1,0.7)* Pearlman /31 4/14 0.9(0.2,2.5) Total 27/108 45/89 0.5(0.3,0.8)* Henderson-Smart and Davis. The Cochrane Library 2002

17 However, 1 / 3 to ¼ of infants with apnea fail methylxanthine therapy and need intubation

19 Why is a Predisposition to Apnea Not Noticed to be a Problem in Infants on a Ventilator? 1. The babies have respiratory distress 2. Apnea/hypoventilation are interpreted as inability to compensate for their respiratory disease 3. A high hypercapnia threshold is interpreted as hypercapnia due to severe RDS 4. The problem is being treated!

20 Consequence of Increased Apnea as RDS Resolves 1. Many infants remain on ventilator when RDS is resolving 2. Many infants with RDS fail extubation attempts 3. Many infants may get lung injury because of being on a ventilator 4. Many infants may get a PDA ligation in part because of being on a ventilator

21 Caffeine RCT: Caffeine 5 mg/kg/day for Apnea/Extubation Patients: <10 days in 35 Centers Results: Caffeine Placebo OR (CI) p value BPD 36% 47% 0.64 (0.52, 0.78) <0.001 Death 5.2% 5.5% 0.96 (0.64, 1.44) NS Surg for PDA 4.5% 12.6% 0.29 (0.20, 0.43) <0.001 Drug for PDA 29% 38% 0.67 (0.54, 0.82) <0.001 IVH/PVL/Other 13% 14% 0.97 (0.74, 1.28) NS Less weight gain first three weeks. No difference by 4-6 weeks. Schmidt et al. NEJM 354:20, 2006

22 Caffeine RCT: 2 Year Outcomes Caffeine Placebo OR (CI) p value Death or disability 40% 46% 0.77 ( ) Death 6.4% 6.5% 0.97 ( ) NS CP 4.4% 7.3% 0.58 ( ) MDI < 85 34% 38% 0.81 ( ) 0.04 Severe retinopathy 5.1% 7.9% 0.61 ( ) 0.01 Medium wt percentile (-3.22,2.05) NS No difference in head circumference or height Schmidt et al. NEJM 357:1893, 2007

23 Caffeine RCT: 5 Year Outcomes Caffeine Placebo OR (CI) P value Death or disability 21% 25% 0.86 ( ) NS Death 6.8% 6.9% 1.03 ( ) NS No difference in growth Schmidt et al. JAMA 307:275, 2012

24 Is earlier caffeine better than later caffeine?

25 Early Caffeine Observational Study 62,000 VLBW infants treated with caffeine Early Caffeine Infants (days 1-2 of age): Lower BPD or death (27.6% vs 34.0%) p<0.001 Lower PDA (12.3% vs 19.0%) p<0.001 Lower late-onset sepsis (21.2% vs 24.5%) p<0.001 Lower mechanical ventilation (11 d vs 17 d) p<0.001 Dobson NR et al. J Peds 164:1244, 2014

26 Early Caffeine Intervention Observational Study 5101 < 31 week infants, 29 Canadian National Network centers Early-First 2 days Late-After 2 days p value BW, median (IQR) 1070 ( ) 1050 ( ) 0.66 GA, median (IQR) 28 (28-29) 28 (26-30) 0.07 Ventilation day 2 46% 58% <0.01 BPD 27.8% 27.7% NS Lodha A et al. JAMA Pediatrics 169:33, 2015

27 Thus, earlier day 1-2 caffeine treatment may be better than later treatment but these data are from respective studies prone to bias.

28 Caffeine to Reduce Intermittent Hypoxemic Episodes 98 infants of week at birth randomized to caffeine/placebo at 33 wks There was a reduction of oxygen desaturations at 35 and 36 weeks but not later. Rhine L et al. JAMA 168:250, 2014

29 Methylxanthines are very effective in preventing ventilation but is high-dose methylxanthine strategy better than a standard dose strategy?

30 Infants Responding (%) High Dose Theophylline on Apnea Response 3 up to 7.5 Theophylline maintenance dose (mg/kg/day) Muttitt et al. J Pediatr 112:115, 1988

31 Effect of Aminophylline/Theophylline 100 on Apnea Treatment Success % Success Dose kg/day

32 RCT of High-Dose Caffeine Design: Multicenter RCT (placebo) Patient population: Inclusion criteria: GA < 30 weeks and expected to be on a ventilator for > 48 hours Exclusion criteria (any of the following): major congenital anomaly, sepsis, major neurological condition, IVH 3 or 4 Intervention: Load of 80 vs 20 mg/kg/day and maintenance of 20 vs 5 mg/kg/day caffeine citrate IV or OG Planned enrollment: 222 infants, 50% reduction from 32% to 16% Primary outcome: failure of extubation within 48 hours after the loading dose

33 RCT of High-Dose Caffeine: Patient Population: N=234 infants 20 mg/kg (n=113) 5 mg/kg (n=121) Gestational age (wks) 27 ± ± 1.4 Birthweight (g) 1009 ± ± 240 Male sex 49% 52% Less than 24 weeks GA 56% 47% Antenatal steroids 86% 88% RDS 85% 91% Exogenous surfactant 80% 84% Age at enrollment (days) 4.0 (1.9-12) 3.9 (2.0-11) Mech vent at enrollment (days) 4.7 (2.5-13) 4.2 ( ) Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

