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Ola Didrik Saugstad, MD Department of Pediatric Research

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1 Management of Neonatal Respiratory Distress Syndrome European Consensus Guidelines 2010 Update
Ola Didrik Saugstad, MD Department of Pediatric Research Oslo University Hospital, University of Oslo, Norway Kiev, Nov 30th 2011 Chairman, ladies and gentlemen, I would like to start by thanking the organising committee and Chiesis for giving me the opportunity to present the updated European consensus guidelines on the management of neonatal respiratory distress syndrome.

2 European Guidelines on RDS: 2010
European panel of experts convened under auspices of EAPM to develop evidence-based guidelines on management of RDS. Supported by an unrestricted educational grant from Chiesi Farmaceutici but none of the panel members received honoraria for their contributions. HLH and CPS are consultants to Chiesi ODS and VPC members of the Chiesi Advisory Board The panel were supported by an educational grant from Chiesi, who facilitated one meeting of the panel in London over two days. The pharmaceutical company had no editorial input into the Guidelines and the panel members did not receive any honoraria for their contributions. Professors Halliday and Speer are consultants to Chiesi and Professors Saugstad and Carnielli are members of the Chiesis advisory board.

3 European Consensus Guideline Panel
Virgilio Carnielli Ancona, Italy Gorm Griesen Copenhagen, Denmark Henry Halliday Belfast, UK Mikko Hallman Oulu, Finland Eren Ozek Istanbul, Turkey Richard Plavka Prague, Czech Republic Ola Saugstad Oslo, Norway Umberto Simeoni Marseille, France Christian Speer Wurzburg, Germany David Sweet Belfast, UK (Secretary) The Guideline Panel of Experts was chaired by Professor Henry Halliday and was made up of 9 senior neonatologists from 9 different European countries. This panel was slightly different from the previous, now including Mikko Hallman from Finland and Eren Ozek from Turkey. You will notice that I was not one of the expert panel, I am much to young for that, but I was asked along again to act as a scribe, not the points in the discussion and come up with a form of words that would represent the consensus opinion.

4 The Guidelines are an evolving work in progress
The Guidelines are an evolving work in progress. The idea originally came about in 2005 when Chiesi Pharmaceuticals asked Professor Henry Halliday to put together a team of senior neonatologists from Europe to come up with consensus guidelines as to how best to manage RDS The original Guideline was published in the Journal of Perinatal Medicine in 2007 and were endorsed by the European Association of Perinatal Medicine and has since been translated into several languages, including Chinese.

5 Updated Guidelines: 2010 What is New?
Guidelines contain new evidence from recent Cochrane reviews and the literature since Many of the previous recommendations on surfactant and CPAP are now more firmly evidence-based. The section on delivery room stabilisation has been considerably expanded. New recommendations on delaying cord clamping and a new section on avoiding or reducing duration of mechanical ventilation, including recommendations on caffeine therapy, nasal ventilation, permissive hypercarbia and the role of newer ventilator modalities. A new miscellaneous section has also been added covering aspects of RDS management that arise infrequently What is new in this Guideline is that it contains more evidence from recent literature and Cohrane Reviews since Many of the recommendations are unchanged, but now more firmly evidence based. The section on delivery room stabilisation has been considerably expanded. There are new recommendations on delaying cord clamping and a new section on avoiding or reducing mechanical ventilation, including recommendations on Caffeine, nasal ventilation, permissive hypercapnia and the role of newer ventilation modalities. A new miscallaneous section has been added cocering aspects of RDS management that occur infrequently

6 Aims Discuss controversies in RDS management
Examine the evidence for best practice Develop consensus guidelines from evidence available up to end of 2009 Publish the consensus recommendations on management of RDS in 2010, updating those of 2007 The Expert group was set the task of discussing the current controversies in RDS management. They were then asked to look for the evidence of best practice from the literature, and finally they were asked to develop consensus Guidelines from the updated evidence to the end of 2007, taking on board some of the feedback regarding the previous 2007 guideline.

7 RDS - Definition Pulmonary insufficiency starting at birth
Mainly confirmed to preterm babies Caused by lack of alveolar surfactant Presents with respiratory distress Development of respiratory failure Natural course is death or recovery after 3-4 days Classical X-Ray appearances Ground glass appearance Air bronchograms I just want to show a few slides to remind us about the definition of condition we are talking about, in order to highlight some of the areas where the controversies still exist. RDS as we know is a disorder of pulmonary insufficiency starting at birth which is mainly confined to preterm babies and is mainly due to a lack of alveolar surfactant. It presents clinically with respiratory distress including grunting, cyanosis and recession and if left untreated can progress to respiratory failure and death. The natural course of the disease is a gradual worsening over 3 to 4 days, after which time if the baby has survived the respiratory function will improve as endogenous surfactant is produced. There is a classical x-ray appearance of ground glass with air bronchograms.

8 Chest radiograph before and after surfactant
This x-ray shows the classical picture of RDS with ground glass appearance and air bronchograms Chest radiograph before and after surfactant

9 RDS - Treatment Oxygen CPAP Mechanical ventilation
Surfactant replacement Supportive Care The standard treatments we are all familiar with, including oxygen supplementation, Respiratory support with CPAP of mechanical ventilation and surfactant replacement therapy whilst at the same time providing good supportive care with careful fluid and nutritional management and temperature control. However within each of these areas controversies still exist. How much oxygen should we give? Who should get CPAP and who should be ventilated? When should you intubate to give surfactant etc.

