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Brian Darlow MD Christchurch, New Zealand

Prevention of ROP - Neonatal perspectives. Brian Darlow MD Christchurch, New Zealand. Objectives __________________________________. Outline the "Third Epidemic of ROP" Outline current knowledge of pathogenesis of ROP

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Brian Darlow MD Christchurch, New Zealand

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  1. Prevention of ROP -Neonatal perspectives Brian Darlow MD Christchurch, New Zealand

  2. Objectives __________________________________ • Outline the "Third Epidemic of ROP" • Outline current knowledge of pathogenesis of ROP • Outline key factors in neonatal care that can decrease mortality and morbidity • Outline recent changes in labour ward care leading to less lung damage and possibly less ROP • Review trials on oxygen saturation targeting

  3. Retinopathy of Prematurity is: An Index of overall quality of perinatal and neonatal care • Good evidence that overall better care reduces incidence and severity of ROP • Still cannot prevent all cases

  4. History of ROP In 1930s in the US and elsewhere it became common practice to give oxygen to well preterm infants, mainly because this led to more regular breathing patterns The first epidemic of ROP was the result But when O2 was restricted more babies died or had CP The second epidemic in the 1970s was the result of increased survival of small babies - much care still “experimental”

  5. Threshold disease Gilbert et al Pediatrics 2005 Data from 1996-02 Third epidemic in Middle Income countries Severe ROP

  6. Third epidemic(Middle income countries 1990s-2000s) Is often a mixture of: First epidemic patterns - Uncontrolled oxygen - often no blenders - No or insufficient monitoring of oxygenation And second epidemic patterns - “Developing” intensive care We already know how to prevent many of these cases but putting that knowledge into practice remains a challenge

  7. 1.4 million of the world’s children are blind 39% 34% 21% 6% Courtesy Clare Gilbert

  8. Proportion of blindness due to ROP, by World Bank region (%) FSE – Former Soviet Economies LAC – Latin America and Caribbean EME – Established Market economies OAI – Other Asian and Islands MEC – Middle East Crescent SSA – Sub Saharan Africa Updated May 2006; Clare Gilbert

  9. Estimates of numbers blind from ROP, by World Bank region Updated May 2006: Clare Gilbert

  10. Role of IGF-1 and VEGF in ROP • Proposed by Lois Smith (Boston), Ann Hellström (Göteborg) • Retinal vessel growth under control of several factors including oxygen-regulated Hypoxia Inducible Factor (HIF) and Vascular Endothelial Growth Factor (VEGF) and non-oxygen regulated Insulin-like Growth Factor-1(IGF-1) • VEGF – hypoxia induces and hyperoxia inhibits. VEGF is a vascular endothelial mitogen and acts via VEGFR-1 • Animal expts (eg mouse model of OIR)suggest IGF-1 has permissive action and is required for VEGF signalling and vessel growth and survival • in utero normal vessel growth from optic disc under control of IGF-1 (from placenta) and VEGF

  11. Role of IGF-1 and VEGF in ROP • Proposed by Lois Smith (Boston), Ann Hellström (Göteborg) • Phase I ROP – preterm birth, low IGF-1, vessels stop growing – hyperoxia can further suppress VEGF • As neural retina develops,  oxygen demand and relative hypoxia, results in VEGF. If sufficient IGF-1, can be normal vessel growth. • Phase II ROP – if excess VEGF (as with hypoxia), proliferative ROP. Critical period 32-34 weeks.

  12. Adjusted OR for significant ROP Gestation (completed weeks)  24 Birthweight centile for gestation 25 <3rd 26 3-9th Sex 27 male 10-24 th 28* 25-75th (IQR)* female* >75th OR 20.0 4.19 1.73 *reference group n = 2105 ANZNN 1998-99 Pediatrics 2005; 115: 990-6

  13. Antenatal steroids Antenatal steroids(betamethasone) are cheap and improve outcome(Roberts Cochrane Review) Improved survival OR 0.60 [95%CI 0.48, 0.75] Less RDS OR 0.53 [95%CI 0.44, 0.63] Also benefit in terms of reduced IVH, white matter injury, ROP Even for outborn babies, obstetricians in other centres should be encouraged to use antenatal steroids

  14. ROP risk factors – current research Many factors suggested to be associated with increased risk of ROP – 50 or more, eg Hyperoxia and hypoxia Hypercarbia Low vitamin E Blood transfusions / excess iron Light Genetic susceptibility, etc Whilst can cause ROP in some preterm babies by inappropriate oxygen use (unmonitored 100% O2), the hope that there might be a single factor that can cause or prevent ROP has largely proven unfounded. It is the summation of care that counts

  15. ROP risk factors – current research • ROP long known to be multifactorial and to be more frequent in sicker babies • Interventions aimed at decreasing co-morbidities frequently also decrease the incidence of ROP • Interventions aimed at keeping very preterm infants more stable also decrease the incidence of ROP

  16. With sick preterm infants – ONE THING LEADS TO ANOTHER babies can quickly become unstable so all aspects of care are equally important