34 RCT of High-Dose Caffeine: Results 20 mg/kg (n=113) 5 mg/kg (n=121) RR (95% Cl) p value NNT Extubation failure 15% 30% 0.51 ( ) < Extubation failure <28 wks 17% 49% 0.36 (0.20, 0.65) < Duration vent < 28 wks days days <0.001 Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

35 RCT of High-Dose Caffeine: Adverse Effects 20 mg/kg (n=113) 5 mg/kg (n=121) p value Tachycardia (HR>200) 4% 1% -- Jitteriness 2% 2% -- Caffeine withheld 8% 4% 0.24 Feed intolerance 35% 31% 0.44 Weight gain (g/kg/day) 12.2 ( ) 12.6 ( ) 0.35 Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

36 RCT of High Dose Caffeine: Morbidity and Death 20 mg/kg (n=113) 5 mg/kg (n=121) RR (95% Cl) p value Proven infection 46% 50% 0.93 (0.71 to 1.21) 0.59 NEC 0% 4% IVH 3 or 4 5% 1% 0.11 PVL/cysts/PH H 7% 11% 0.64 (0.26 to 1.61) 0.34 ROP 3 and 4 3% 8% 0.42 (0.11 to 1.52) 0.22 Pulmonary air leak 4% 6% 0.77 (0.25 to 2.35) 0.64 BPD (36 wks) 34% 48% 0.72 (0.51 to 1.01) 0.06 Death before discharge 4% 6% 0.77 (0.25 to 2.34) 0.64 Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

37 RCT of High Dose Caffeine: Outcomes at 12 Months Corrected for Prematurity 20 mg/kg (n=87) Dev assessment n=80 n=78 5 mg/kg (n=86) RR (95% Cl) p value General quotient (GQ) 96.6 (13.2) 92.2 (17.3) 0.08 Major disability (0.17 to 1.05) Death up to 12 months 7 8 Death or disability (0.32 to 1.08) Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499,

38 Should caffeine levels be monitored before or during a high-dose trial? Pharmacokinetic study of 5 and 20 mg/kg dosage with 431 samples in 110 infants, GA 27 weeks, BW 1.0 kg Clearance (Cl) increased nonlinearly with PNA up to 6 weeks Volume of distribution (Vd) increased linearly with weight Mean elimination half life was 101 hours Inter-individual variability of Cl was 19% Inter-occasion variability of Cl was 33% Caffeine was completely absorbed (thus same IV and enteral dosage) Thus, routine serum caffeine concentration monitoring in these patients is not warranted Steer PA and Caffeine Collaborative Study Group. Ther Drug Monit 30; 709, 2008

39 Treatment High-dose Caffeine RCT High-dose Caffeine (N=60) Usual-dose Caffeine (n=60) p value Extubation failure <0.05 Apnea frequency <0.001 Days of apnea <0.001 Mohammed S. Eur J Pediatr 2015

40 Prophylactic (day 1) High-dose Caffeine RCT Neuroimaging Results High-dose caffeine (n=37) Standard-dose caffeine (n=37) P value Cerebellar hemorrhage 36% 10% 0.03 Intraventricular hemorrhage % 11% >0.99 Periventricular leukomalacia 8% 5% 0.78 White matter injury 7% 14% 0.75 Death or cerebellar hemorrhage 49% 23% 0.03 Bayley III MDI 86% 88% 0.42 Bayley III PDI 85% 86% 0.86 McPherson CM et al. Pediatric Res 2015

42 Conclusion Take Home Message 1. Methylxanthine treatment has important short term benefits (less BPD, less PDA ligation, less ventilator days) 2. Currently recommended doses of methylxanthines are substantially lower than doses found to be most effective 3. High dose methylxanthines treatment is safe as evidenced by trends for improved neurologic development at follow-up but further research is needed 4. It is unclear if earlier caffeine is superior to the usual timing of initiation of caffeine

43 Caffeine - The Silver Bullet in Neonatology (Jack Aranda) Standard of care Apnea of prematurity Extubation of ventilated babies Post-operative apnea prevention Non-intended benefit. Reduction in BPD PDA ROP Cerebral palsy, Cognitive impairment Save Money NO EFFECT ON IVH or NEC

44 NIH/FDA Apnea of Prematurity Group Recently, a panel convened by the NIH and FDA reported the summary proceedings of the Apnea of Prematurity Group. The group recommended that a large (3000 patient) randomized trial powered to assess long term outcomes should be performed in preterm infants with apnea. Finer NN et al. Pediatrics 117:S47-51, 2006

MD Aaron Yee, MD Namasivayam Ambalavanan, MD Carl Coghill, MD Reed Dimmitt, MD, MSPH George El

45 THANKS! Prem Fort, MD Pankaj Jain, MD Jegen Kandasamy, MD Erin Mack, MD Viswanathan Prabhu, MD Colm Travers, MD Aaron Yee, MD Namasivayam Ambalavanan, MD Carl Coghill, MD Reed Dimmitt, MD, MSPH George El Ferzli, MD Hannah Hightower, MD Tamas Jilling, MD Virginia Karle, MD Joe Philips, MD Vivek Lal, MD Maran Ramani, MD Brian Sims, MD, PhD Elaine St. John, MD Trent Tipple, MD Rune Toms, MD Lindy Winter, MD

Hazards and Benefits of Postnatal Steroids. David J. Burchfield, MD Professor and Chief, Neonatology University of Florida

Hazards and Benefits of Postnatal Steroids David J. Burchfield, MD Professor and Chief, Neonatology University of Florida Disclosures I have no financial affiliations or relationships to disclose. I will