10 RDS – Aims of Management
Maximise numbers of survivors Minimise potential adverse effects of disease or therapy Many interventions have been studied in randomised controlled clinical trials and systematic reviews We have to remember what we are trying to achieve. RDS can be fatal and we are clearly trying to maximise the number of survivors, however many of the interventions have side effects, such as intubation and ventilation causing BPD and we are trying to minimise the effects of these interventions. Many of them have been studied in randomised trials and subjected to systematic reviews.

11 Grades of Evidence and Levels of Recommendation
A = Meta-analysis or high quality RCT B = Smaller RCT or systematic review of case-control studies C = Good quality case-control or cohort study D = Case series or expert opinion Modified from SIGN guidelines handbook / The panel were asked to look at the evidence, and grade the quality of the evidence supporting each of the recommendations. The grading system was a simplified version of that used for the SIGN guidelines. Grade A evidence comes from high quality randomised trials or meta-analysis of these trials. Grabe B evidence comes from smaller randomised trials or systematic review of case controlled studies, grade C evidence from good quality case control or cohort studies and grade D evidence from case series or simple expert opinion.

12 European Guidelines on RDS: 2010
Prenatal Care Delivery Room Stabilisation Surfactant Therapy Oxygen Supplementation Beyond Stabilisation Role of CPAP Mechanical Ventilation (MV) Strategies Avoiding or Reducing Duration of MV Prophylactic Treatment for Sepsis Supportive Care: thermal, fluid and nutrition, tissue perfusion, ductus arteriosus Miscellaneous Considerations The 2010 Guideline is divided into the following broad areas: Prenatal care... The Avoiding or reducing duration of mechanical ventilation and miscellaneous considerations were not in the previous version of the guideline.

13 Management of RDS can be influenced before birth
Consider place of delivery Role of infection in initiation of preterm labour Role of antibiotics? Role of antenatal steroids Which steroid? How many courses? Who should get them? Role of tocolytic agents Allow steroids to take effect or time to transfer The RDS guidelines begin with prenatal care. Paediatricians should be working closely with obstetricians in order to plan best place for delivery. Preterm labour or ruptured membranes are often associated with infection and thought needs to be given to the role of antibiotics. We all know antenatal steroids are essential, but which steroid is best, how many courses should be used and between which gestations. What about the role of tocolysis?

14 Prenatal Care Recommendations: 2010
Mothers at high risk should be transferred to a perinatal centre (C) Single course of prenatal steroids should be given if threatened preterm labour from 23 to 35 wk gestation (A) Antibiotics should be given to mothers with PPROM (A) Consider short-term tocolytics to allow transfer in utero or time to complete course of steroids (A) Consider a second course of steroids if risk of RDS outweighs uncertainty about long-term adverse effects (D). Multiple pregnancy might be an example (C). There is evidence that outcomes are better if small babies are born in centres with a higher throughput of extremely low gestational age infants so it is recommended that transfer should take place where possible. There is grade A evidence that a single course of steroids should be given with threatened preterm labour. The panel felt that all babies between 23 and 35 weeks should be treated even though there is a paucity of evidence for the very immature babies. The choice of steroid is unclear, with both betamethasone and dexamethasone showing conflicting results for being associated with a higher incidence of adverse neurological outcome. There is grade A evidence that antibiotics delay the onset of labour in PPROM. The previous recommendation was for erythromycin because of increased risk of NEC with Augmentin in the ORACLE trial. This is less clear now as there are no differences in long term follow up between the groups, and erythromycin is associated with a higher incidence of cerebral palsy when the membranes are intact. Tocolytics are considered useful for delaying labour long enough to effect transfer,or to allow time for antenatal steroids to take effect. Second courses of steroids are more controversial. There is grade A evidence that they further reduce respiratory morbidity but follow up studies are now emerging showing that they may be associated with increased rates of cerebral palsy and increased insulin resistance in later life. The panel have left it up to individuals to decide if further reduction in RDS outweighs the uncertainty about possible long term sequelae.

15 Delivery Room Stabilisation
Babies with RDS have difficulty maintaining FRC and alveolar aeration. Traditionally, many are resuscitated with bag & mask using 100% oxygen and there is emerging evidence that 100% oxygen may be harmful Many are intubated for prophylactic surfactant Uncontrolled tidal volumes are also detrimental to the immature lung and early CPAP is being advocated Delayed clamping of the cord may confer benefits Hypothermia should be avoided The section on delivery room stabilisation is now much more evidence based. We know that the majority of babies with RDS breath spontaneously after birth but have difficulty maintaining a functional residual capacity and alveolar aeration. Unfortunately many trainee paediatricians and midwives are trained to resuscitate babies in the context of term babies with apnoea where they are encouraged to “bag” babies with 100% oxygen until they see their chest lifting and they become pink although this is probably not appropriate for the preterm baby with RDS. Many babies are intubated for prophylactic surfactant, although it is becoming clearer that not all preterm babies necessarily benefit from this. Early CPAP is increasingly being advocated and in recent years there have been several studies of its application from birth. There is also now evidence that delaying cord clamping to allow a placento fetal transfusion may confer benefits and we know that hypohermia after birth must be avoided.