  17. In first 4 days of life very preterm infants are handled on average 18% of the time Arch Dis Child 1984 Subject to many other stimuli - eg loud noise We should minimiseunpleasanthandling

  18. Vermont-Oxford Network - Evidence-Based Quality Improvement CollaborationePediatrics April 2003 9 centres 9 PotentiallyBetter Practices to reduce CLD

  19. Payne Pediatrics 2006;118:S73Vermont-Oxford Network : 2001-2003 Focus on evidenced-based care to reduce incidence of Chronic Lung Disease (BPD) By introducing better care practices reduced BPD (37% to 27%) also reduced severe ROP (12.3% to 9.1%)

  20. It is well known that there are wide variations in outcome between NICUs across a range of morbidities. • Reasons for such variation include: • Differences in case-mix • Differences in size of NICU • Differences in case ascertainment • Differences in care practices

  21. Factors contributing to overall BETTER neonatal care in preterm babies Antenatal steroids (betamethasone) Place of birth - Labour Ward care Temperature control Lack of painful experiences – Adequate analgesia Avoidance of infection Good nutrition / early maternal breast milk feeding Careful fluid balance – do not over hydrate Appropriate oxygenation Appropriate nurse to patient ratios Avoid anything that makes baby unstable – e.g. unnecessary handling, loud noise etc Many positive things can be done, eg Breast milk feeding, Kangaroo Care

  22. Analgesia • Very preterm babies do feel pain • Be aware of the many things which may cause pain, eg heel prick, inserting nasogastric tube, line insertion etc • Avoid unnecessary and unpleasant handling • Prevent pain - swaddling or kangaroo care / non-nutritive sucking / oral sucrose • Sucrose – 24% solution, 0.05 to 0.5ml Stevens, Cochrane review 2004 Ouch!!!!!!

  23. Analgesia • Be aware of signs of pain Behavioural response - withdrawal / facial signs Physiological - increase heart rate, increase BP - increased respiratory rate • Good scores are available to assess and document pain in the newborn • Use of Pain Scores increase awareness of pain and allow appropriate treatment Ouch!!!!!!

  24. Avoid infection • Sepsis is important cause of death and serious morbidity in Very Preterm infants • Israel Neonatal Network: (Pediatrics2010; 125: e736)Early-onset sepsis increased risk of severe ROP • OR 2.04 (95%CI 1.32 to 3.16) • Candida infection strongly linked with ROP 6 studies reviewed (J Perinatol 2008; 28: 61) • Nested case-control study, Boston (Neonatology 2011;99:125)Sepsis was stronger risk factor for ROP at higher gestations

  25. Avoid infection • Reducing infection rates has the potential to make the greatest impact on overall morbidity • Senior nurse should have infection control role • Careful handwashing each time go to baby and between babies / Can provide hand disinfectant by alcohol rub also • Display notices about hand washing • Do not leave toys in cot (they become colonised with bacteria) • ALL visitors must wash hands on entering

  26. No-one should be too posh to wash! Carla Bruni-Sarkozy visiting NICU in Rio de Janeiro Courtesy Andrea Zin

  27. Avoid infection • Skin care • Careful preparation before blood tests or inserting iv lines • prevent breakdown • Careful antibiotic use • Use narrow spectrum antibiotics with strict indications • Stop antibiotics early if no proven sepsis • Avoid new broad spectrum antibiotics except in exceptional circumstances • Prophylaxis • In <1000g (<28 week gest) infants can use oral nystatin prophylaxis: 100,00 iu/ml – 1ml 6 hrly. Isaacs D, Curr Opin Infect Dis 2008

  28. Darmstadt J Perinatol 2005;25:331 Bangladesh introduced infection control measures in three stages

  29. Optimal nutrition and growth • Good nutrition during a critical time of brain development is a key to better long term outcomes • Several studies linking poor post-natal growth with increased risk of ROP • May be linked with poor production of IGF-1 Need adequate IGF-1 for normal retinal vessel developmentIGF-1 is made in many organs and tissues including the liver: poor nutrition and infection reduce levels.

  30. Lines are Median, 95th, 5th centile for fetal IGF-1 Data from 84 infantsHellstrom A Pediatrics 2003; 112: 1016

  31. Other factors – current research • Breast milk • Many reasons to support early and continued feeding with mother's own breast milk • Several studies suggest human milk may reduce risk of ROP Hylander (J Perinatol 2001) Observational cohort study - Any ROP Okamoto (Peds Internat2007)Retrospective audit - Severe ROP • But Heller (Pediatrics 2007) RCT secondary analysis – no difference severe ROP • Breast milk has higher IGF-1 than formula. But optimal nutrition and growth is the most important aim and BM often needs to be supplemented to achieve this

  32. Key role of nurses Nurses have a key role in the care of high-risk and preterm infants. In many countries there are a lack of trained nurses and a great deal of care is administered by nurse assistants (NAs), who often have minimal training. There is often a lack of continuing education programmes for nurses and NAs and many neonatal intensive care units (NICUs) lack protocols for common care practices.

