Impact of Best Evidence on the Management of ROP

1. Impact of Best Evidence on the Management of ROP Dale L. Phelps, MD University of Rochester, NY Israel Neonatology Association The Dead Sea, Dec. 14-15, 2006

2. Case Report • 780g male, 25 weeks • RDS & BPD, sepsis x1, PDA, ROP • 4 ROP exams prior to discharge at 36 weeks • Next exam due Aug. 1, discharged Jul.31(Sat.). Instructed to call for appointment Mon. • Called MD Mon., given appointment for 8/23 • Bilateral retinal detachments when seen • … Effective treatment depends on timing

3. Evidence and Practice • Newer Oxygen Story • Can we Prevent ROP otherwise? • Data on Treatment of threshold • (Screening) Detecting Serious ROP • Follow up of ROP

4. An RCT of Transcutaneous Oxygen Monitoring • Continuous TcO2 monitor while on any O2 • vs Intensive TcO2 only when acutely ill • n= 296, 500g-1300g birth weight • No significant differences • any ROP: 51.0% vs 59.0% • Cicatricial ROP: 4.0% vs 4.4% Bancalari, Flynn, et al Pediatrics 1987;79:663

5. An RCT of Transcutaneous Oxygen Monitoring • Secondary analysis: • Continuously Monitored Group • For each 12 hrs of time from birth to 4 weeks that Tc-PO2 was over 80 torr, • odds ratio for ROP increased 1.9 • In weeks 2 through 4, for each 12 hours that the Tc-PO2 was over 80 torr • the odds ratio was increased 3.1 Bancalari, Flynn, et al Pediatrics 1987;79:663

6. UK- Results from Differing Pulse Oximetry NICU A Stated Pulse Oximetry Goals 88-98% NICU B 70-90% Tin et al, Arch Dis Child Fetal Neonatal, 2001;84:F106-10

7. Infants <28 weeks 1990-1994 Tin et al, Arch Dis Child Fetal Neonatal, 2001;84:F106

8. Reduction in Rates of ROPAn Historical Comparison-USA • BW 500-1500g • Rates of stage 3 or worse ROP • Pre-intervention 1997 • Intervention 1998 forward • Delivery Room: blender and saturation monitor • NICU: proportional response, prompt weans • Target saturations: 85-93% Chow, Sola, et al, Pediatrics 2003;111:339

9. Laser Treatment of ROP Chow, Sola, et al, Pediatrics 2003;111:339

10. Seymore(see-more) Ochsner, with permission: NICU, New Orleans

11. Oxygen Targeting: Effect of New Targets on % Time at Certain Saturation Ranges 100 Old Target: 90-100%, Alarm at 85% No upper alarm New Target: 85-93%, Alarm at 80-95% 90 80 70 60 50 % Time at Saturation 40 30 Old Target 20 New Target 10 0 60 70 80 90 100 O2 Saturation Ochsner, with permission: NICU, New Orleans

12. Contract Summary birth weights 500-1500 g 1. Set saturation alarm limits at 80-95%. 2. Goal of saturations to be 85-93%. 3. Allow baby to fluctuate 5. Never increase the FiO2 without first assessing the baby. 6. When altering oxygen, stay until saturations are stabilized within an acceptable range Summarized from Ochsner: New Orleans

13. % Stage 3-4 ROP in <1500 gm Ochsner, with permission: NICU, New Orleans

14. Individual Nurse Performance in Titration of O2 to Prescribed SpO2 Ranges Ochsner NICU: New Orleans

15. Oxygen Delivery • Not just saturation • Cardiac Output • Hemoglobin • Hemoglobin Oxygen Affinity • Growth is modified by oxygen delivery as well a nutrient delivery: together William Hay, Denver, Colorado

16. International Pulse Oximetry Studies Beginning • Primary Outcome • Neuro-Development at 2 yrs • Secondary Outcome • Survival without ROP requiring Surgery • (or meeting criteria for surgery)