16 Delivery Room Stabilisation – Recommendations - 1
If possible, delay cord clamping for at least sec (A). Oxygen should be controlled with a blender and the lowest possible concentration should be used (~30%), provided there is an adequate heart rate response (B). 30% oxygen to start and titrate using pulse oximetry but note normal sats may be 40-60%, reaching 50-80% by 5 min but should be >85% by 10 min. Avoid hyperoxia (B). If spontaneous breathing, stabilise with CPAP of 5-6 cm water via mask or prongs (B). If breathing is insufficient consider a sustained inflation rather than IPPV (B). Ventilation with a T-piece device is preferable to a self-inflating or flow-inflating bag to generate PEEP (C). The recommendations for delivery room management are that we should start if possible by trying to delay cord clamping for seconds as this improves hamatocrit and blood pressure. Oxygen delivery should be controlled with a blender, starting with about 30% and only increasing if there is an inadequate heart rate response – detected using pulse oximetry. We need to be aware of the recently published normative values of saturations in preterm infants, accepting starting saturations of 40-60%, reaching 50-80% by 5 minutes and more than 85% by 10 minutes. In spontaneously breathing preterm babies it is recommended that we initiate stabilisation in the delivery room using CPAP via a face mask or prongs. Only if breathing is insufficient should the chest be inflated and there is evidence that a single sustained inflation is better than repeated bagging in preterm babies. It is recommended that we use a T-piece device that enables control of PEEP rather than a self inflating or flow inflating bag.

17 Delivery Room Stabilisation – Recommendations - 2
If PPV is needed avoid excessive tidal volumes and maintain PEEP (D). Reserve intubation for babies not responding to PPV or those requiring surfactant (D). Verify correct position of the endotracheal tube using colorimetric CO2 detection (D). Plastic bags or occlusive wrapping under radiant warmers should be used for babies < 28 weeks’ gestation (A). If positive pressure is required, we should aim to avoid excessive tidal volumes and maintain PEEP. Intubation should be reserved for those babies not responding to T-Piece inflations or those in whom it has been decided should be treated with surfactant. Once intubated, the correct placement of the ET tube can be verified even in the smallest babies using a colorimetric CO2 detector. Babies under 28 weeks should be put inside plastic bags during stabilisations as this helps to preserve body temperature.

18 Surfactant Therapy Surfactants have revolutionised respiratory care over past 2 decades, and when given prophylactically or as rescue therapy reduce death and pulmonary airleaks in RDS Many RCTs have been performed to determine the best surfactant, and the optimal timing of dosing and redosing However, most trials were in the era of low prenatal steroid and CPAP use What about surfactant? Surfactants have revolutionised respiratory care over 2 decades and when given prophylactically, or as rescue therapy reduce death and pneumothoraces in RDS. Many randomised trials have been undertaken to determine the best surfactant and the optimal timing of dosing and redosing, but most of the trials were conducted in the era of low use of antenatal steroids and surfactant

19 Surfactant Therapy – dosing and redosing
At least 100 mg/kg phospholipid is required and 200 mg/kg may be better for established RDS Administration by bolus results in better distribution Prophylaxis reduces mortality and air leaks, but more babies end up being treated Surfactant can be given whilst avoiding mechanical ventilation using INSURE technique A second (and occasionally a third) dose is sometimes required We know from pharmakokinetic studies that at least 100mg/kg of phospholipid is required and that 200mg/kg may be even better for treating established RDS. We know that administration by bolus results in better distribution. We know that the earlier it is given, the better it works. Prophylaxis seems to be the best, with randomised trials showing prophylaxis reducing mortality, however the studies often compared prophylaxis with fairly late rescue, more babies ended up receiving intubation and no reduction in BPD was demonstrated. We know that surfactant can also be given without mechanical ventilation using the INSURE technique – Intubate, surfactant, extubate to CPAP. We know that a second, and occasionally a third dose is sometimes required

20 Surfactant Therapy - Recommendations
Babies with or at high risk of RDS should be given a natural surfactant preparation (A). Prophylaxis for most babies < 26 weeks’ gestation. Prophylaxis also if intubation required (A). Early rescue for untreated babies if evidence of RDS such as increasing oxygen requirement (A). Poractant alfa 200 mg/kg is better than 100 mg/kg (of poractant or beractant) for moderate to severe RDS (B). Consider early extubation to CPAP if stable (B). A 2nd/ 3rd dose should be given if ongoing evidence of RDS such as persistent oxygen or MV need (A). The recommendations from the panel are that babies with or at risk of RDS should be given natural surfactant. They felt that even in the current era of CPAP there are a group that warrant delivery room prophylaxis including any babies of 23, 24 and 25 weeks gestation and those who require intubation for stabilisation. Babies who do not receive prophylaxis should be offered early rescue surfactant as soon as the signs of RDS become apparent, such as increasing oxygen requirement. For rescue treatment Poractant Alpha at 200mg/kg is better that 100mg/kg or 100mg/kg of Beractant in moderate to severe RDS. Following surfactant we should try and extubate to CPAP as soon as possible. For babies with ongoing signs of RDS such as persistent need for oygen and mechanical ventilation should be given a second, and occasionally a third dose of surfactant.

