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Management of Neonatal Respiratory Distress Syndrome European Consensus Guidelines 2010 Update Ola Didrik Saugstad, MD Department of Pediatric Research.

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Presentation on theme: "Management of Neonatal Respiratory Distress Syndrome European Consensus Guidelines 2010 Update Ola Didrik Saugstad, MD Department of Pediatric Research."— Presentation transcript:

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

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

3 European Consensus Guideline Panel Virgilio Carnielli Ancona, Italy Gorm GriesenCopenhagen, Denmark Henry Halliday Belfast, UK Mikko Hallman Oulu, Finland Eren OzekIstanbul, Turkey Richard Plavka Prague, Czech Republic Ola SaugstadOslo, Norway Umberto SimeoniMarseille, France Christian Speer Wurzburg, Germany David Sweet Belfast, UK (Secretary)


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

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

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

8 Chest radiograph before and after surfactant

9 RDS - Treatment Oxygen CPAP Mechanical ventilation Surfactant replacement Supportive Care

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

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 /

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

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

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).

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

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).

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 CO 2 detection (D). Plastic bags or occlusive wrapping under radiant warmers should be used for babies < 28 weeks’ gestation (A).

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

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

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 2 nd / 3 rd dose should be given if ongoing evidence of RDS such as persistent oxygen or MV need (A).

21 Comparison of Animal Derived Surfactants Surfacta nt Preparation/ Composition Phospholi pids Plasma logens *mol % SP- B mg/ml SP- C mg/ml Survanta (S 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 (Alveofact) Curosurf(C) Minced Porcine Lung Extract/DPPC, Polar lipids (Liquid Gel Chromatography) 99 % * High Plasmalogen content is associated with lower BPD rate. Rudiger et al. AJP 2005

22 Tracheal Aspirates with High Levels of Plasmalogens Associated with Lower BPD Rates Aspirates were collected prospectively from preterm infants ≤32 wks GA intubated within 1hr of birthAspirates were collected prospectively from preterm infants ≤32 wks GA intubated within 1hr of birth Rüdiger M, et al. Critical Care Med. 2000;28: BPD X X X X X X X X X X non BPD P<0.001 % DMAs on all Fatty Acids

23 Comparison of Animal Derived Surfactants Curosurf vs. Survanta (5 studies) Trials (6-10)SurfactantNTypePatient s Results Speer 1995 Curosurf vs. Survanta 73Tx g Curosurf: Lower FiO 2, PIP & h Baroutis 2003 Curosurf vs. Survanta vs. Alveofact 80Tx< 2000 g Curosurf: Fewer days on O 2 & PPV; Decreased LOS Ramanathan 2004 Curosurf vs. Survanta 293Tx g Curosurf: Lower FiO 2, Fewer doses, Decreased Mortality < 32 wks Malloy 2005 Curosurf vs. Survanta 58Tx< 37 wks Curosurf: Lower FiO2 up to 48 h, Fewer doses, lower volume Fujii, 2010Curosurf vs. Survanta 52Tx< 30 wks Curosurf: Faster weaning, Less Air-Leaks, PDA & MV at 72 hrs

24 Curosurf (n= 33) Survanta (n = 40) PIE3 %10 % PTX6.1 %12.5 % IVH Total21.2 %35 % IVH Gr. III-IV3 %12.5 % O 36 wks PCA 12.5 %11.4 % Mortality3 %12.5 % Speer C et al. Arch Dis Child 1995; 72: F8-F13 No Difference in Death or BPD Curosurf vs. Survanta – Rescue Trial (6)

25 Curosurf vs. Survanta – Rescue Trial (6) Changes in FiO 2, PIP & MAP FiO 2 Speer C et al. Arch Dis Child 1995; 72: F8-F13 PIP & MAP Faster Weaning

26 * * Data : Mean  SEM *,* = p < 0.05 FiO 2 vs. Time curves after the first dose of Surfactant (n=293) Trial #8 0 15’ 30’ 2 h 6 h FiO 2 Ramanathan R et al. AJP 21: ; 2004 Faster Weaning

27 % Infants % of Infants Requiring Additional Doses of Surfactant #8 * * p < % (C200) vs. 68 % (S100) received 2 or more doses Fewer Doses

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

29 Meta-analysis – Curosurf vs Survanta Trials (6&8)* OR( 95 % C.I. ) PTX , 1.53 O 36 wks , 1.74 PDA , 2.08 Pulmonary Hge , 3.21 IVH Gr. I-II , 2.96 IVH GR.III-IV , 1.53 Neonatal Mortality , 0.92 (* Speer et al. & *Ramanathan et al.) Halliday HL. Biol Neonate 2005; 87:317-22