  33. Key role of nurses Andrea Zin – Study in 7 NICUs in Brazil NICU with highest survival rate had lowest rate of ROP All babies on O2 had oximeter Nurse : baby ratio 1 : 2 in level III NICU with highest rate ROP Only 50% babies on O2 had monitors Nurse : baby ratio 1 : 17 World ROP Congress 2006Pediatrics 2010; 126: e410-e417

  34. Appropriate nurse : patient ratios Have critical look at nurse : patient ratios If NICU has nurse aids / assistant nurses they should be trained in key aspects of care and be able to take responsibility Ongoing training for nursing staff essential Mothers can also be trained to help provide care Development of evidence based protocol book

  35. Oxygen is the commonest “drug” we give to preterm babies We should be as careful with the amount of oxygen we give as with any other drug MORE is NOT BETTERbut also many dangers in too little

  36. Both too much and too little oxygen can cause harm Harm Benefit Free-radical damage Cell damage / death Unfortunately, despite 60 years of research and debate we still do not know exactly how much is too much or too little

  37. Three phasesof care for preterm infants • Transition(labour ward) • Acute phase of illness(first few weeks) • Chronic phase of illness(recovery / c.32 weeks on) • In theory, at least, might need different oxygen saturation targets in these different phases

  38. Transition from in utero at birth Danger zone Hey, in Richmond Clin Perinatol 2006 In utero the fetus is in a low oxygen environment pO2 is 30-35 mm Hg and the saturation 50-70% At birth, in healthy term babies, the SaO2 may take 10 minutes or more to rise to 95%

  39. SaO2 in first 10 mins from birth – no intervention (term babies) Dawson Pediatrics 2010

  40. Finer Pediatr Res 2009 <37 weeks no resus: SpO2 75% at 4.2 mins; 90% at 6.5 mins

  41. Labour ward stabilisation – has key impact • Oxygen versus air: • Meta-analysis of five trials of air vs 100% oxygen in 1302 infants (1993-2003)Davis Lancet 2004;364:1329 • Air favoured: RR NNT • Death at latest follow-up 0.71 (0.54 to 0.94) 20 • Time to 1st breath >3mins 0.53 (0.35 to 0.80) 11 • These data are for term babies – a few 32-36 weeks • One in five babies started in air do need oxygen • Many babies are exposed to excess oxygen in LW. • If start with 100% O2 babies often stay in 100% for a long time

  42. Labour ward stabilisation • ILCOR 2010 consensus for neonatal resuscitation Circulation 2010; 122: S516-S538 • “For babies at term it is best to begin resuscitation with air rather than 100% oxygen." • WHO – also recommend air for basic resuscitation, but 100% O2 when neonatal condition/colour does not improve

  43. Labour ward stabilisation • ILCOR 2010 consensus for neonatal resuscitation Circulation 2010; 122: S516-S538 • "For preterm infants <32 weeks ….. initiation of resuscitation with 30% or 90% oxygen and titration to oxygen saturation" will be less likely to result in hyperoxaemia or hypoxia. • "Blended air and oxygen may be given judiciously and ideally guided by pulse oximetry" • "If a blend of oxygen and air is not available……(start) with air"

  44. Labour ward stabilisation • Practices in LW have changed quite radically in recent years • Gentler respiratory management - Avoidance of baro- and volu-trauma • nCPAP at birth can avoid intubation (Morley NEJM 2008) • Many units also now start with 30%-40% O2 in VP babies, place saturation monitor, give blended oxygen to achieve SaO2 of 85 - 90% by 3 to 5 mins.(Leone, Finer. NeoReviews April 2005) • As yet, the impact of this on morbidity, including ROP, is unknown but we are now seeing a milder form of CLD in most preterm infants.

  45. Oxygen therapy_____________________________ • The AAP (1976 and 1988) recommended a PaO2 target range of 50 to 80 mm Hg but this was based on consensus not evidence • Flynn (1992) ROP occurred more often with longer time PaO2 (TcO2) > 80mm Hg in <1000g infants • Translating this range to saturation, a SaO2 of 90 - 95% often used • There is considerable variation in SaO2 targets amongst NICUs in all recent surveys

  46. Oxygen saturation targeting Several studies have suggested that the blood oxygen levels adopted for preterm infants might be too high STOP-ROP Trial. Pediatrics 2000; 105; 295-310 Infants with pre-threshold ROP: RCT of SaO2 89-94% vs 96-99% High target more respiratory morbidity Tin W, Milligan DWA, Pennefather PM, Hey E. Arch Dis Child 2001; 84: F106-110 Retrospective unit comparisons – SaO2 70-90% vs 88-98% Lower inc. of ROP in NICUs with lower targets

  47. Oxygen saturation targeting Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. N Engl J Med 2003; 349: 959-67 BOOST trial <30 wk infants still in O2 at 32 wks: RCT of SaO2 91-94% vs 95-98% High target increased rate BPD Chow LC, Wright KW, Sola A. Pediatrics 2003; 111: 339-345 Single unit, practice change vs historical controls: SaO2 85-93% vs 90-98% Severe ROP fell to 2% vs 10%; Treatment for ROP fell to nil from 4%

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