21 Comparison of Animal Derived Surfactants
Rangasamy Ramanathan, M.D. Comparison of Animal Derived Surfactants Surfactant Preparation/ Composition Phospholipids Plasma logens *mol % SP- B mg/ml SP- C mg/ml Survanta (S) Minced Bovine Lung Extract/ DPPC, Palmitic Acid, Tripalmitin 84 % 1.5 Total <1mg/ml (µg/µmol PL) 1 – 20 (µg/µmol PL) Infasurf (I) Bovine Lung Lavage/DPPC, Cholesterol 95 % NA 0.26 0.44 0.9 (Alveofact) Curosurf (C) Minced Porcine Lung Extract/DPPC, Polar lipids (Liquid Gel Chromatography) 99 % 3.8 0.45 0.55 * High Plasmalogen content is associated with lower BPD rate. Rudiger et al. AJP 2005 21

22 % DMAs on all Fatty Acids
Tracheal Aspirates with High Levels of Plasmalogens Associated with Lower BPD Rates 5 4 3 2 1 BPD X non BPD P<0.001 % DMAs on all Fatty Acids Aspirates were collected prospectively from preterm infants ≤32 wks GA intubated within 1hr of birth In a prospective study by Rudiger, a correlation was identified between high levels of plasmalogen and low incidence of BPD, underscoring the importance of plasmalogens as a component of surfactants. In the chart on the left, concentration of plasmalogens are represented as relative percentage (DMA%) on all fatty acids. During sample collection, the investigators used gas chromatography to separate fatty acid methylesters and the dimethylacetals. Rüdiger M, et al. Crit Care Med. 2000;28: Figure 1 and accompanying description on p See also Materials and Methods p for bullets Rüdiger M, et al. Critical Care Med. 2000;28: 22

23 Rangasamy Ramanathan, M.D.
Comparison of Animal Derived Surfactants Curosurf vs. Survanta (5 studies) Trials (6-10) Surfactant N Type Patients Results Speer 1995 Curosurf vs. Survanta 73 Tx g Curosurf: Lower FiO2, PIP & h Baroutis 2003 Curosurf vs. Survanta vs. Alveofact 80 < 2000 g Curosurf: Fewer days on O2 & PPV; Decreased LOS Ramanathan 2004 293 g Curosurf: Lower FiO2, Fewer doses, Decreased Mortality < 32 wks Malloy 2005 58 < 37 wks Curosurf: Lower FiO2 up to 48 h, Fewer doses, lower volume Fujii, 2010 52 < 30 wks Curosurf: Faster weaning, Less Air-Leaks, PDA & MV at 72 hrs 23

24 Curosurf vs. Survanta – Rescue Trial (6)
Rangasamy Ramanathan, M.D. Curosurf vs. Survanta – Rescue Trial (6) Curosurf (n= 33) Survanta (n = 40) PIE 3 % 10 % PTX 6.1 % 12.5 % IVH Total 21.2 % 35 % IVH Gr. III-IV 36 wks PCA 11.4 % Mortality No Difference in Death or BPD Speer C et al. Arch Dis Child 1995; 72: F8-F13 24

25 Curosurf vs. Survanta – Rescue Trial (6) Changes in FiO2 , PIP & MAP
Rangasamy Ramanathan, M.D. Curosurf vs. Survanta – Rescue Trial (6) Changes in FiO2 , PIP & MAP FiO2 PIP & MAP Comments Infants started with similar oxygen requirements, with a more rapid decrease following Curosurf administration. However, 24 hours after dosing, the oxygen requirements were similar. References Speer CP, Gefeller O, Groneck P, et al: Randomized clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child 1995;72:F8-F13. Faster Weaning Speer C et al. Arch Dis Child 1995; 72: F8-F13 25

26 Rangasamy Ramanathan, M.D.
FiO2 vs. Time curves after the first dose of Surfactant (n=293) Trial #8 Faster Weaning FiO2 * * ’ ’ 2 h h Data : Mean  SEM *,* = p < 0.05 Ramanathan R et al. AJP 21: ; 2004 26

27 % of Infants Requiring Additional Doses of Surfactant #8
Rangasamy Ramanathan, M.D. % of Infants Requiring Additional Doses of Surfactant #8 Fewer Doses * % Infants * p < 0.05 36 % (C200) vs. 68 % (S100) received 2 or more doses 27

28 Rangasamy Ramanathan, M.D.
Curosurf vs. Survanta (n=50): (Rescue Trial # 10) Less Air Leaks & PDA with Curosurf P = 0.002 % P = 0.047 Fujii AM et al. J Perinatol, 1-6; March 2010 28