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

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

32 Marsh W, Smeeding J, York JM, Ramanathan R, Sekar K. JPPT 9: ; 2004 Cost per patient: Curosurf vs. Survanta Cost / Patient ($) 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  53% (  $ 950)  46% (  $ 618)  20% (  $ 220)  20% (  $ 200) Cost Effective

33 Surfactant for RDS: Evidence Based Approach 1.Animal Derived Surfactants: Faster weaning of O 2, and MAP, Fewer air leaks, and Decreased Mortality when compared to synthetic Surfactants. 2.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 3.Best Timing: < 60 minutes of Age

34 Why Poractant Alfa (Curosurf)? 1.Highest amount of Phospholipids Lowering Surface Tension & Better anti- inflammatory effects 2.Phosphotidylcholine molecular species closely resembles human surfactant Better interaction with SP-B 3. Highest amount of SP-BRapid 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

35 What is the Right Dose? 3.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 1 st dose, & 100 mg/kg with 2 further doses (max. cumulative dose = 300 mg/kg) Higher (High) Dose: 200 mg/kg 1 st 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 wk29-31 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 FiO 2 > white CXR. Start Caffeine Delayed Rescue with 100 mg/kg if FiO 2 > white CXR Caffeine if symptomatic Redosing: FiO 2 > 0.30 How soon: 2-12 hrs from the 1 st dose Redosing: FiO 2 > 0.35 How soon: 12 hrs from the 1 st dose Redosing: FiO 2 > 0.40 How soon: 12 hrs from the 1 st dose

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

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).

39 What is new and why this topic? Stabilisation/Resuscitation: How to titrate FiO 2 if oxygen is needed? Optimal FiO 2 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 SpO 2 reduces ROP and BPD but increases mortality Consequences for clinical practice Previous reccommendations of SpO 2 targets should perhap be changed

40 Should we resuscitate extremely low birth weight infants with a low FiO 2 ?

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


43 SpO2 in extremely low gestational age neonates Time after birth (min) SpO2 (%) 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

46 TRANSITIONAL OXYGEN TRACKING SYSTEM Allowing to individualize FiO2 avoiding hyper/hypoxia Rich W et al non published data % 10%

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 ELBWI S. Of these 3 only are randomized

48 Studies regarding high or low SpO2 targets in VLBWI or ELBWIs – Characterisation of Studies Study GA w/BW g Study designHigh SaO 2 Low SaO 2 STOP ROP 2000Mean 25.4 wRandomized Tin 2001<28 weeksObservational Sun grSurvey>95≤ 95 BOOST <30 weeksRandomized Chow grObservational VanderVeen 2006≤28 weeks ≤ 1250 gr Historical control Deulofeut 2006≤ 1250 grHistorical control Noori 2009< 1000 grHistorical control SUPPORT weeksRandomized Saugstad and Aune, Neonatology 2010;100:1-8.

49 BPD and SpO2

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

51 Terms and Conditions 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

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

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

54 Summary Postnatal oxygenation of ELBWIs H igh SpO 2 Increases severe ROP and BPD  Fluctuations should be avoided – especially first 5 days  Should not exceed 95% L ow SpO 2 increases mortality  Is a SpO 2 at 85% too low ? How to find the right balance of SpO 2 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

55 SpO % Vs % BPD 25% ROP 50% Mortality 20%

56 SpO 2 ? 89-93% ?? % ?? What is the ”right” balance between mortality and morbidity?


58 Oxygen saturation in ELBWIs revisited Updated recommendations Updated recommendations “This means that SpO 2 of ELBWIs should not be targeted at % 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 SpO 2 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 Conclusions It is best to initiate resusctiation of term babies with airIt is best to initiate resusctiation of term babies with air Low SaO 2 (85%) beyond the DRLow SaO 2 (85%) beyond the DR probably reduces BPD and ROP But may increase mortality Do not target SaO 2 between 85-89% The optimal FiO 2 for resuscitation of ELGANs isThe optimal FiO 2 for resuscitation of ELGANs is not known. But do not use 100% oxygen, start low not known. But do not use 100% oxygen, start low with 21 or 30% with 21 or 30%

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).

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).

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

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).

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).

65 Supportive Care Temperature Control Fluid and Nutritional Management Maintenance of Tissue Perfusion Management of Persistent Ductus Arteriosus 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 o C at all times (C)

67 Very preterm baby being placed in a plastic bag

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.

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).

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).

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.

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).

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

74 Thank You

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