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High Dose Methylxanthine: Are we Using the Correct Dose?

High Dose Methylxanthine: Are we Using the Correct Dose?. Wally Carlo, M.D. University of Alabama at Birmingham Department of Pediatrics Division of Neonatology wcarlo@peds.uab.edu. Objectives. Learn which neonates may benefit from methylxanthines therapy

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High Dose Methylxanthine: Are we Using the Correct Dose?

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  1. High Dose Methylxanthine: Are we Using the Correct Dose? Wally Carlo, M.D. University of Alabama at Birmingham Department of Pediatrics Division of Neonatology wcarlo@peds.uab.edu

  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. High-Dose Methylxanthines Questions • Which of the following can occur in preterm infants with severe apnea? A. Failing extubation attempts B. Remaining on the ventilator C. Getting a PDA ligation D. A and B E. A, B, and C • Withholding caffeine treatment when indicated in ELBW infants can result in: • A. Increased risk of BPD • B. Increased risk of neurodevelopmental impairment • C. Increased death • D. A and B • E. A, B, and C

  4. 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?

  5. Pharmacokinetics of Theophylline and Caffeine Theophylline Caffeine Half life (hr) 30 100 Range (hr) 12-4 40-230 Loading dose (mg/kg) 5-6 10 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

  6. Effect of Theophylline on Apnea with Orally Administered Theophylline 10 25 8 20 Apnea Requiring Ventilation (N) 6 15 Apnea/day 4 10 2 5 0 0 Pre Theophylline Post Theophylline Pre Theophylline Post Theophylline Uauy et al. Pediatrics 55:595, 1975

  7. Effect of Caffeine on Apnea 44 30 26 p<0.001 22 Apnea/Day 16 12 8 4 0 Pre Caffeine With Caffeine Aranda et al. J Pediatr 90:467, 1977

  8. Effectiveness of Theophylline vs Caffeine Caffeine Theophylline 1.5 1.0 Apnea Frequency 100/min 0.5 0 1 5 0 1 5 Days

  9. Methylxanthine Treatment for Apnea of Prematurity Outcome RR (95% Cl) 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 0.1 0.2 1 5 10 Modified from Henderson-Smart DJ and Steer P. Cochrane Collaboration 2001.

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

  11. Meta-analysis Caffeine vs. Theophylline in Preterm Apnea Tachycardia/feed intol 3% in caffeine vs 31% in theophylline (p<0.05) Apnea at days 1-3 5.8 (range 4.6-6.6) less apnea per day in theophylline group (p<0.05) Steer and Henderson-Smart. Cochrane 2003

  12. Possible Mechanisms of Action of Methylxanthines in Neonates with Apnea • Increased respiratory center drive • Improved respiratory muscle contractions • Preferential activation of upper respiratory muscles • Decreased pulmonary resistance • Blockade of adenosine (a respiratory inhibitory neurotransmitter) • Diuresis

  13. Methylxanthine Effect on Extubation Failure RR Methylxanthine Control (95% CI) Viscardi 1985 5/14 10/11 0.4(0.2,0.8)* Greenough 1985 2/18 8/20 0.3(0.1,1.1) Barrington 1993 3/10 2/10 1.5(0.3,7.1) Durand 1987 5/23 15/28 0.4(0.2,1.1) Muro 1992 4/12 6/6 0.3(0.1,0.7)* Pearlman 1991 8/31 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

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

  15. Why are preterm infants so predisposed to apnea and how does caffeine work?

  16. INFANTS WITHOUT APNEA INFANTS WITH APNEA 500 400 MINUTE VENTILAITON (ml/min/kg) 300 DIFFERENCE IN SLOPE P<0.001 200 40 45 50 55 35 PACO2 (mmHg) Modified from Gerhardt T, et al. Pediatrics 74:58, 1984

  17. CO2 Threshold for Various Respiratory Muscles CO2 Threshold (mmHg) Carlo and DiFiore. J Appl Physiol 68:1041, 1990

  18. Resolving RDS Predisposes to Apnea p < .05 NS NS Apnea duration (sec/hr) Carlo et al. Am Rev Resp Dis 126:103, 1982

  19. Thus, infants will have an increased predisposition to apnea as: 1. Prematurity is more severe 2. PCO2 decreases 3. RDS is resolving

  20. Possible Mechanisms of Action of Methylxanthines in Neonates with Apnea or Extubation Failure • Increased respiratory center drive • Improved respiratory muscle contractility • Preferential activation of upper respiratory muscles • Decreased pulmonary resistance • Blockade of adenosine (a respiratory inhibitory neurotransmitter) • Diuresis

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

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

  23. Caffeine RCT: Caffeine for Apnea Patients: 2006 500-1250 <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 Schmidt et al. NEJM 354:20, 2006

  24. Caffeine RCT: 2 Year Outcomes Caffeine Placebo OR (CI) p value Death or disability 40% 46% 0.77 (0.64-0.93) 0.008 Death 6.4% 6.5% 0.97 (0.67-1.40) NS CP 4.4% 7.3% 0.58 (0.39-0.38) 0.009 MDI < 85 34% 38% 0.81 (0.66-0.99) 0.04 Schmidt et al. NEJM 357:1893, 2007

  25. Caffeine RCT: 5 Year Outcomes No difference in growth Schmidt, et al. JAMA 307:275, 2012

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

  27. Effect of Aminophylline/Theophylline on Apnea Treatment Success % Success Dose kg/day

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

  29. RCT of Short-term Administration of Three Dosages of Caffeine 3, 15, and 30 mg/kg/day x 1 week; 127 infants <32 weeks 15 and 30 gm/kg groups had less apnea Trend for less extubation failure with higher doses Steer et al. J Paediat Child Health 39:511, 2003

  30. 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

  31. RCT of High-Dose Caffeine: Patient Population: N=234 infants Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

  32. RCT of High-Dose Caffeine: Results Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

  33. RCT of High-Dose Caffeine: Adverse Effects Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

  34. RCT of High Dose Caffeine: Morbidity and Death Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

  35. RCT of High Dose Caffeine:Outcomes at 12 Months Corrected for Prematurity Steer et al. Arch Dis Child Fetal Neonatal Ed 89:F499, 2004

  36. 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

  37. Conclusion – Take Home Message • Methylxanthine treatment has important short term benefits (less BPD, less PDA ligation, less ventilator days) • Currently recommended doses of methylxanthines are substantially lower than doses found to be potentially more effective • High dose methylxanthines treatment may be safe as evidenced by trends for improved neurological outcome at follow-up but more research is needed.

  38. THANKS! Alain Cuna, MD Mackenzie Dreher, MD Prem Fort, MD Hannah Hightower, MD Jegen kandasamy, MD Maran Ramani, MD Ariel Salas, MD Lindy Turner, MD Namasivayam Amalavanan, MD Allison Black, MD Carl Coghill, MD Reed Dimmitt, MD, MSPH George El-Ferzli, MD Tamas Jilling, MD Virginia Karle, MD Rees Oliver, MD Joe Philips, MD Brian Sims, MD, PhD Elaine St. John, MD Rune Toms, MD

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