29 Meta-analysis – Curosurf vs Survanta Trials (6&8)*
Rangasamy Ramanathan, M.D. Meta-analysis – Curosurf vs Survanta Trials (6&8)* OR ( 95 % C.I. ) PTX 0.54 0.19, 36 wks 1.03 0.61, PDA 1.29 0.79, Pulmonary Hge 1.01 0.32, IVH Gr. I-II 1.39 0.65, IVH GR.III-IV 0.65 0.28, Neonatal Mortality 0.35 0.13, (* Speer et al. & *Ramanathan et al.) Halliday HL. Biol Neonate 2005; 87:317-22 29

30 Mortality of 3 different surfactants
Ramanthan et al Journal of Perinatology (2011), 1–7 

31 Mortality of 3 different surfactants
Ramanthan et al Journal of Perinatology (2011), 1–7

32 Cost per patient: Curosurf vs. Survanta
Rangasamy Ramanathan, M.D. Cost per patient: Curosurf vs. Survanta  53% ($ 950)  46% ($ 618)  20% ($ 220)  20% ($ 200) Cost / Patient ($) Cost Effective Model 1: Speer et al (mean wt, single-use vial) Model 2: Ramanathan et al. (mean wt, single-use vial) Model 3: Ramanathan et al. (Actual wt, single-use vial) p=<0.01 Model 4: Ramanathan et al. (Actual wt, Survanta as multi-use vial) p=0.018 Marsh W, Smeeding J, York JM, Ramanathan R, Sekar K. JPPT 9: ; 2004 32

33 Surfactant for RDS: Evidence Based Approach
Rangasamy Ramanathan, M.D. Surfactant for RDS: Evidence Based Approach Animal Derived Surfactants: Faster weaning of O2, and MAP, Fewer air leaks, and Decreased Mortality when compared to synthetic Surfactants. Among Animal Derived Surfactants, Porcine surfactant, Curosurf provides Faster Weaning, Rapid Extubation, Less PDA, Survival Advantage & Cost-effectiveness when compared to Bovine surfactants, Survanta or Infasurf Best Timing: < 60 minutes of Age 33

34 Why Poractant Alfa (Curosurf)?
Rangasamy Ramanathan, M.D. Why Poractant Alfa (Curosurf)? Highest amount of Phospholipids Lowering Surface Tension & Better anti-inflammatory effects Phosphotidylcholine molecular species closely resembles human surfactant Better interaction with SP-B 3. Highest amount of SP-B Rapid adsorption of Phospholipids 4. Highest amount of Plasmalogens Highest anti-oxidant activity 5. Highest amount of PUFA in a smaller volume and lower Viscosity Rapid distribution and less reflux 34

35 Also endorsed by European Association of Perinatal Medicine
What is the Right Dose? High vs. Higher Dose Curosurf Trial: Multicenter, RCT, 82 Centers, n= 2,168; [the Curosurf 4 trial] (Halliday HL et al. Arch Dis Child 69: , 1993) High (Low) Dose: 100 mg/kg 1st dose, & 100 mg/kg with 2 further doses (max. cumulative dose = 300 mg/kg) Higher (High) Dose: 200 mg/kg 1st dose, & 100 mg/kg up to 4 doses (max. cumulative dose= 600 mg/kg) No differences in outcomes. Mean dose of Curosurf in the “low dose” group was 242 mg phospholipid/kg, probably enough to replace the entire pulmonary surfactant pool, according to the study authors Based on Evidence, European Consensus Guidelines (2010) recommends initial dose of 200 mg/kg of Curosurf for early rescue Rx of smallest RDS babies. Also endorsed by European Association of Perinatal Medicine

36 Guidelines for Surfactant Treatment of RDS
< 28 wk 29-31 wk > 32 wk NIPPV in DR, Early Rescue (<30’) in DR or NICU with 200 mg/kg of Poractant Alfa Early CPAP/NIPPV Surfactant if intubated for resuscitation Observe CPAP/NIPPV if respiratory distress Extubate to NIPPV as soon as possible (> 24 wk). Start Caffeine Early Rescue with mg/kg if FiO2 > white CXR. Delayed Rescue with 100 mg/kg if FiO2 > 0.40 + white CXR Caffeine if symptomatic Redosing: FiO2 > 0.30 How soon: 2-12 hrs from the 1st dose FiO2 > 0.35 How soon: 12 hrs from the 1st dose FiO2 > 0.40 36

37 Oxygen supplementation beyond stabilisation
Currently no firm evidence to guide optimal oxygen saturations in NICU Suggestions to target between 85% and 93% and not exceed 95% to reduce ROP and BPD Long-term neuro-developmental outcomes are unknown Hyperoxia can occur following surfactant therapy Fluctuations in oxygen saturations may also increase the risk of ROP Optimal saturation targets currently being studied in BOOST-II, COT and SUPPORT There is a section in the guideline on oxygen supplementation beyond stabilisation. There is currently no firm evidence to guide optimal saturations in the NICU, but there is a consensus that at present we should target saturations somewhere between 85 and 93% and not exceed 95% when in oxygen in order to reduce ROP and BPD. Targeting lower saturations within this range may further reduce ROP but the long term sequelae of this approach are not known and we are awaiting data from BOOST-II, SUPPORT and COT to guide us. At present all we know is that we should avoid hyperoxia such as often occurs following surfactant and that fluctuations in saturation may also increase the risk of ROP

38 Oxygen supplementation beyond stabilisation
In oxygen, saturations should be maintained at all times between 85 and 93% (D). After surfactant, avoid a hyperoxic peak, which is associated with IVH, by rapid reduction in oxygen (C). Avoid fluctuations in oxygen saturations in the postnatal period (D). The present recommendations unfortunately aren’t evidence based. Maintain saturations when in oxygen between 85 and 93%, avoid hyperoxia, especially following surfactant and aim to avoid too many fluctuations in saturation in the postnatal period.