17. ROP--pulse Oximetry Trials • Target Saturations 85-89% vs 90-95% • double blind RCT, with research Oximeters • Orders: “Maintain saturation 88-92%”

18. Normal Term Normal in utero 60-75 % SATURATION Target Ranges in the Oximeter Trials PaO2 20 40 60 80 100 120 2

19. Evidence and Practice • Newer Oxygen Story • Can we Prevent ROP otherwise? • Data on Treatment of threshold • (Screening) Detecting Serious ROP • Follow up of ROP

20. Preventing ROP • Prevent Preterm Birth • Birth intervals at least a year • 17-OH progesterone • Manage Oxygen Wisely • Others? • Light, Vitamin E, Inositol, d-penicillamine

21. Restricting Light (Cochrane) • 3 Randomized Controlled trials with n= 184, 127, and 409. • Patching or high density goggles from birth to ~34 weeks • No evidence that ambient light affects the incidence or severity of ROP Cochrane Review: Phelps and Watts • May be other reasons than ROP to limit light exposure

22. Vitamin E to Reduce ROP • One Systematic Review 6 RCTs summarized • n = 1428 infants, 704 Vit E prophylaxis • Any ROP: 43% vs 40% (vit E) • Stage 3+ ROP: • pooled odds ratio 0.44 [0.21-0.81, 95% CI] • Number Needed to Treat = 35 • Recommended further, focused trials • (Raju, J Peds 1997;131:834)

23. Inositol to Reduce ROP • Hallman: 2 RCTs with IV Inositol • n = 74, n = 221 • Outcomes: Relative Risk [95% confidence interval] • Death RR 0.48 [0.28, 0.80] • Death or BPD 0.56 [0.42, 0.77] • Severe ROP 0.09 [0.01, 0.67] See Cochrane Review: Howlett, A, 2000

24. MulticenterRCT FundedInositol to REDUCE ROP • Infants of <28 weeks gestation • double blind, placebo controlled • Primary Outcome survival without meeting criteria for Surgical ROP • Pilot Studies on pharmacokinetics in extremely preterm are enrolling Phelps DL, & NIH Neonatal Research Network

25. d-penicillamine to prevent ROP • Two RCT reported by Lakatos • n=204, 750-2000g birth weight • Acute ROP in 0/71 penicillamine vs 6/70 control survivors • n=77, 751-1500g birth weight • Acute ROP in 0/27 penicillamine vs 3/22 controls • to be continued… Trials needed Phelps et al, Cochrane Review 2001

26. Evidence and Practice • Newer Oxygen Story • Can we Prevent ROP otherwise? • Data on Treatment of threshold • (Screening) Detecting Serious ROP • Follow up of ROP

27. CRYO-ROP: 15 Years • Controls Worse % poor Control Good News: Something we can do ! CRYO Bad News: Something we can do ! but doing it is not easy. Arch Ophthal 2005; 123:311

28. ETROP Study • Earlier Treatment • Prethreshold that was “High Risk”, • meant a >15% chance of poor outcomes • Used Laser • Zone I more common Arch Ophthal 2003 121:1684

29. ETROP Outcomes Percent Poor Retinal Outcomes P<0.001 15.6 9.1 Arch Ophthal 2003 121:1684

30. Revised Indications for ROP Modified from: Arch Ophthal 2003 121:1684

31. Surgery for Stage 4b or 5 ROP • Vitrectomy /lensectomy • Outcomes disappointing at best • Rarely: ambulatory vision, usually none • 72 eyes receiving vitrectomy from the CRYO-ROP study: 1 with pattern vision at 5 years, otherwise no LP or just light perception • Devastating to Families who reach for any hope, and often give all they have • Neonatology should counsel too, separate perspective Ophthal 1996; 103:595