39 What is new and why this topic?
Stabilisation/Resuscitation: How to titrate FiO2 if oxygen is needed? Optimal FiO2 for preterm infants is not known Oxygen saturation beyond the DR in ELBWI: New data on mortality has created uncertainty of safety A too low SpO2 reduces ROP and BPD but increases mortality Consequences for clinical practice Previous reccommendations of SpO2 targets should perhap be changed

40 Should we resuscitate extremely low birth weight infants with a low FiO2?

41 High (90% Vs low (30%) FiO2 Resuscitating ELBWIs
Raquel E et al Pediatrics May 2008


43 SpO2 in extremely low gestational age neonates
120 100 80 SpO2 (%) 60 40 20 5 10 15 20 25 30 35 Time after birth (min) Hox group (n=41) Lox group (n=37) Vento et al, Pediatrics 2009

44 Isofurans ** **

45 How could SpO2 centiles be used to inform decision making in the DR?
Dawson, Vento, Finer, Rich, Saugstad, Morley, Davis J Pediatrics 2011

Allowing to individualize FiO2 avoiding hyper/hypoxia 50% 10% Rich W et al non published data 2010

47 High or Low Saturation for ELBWIs? Effect on BPD and ROP
At least 9 studies have been published investigating the effect on BPD and ROP of low or high oxygen saturation in VLBWI or ELBWIS. Of these 3 only are randomized 47

48 Study Study design High SaO2 Low SaO2 GA w/BW g
Studies regarding high or low SpO2 targets in VLBWI or ELBWIs – Characterisation of Studies Study GA w/BW g Study design High SaO2 Low SaO2 STOP ROP 2000 Mean 25.4 w Randomized 96-99 89-94 Tin 2001 <28 weeks Observational 88-98 70-90 Sun 2002 gr Survey >95 ≤ 95 BOOST <30 weeks 95-98 91-94 Chow 2003 gr 90-98 85-93 VanderVeen 2006 ≤28 weeks ≤ 1250 gr Historical control 87-97 Deulofeut 2006 92-100 Noori 2009 < 1000 gr 83-89 SUPPORT 2010 24-28 weeks 91-95 85-89 Saugstad and Aune, Neonatology 2010;100:1-8.

49 BPD and SpO2 Saugstad and Aune, Neonatology 2010;100:1-8.

50 ROP and SpO2 Saugstad and Aune, Neonatology 2010;100:1-8.

51 Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial Wolfgang Göpel, MD, Angela Kribs, MD, Andreas Ziegler, PhD, Reinhard Laux, MD, Thomas Hoehn, MD, Christian Wieg, MD, Jens Siegel, MD, Stefan Avenarius, MD, Axel von der Wense, MD, Matthias Vochem, MD, Peter Groneck, MD, Ursula Weller, MD, Jens Möller, MD, Christoph Härtel, MD, Sebastian Haller, MD, Bernhard Roth, MD, Egbert Herting, PhD and on behalf of the German Neonatal Network The Lancet September 30, 2011 Proportion of infants who receive no intubation (A), mechanical ventilation (B), and supplemental oxygen (C) during the first 28 days after birth Terms and Conditions

52 Randomized studies high or low SpO2 for ELBWI
SUPPORT BOOST 2 (UK, Australia, New Zealand) COT High % Low %

53 Mortality at 36 weeks PMA in High or Low SpO2 - Support + BOOST 2
Stenson B et al, NEJM, April 28, 2011 p 1681

54 Summary Postnatal oxygenation of ELBWIs
High SpO2 Increases severe ROP and BPD Fluctuations should be avoided – especially first 5 days Should not exceed 95% Low SpO2 increases mortality Is a SpO2 at 85% too low ? How to find the right balance of SpO2 between: 1) lowest mortality rate 2) lowest incidence of morbidity (BPD, ROP)? Randomized controlled trials are needed and one more large study is underway However, new studies would probably be needed 54

55 SpO % Vs % BPD 25% ROP 50% Mortality %

56 ROP BPD Mortality 89-93% ?? 91-95 % ?? SpO2 ?
What is the ”right” balance between mortality and morbidity? ROP BPD Mortality SpO ? 89-93% ?? 91-95 % ??


58 Oxygen saturation in ELBWIs revisited Updated recommendations
“This means that SpO2 of ELBWIs should not be targeted at 85-89 % until further data become available”. “This recommendation may be controversial knowing that even if mortality is slightly reduced it may lead to considerably higher rates of severe ROP and BPD”. “The SpO2 targets describing the optimal balance between mortality on one hand and complications such as ROP and BPD on the other is therefore presently not known”. “In fact, it may take several years until more precise information is available to guide clinical practice”. Saugstad, Halliday, Speer, Neonatology, October 2011 (editorial)

59 Conclusions It is best to initiate resusctiation of term babies with air The optimal FiO2 for resuscitation of ELGANs is not known. But do not use 100% oxygen, start low with 21 or 30% Low SaO2 (85%) beyond the DR probably reduces BPD and ROP But may increase mortality Do not target SaO2 between 85-89%

60 CPAP - Recommendations
CPAP should be started from birth in all babies at risk of RDS, such as those <30 wk not needing MV, until clinical status can be assessed (D). Short binasal prongs should be used rather than a single prong and a pressure of at least 6 cm water should be used (A). CPAP with early rescue surfactant should be considered in babies with RDS to reduce MV (A). The panel were unanimously in favour of maximising the use of CPAP. They recommended that CPAP should be initiated in all babies at risk of RDS, such as those less than 30 weeks gestation until their clinical status can be assessed. We should use short binasal prongs such as the Hudson prong and a pressure of at least 6 cm water should be applied. CPAP with early rescue surfactant should be considered in babies with RDS in order to reduce the need for mechanical ventilation.

61 Mechanical Ventilation Recommendations
MV should be used to support babies with respiratory failure as this improves survival (A). Avoid hypocarbia, as this is associated with increased risks of BPD and PVL (B). Settings of MV should be adjusted frequently with the aim of maintaining optimum lung volume (C). Duration of MV should be minimised to reduce injurious effect on the lung (B). The recommendations are that of course we should mechanical ventilation in babies with respiratory failure. If ventilating we should avoid hypocarbia as this is associated with increased of BPD and PVL. If ventilating we should adjust the settings frequently with the aim of maintaining optimum lung volume and we should aim always to minimise the duration of ventilation to reduce the risk of lung injury.

62 Avoiding or Reducing Duration of MV
Clear links between MV and development of BPD and neurological sequelae Interventions to avoid or shorten MV include: caffeine, CPAP or NIPPV with or without surfactant, INSURE technique, permissive hypercarbia and aggressive weaning with early extubation The present Guideline has a new section on avoiding or reducing duration of mechanical ventilation. There are clear links between mechanical ventilation and adverse outcome such as BPD and neurological sequelae. Interventions that have been employed to reduce the duration of mechanical ventilation include caffeine, CPAP or NIPPV, INSURE technique and permissive hypercarbia with aggressive weaning towards extubation

63 Avoiding or Reducing Duration of MV: Recommendations: 2010
Caffeine should be used to treat apnoea and to facilitate weaning from MV (A). It should also be considered for those at high risk of MV (e.g. <1250 g on CPAP or NIPPV) (B). CPAP or NIPPV should be used if possible to avoid MV through an endotracheal tube (B). Weaning from MV - reasonable to tolerate moderate hypercarbia provided pH > 7.22 (D). Synchronised and targeted tidal volume modes with aggressive weaning should be used (B). There is now grade A evidence from the CAP trial that Caffeine should be used to facilitate weaning from ventilation as it shortens duration of ventilation and improves long term outcomes. It should also be used in babies at high risk of needing ventilation such as those less than 1250 g on CPAP. Where possible babies should be maintained on CPAP or nasal ventilation to avoid mechanical ventilation. When weaning, it is reasonable to tolerate moderately high carbon dioxide levels provided the pH is maintained above When ventilating we should use synchronisation and targeted tidal volume modes if possible in order to minimise time on the ventilator.

64 Prophylactic Treatment for Sepsis: Recommendations: 2010
Antibiotics should be started in all babies with RDS until sepsis is ruled out. Penicillin or ampicillin with an aminoglycoside is commonest but units need to develop local protocols (D). Protocols should also be developed for antifungal prophylaxis in very preterm babies based on local incidence and risk factors (D). The panel recommended that antibiotics should be started in all babies with RDS until sepsis has been ruled out. The exact antibiotics will depend on local microbiological profiles but a suggested regimen is penicillen in combination with an aminoglycoside such as gentamicin. Protocols should also be developed for antifungal prophylaxis based on local incidence and risk factors

65 Supportive Care Temperature Control Fluid and Nutritional Management
Maintenance of Tissue Perfusion Management of Persistent Ductus Arteriosus Support of the Family The Guideline contains a broad section outlining some of the other issues that will need to be dealt with during management of RDS. These include temperature control, fluid and nutritional management, maintenance of tissue perfusion and management of the PDA along with support of the family

66 Temperature Control All efforts should be made to reduce heat loss
Use of polythene bags < 28 weeks reduces heat loss and may improve survival Incubators reduce insensible water losses compared to radiant warmers Servo-controlled temperature decreases mortality Recommendation: 2010 Maintain axillary temp 36.5 – 37.5 oC at all times (C) All efforts should be made to prevent hypothermia. Plastic bags in delivery suite clearly prevent hypothemia and may improve survival. Incubators should be used in preference to overhead warmers as these reduce insensible fluid losses and the use of servo-control is ideal as it has been shown to reduce mortality. The recommendations are that we use whatever means at our disposal to maintain a normal body temperature at all times

67 baby being placed in a plastic bag Very preterm
This picture is just to remind us what we should be doing in delivery suite, with babies being placed in plastic bags under the overhead radiant warmer during stabilisaton.