32. Progression to Retinal Detachment Stage 4a Stage 4b Stage 5 Arch Ophthal 1987; 105:906, used with permission

33. Surgery for Stage 4A ROP • Partial Detachment, not macula • From CRYO-ROP, condition documented as unstable • Surgery is not established treatment, but is being attempted: • A vitrectomy (with lens sparing, or with lensectomy), done as soon as any detachment is seen • Watch for the data (outcomes)

34. Evidence and Practice • Newer Oxygen Story • Can we Prevent ROP otherwise? • Data on Treatment of threshold • (Screening) Detecting Serious ROP • Follow up of ROP

35. Screening for ROP Goal: Detect New/Threshold ROP in time to treat it

36. Screening for ROP (2) • Who to examine? • When to start exams? • When to repeat exams?

37. 2006 USA Guidelines Who? • Note: Varies by Country • Who? • <31 weeks gestation (i.e. 30 and less) • <1500 grams birth weight • other premature infants, if medically unstable

38. Who are: “Other Preterm, Unstable” Babies ? • 310/7 to 360/7 weeks • If hypotensive (pressors, volume, steroids) • If on oxygen more than 6 hours • If culture proven septic (early or late) • Exchange Transfusion • Small for Gestational Age • Others as judged by physician

39. Recommended First Examination Range 31-33 weeks Timing of Threshold ROP Youngest, 31.6 weeks

40. When to Start Exams? • 31-33 weeks PMA official • Because in ETROP, High Risk Prethreshold occurred at • mean 35.2 weeks, • range 30.6-42.1 weeks • Consider • Targeting 31 weeks PMA

41. Recommended First Examination Range 31-33 weeks Mean ETROP threshold ETROP Type 1 ROP Youngest now 30.6 weeks

42. When to Examine GA PMA Postnatal Age at birth at exam at exam . 24 weeks 31 weeks 7 weeks 25 31 6 26 31 5 27 31 4 28 32 4 29 33 4 30 34 4 31 35 4* * OK to do the exam before discharge 32 36 4* home, if sooner. This is because if the 33 37 4* retinalvesselsare mature by then, no 34 38 4* further exams are needed asan 35 39 4* outpatient. 36 40 4* Modified from Reynolds: Arch Ophthal 2002 120:1470

43. When to Repeat Exams ? • Confer with Ophthalmology • Your population • Monitor it • If Type 2 ROP (watch and wait) • Examine every 2-4 days (twice weekly) • Close to Type 2, ? Weekly • (only prethreshold used to be weekly) • Zone I, no ROP • Zone II, stage 2

44. Recommended First Examination Range 31-33 weeks Mean Time for ETROP threshold Discharge Home ETROP Type 1 ROP Youngest now 30.6 weeks

45. Tracking for ROP Must be a Collaborative Policy with Neonatologists, Ophthalmologists & Pediatricians We work hard on these Policies Ask: Have you done a QA on its effectiveness?

46. Testing Effectiveness in your NICU • Test a 6-12 month period • List all births <1500g or <=30 weeks • Determine final outcome of each • Death • Was ROP status “final” before discharge? • Death, mature, regressed, zone III x2 • If not, did parents return for timely and complete follow-up?

47. Evidence and Practice • Newer Oxygen Story • Can we Prevent ROP otherwise? • Data on Treatment of threshold • (Screening) Detecting Serious ROP • Follow up of ROP

48. 2 Kinds of Ophthalmic F/U • Urgent-Immediate Follow-up • Goal: Prevent Blindness • Window: Days to Weeks !!!! • Ongoing Ophthalmic Care • Goal: Optimize Vision • Window: Months to Years

49. Discharge Planning and ROP • Schedule Appointment before discharge • Letter with appointment, phone numbers and signature of family • Copies to home, medical record, ophthalmologist’s office • If very close to ROP treatment, consider delaying discharge

50. Pediatrician Role • Understand it is sometimes Urgent • Ask family about ROP, and ask at discharge • Insist family attend follow up appointments • Don’t be afraid to say ‘blind’, and that treatment might prevent it.