68 Fluid and Nutrition Management: Recommendations: 2010
Most babies should be started on mL/kg/day and nursed in high humidity (D). Fluid and electrolyte therapy should be tailored individually allowing a 2.5-4% daily weight loss (15% total) over first 5 days (D). Sodium intake should be restricted over first few days and initiated after onset of diuresis with careful monitoring of fluid and electrolyte levels (B). Full parenteral nutrition can be started on day 1 (A). May include protein 3.5 g/kg/day and lipid 3 g/kg/day in 10% dextrose. Minimal enteral feeding should be started from the first day (B). Early aggressive feeding is popular but level A evidence is lacking. It is recommended that we start fluids at about 70-80mL/kg/day and nurse initially in high humidity. Fluid and electrolytes should then be tailored individually allowing a small daily weight loss over the first 5 days. Sodium should initially be restricted with careful monitoring of fluid and electrolyte levels. Full TPN can be started on day 1. This may include protein of up to 3.5 g/kg/day and lipid up to 3g/kg/day in 10% dextrose. Minimal enteral feeding should also be started from the first day.

69 Maintenance of Tissue Perfusion: Recommendations: 2010
Treatment of hypotension is recommended when confirmed by evidence of poor tissue perfusion (C). Volume expansion with mL/kg normal saline as first line if myocardial dysfunction excluded (D). Dopamine (2-10 ug/kg/min) if volume expansion fails (B). Dobutamine (10-20 ug/kg/min) as first line and epinephrine ( ug/kg/min) if low systemic blood flow and myocardial dysfunction need to be treated (D). Hydrocortisone (1 mg/kg 8 hourly) in cases of refractory hypotension when conventional therapy has failed (B). Echo may help decisions when to start treatment for hypotension and what drug to use (B). The recommendations are that we should treat hypotension when it is confirmed by accompanying evidence of poor tissue perfusion, such as slow capillary refill, poor urine output and worsening base deficit. If myocardial dysfunction is unlikely, then it is reasonable to start with a single bolus of 10-20mL/kg of normal saline for volume expansion. If this fails, start dopamine as first line hypotensive management. If myocardial dysfunction suspected use doputamine first line and epinephrine second line. In cases of refractory hypotension hydrocortisone can be used. Echocardiography is increasingly being used to guide management, differentiating between hypovolaemia, myocardial dysfunction and effects of PDA.

70 Management of the Ductus Arteriosus
PDA may cause clinical problems for preterm babies with RDS Insufficient data on long-term outcomes when treating PDA with indomethacin, ibuprofen or surgical ligation. Treatment must be based on individual assessment Recommendations: 2010 If decision to try to close PDA then indomethacin or ibuprofen are equally effective (B). Pharmacological or surgical treatment of PDA must be based on assessment of clinical signs and echo findings suggesting poor tolerance of the PDA (D). The recommendations for the management of PDA are unchanged since the previous guideline. PDA may cause problems for babies with RDS but there are insufficient data on long term outcomes to make firm recommendations regarding whom and when to treat. If a decision is made to treat the ductus then indomethacin and ibuprofen appear equally efficacious. Pharmacological or surgical treatment of PDA must be based on assessment of clinical signs and echo findings suggesting poor tolerance of the PDA.

71 Miscellaneous Considerations
Babies at or near term, especially if born by elective caesarean section, can develop severe RDS. Some term babies with RDS may have genetic disorders (SP-B or ABCA3 deficiency). If pulmonary hypertension is present iNO may help, otherwise not. If pulmonary haemorrhage occurs surfactant may help at least transiently. Later surfactant therapy has not been shown to reduce or modify course of BPD. The present Guideline has a new section entitled miscellaneous considerations. Not all babies with RDS are preterm infants, and near term babies can also develop quite severe RDS, particularly if born by elective caesarean section. Occasionally babies have genetic mutations rendering them incapable of producing surfactant. Nitric oxide can be helpful in term babies with RDS if pulmonary hypertension is present. Surfactant may also be helpful in improving oxygenation in babies following pulmonary haemorrhage. Surfactant has been tried in BPD but results in only short term improvements in oxygenation

72 Miscellaneous Considerations: Recommendations: 2010
Elective caesarean section in low risk pregnancies should not be done < 39 wk (B). Inhaled NO is not beneficial in management of babies with RDS unless pulmonary hypertension is present in near term infants (A). Surfactant improves oxygenation in babies with pulmonary haemorrhages (C). Surfactant cannot be recommended for prevention of evolving BPD (C). Recommendations are that we should aim to reduce RDS by avoiding elective caesarean section before 39 completed weeks of gestation. We should only use inhaled nitric oxide in the setting of term or near term babies in whom pulmonary hypertension has been demonstrated. Surfactant may be used to improve oxygentation in babies with pulmonary haemorrage but not for babies with established BPD.

73 Summary – Management of RDS
Prenatal Care Delivery Room Stabilisation Surfactant, CPAP and Mechanical Ventilation Temperature Control Fluid Management Nutritional Support Management of PDA and Poor Tissue Perfusion Miscellaneous Considerations To summarise then, then Updated European consensus guideline contains recommendations in each of these areas

74 Thank You Thank you

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