The Optimization of Preterm Newborn Resuscitation Ola Didrik Saugstad Dep of Pediatric Research & Ann and Robert H. Lurie Children’s Hospital of Chicago / Feinberg School of USA

1 Outline

1. Need of ventilation 2. Resuscitation algorithms 3. Oxygen in DR 4. Recommendations for use of oxygen

5. SpO2 and HR at 5 min as predictors 6. Heat loss prevention DISCLOSURE STATEMENT

Dr. Ola Didrik Saugstad has disclosed the following financial relationships. Any real or apparent conflicts of interest related to the content of this presentation have been resolved.

Affiliation / Financial Interest Organization An unrestricted grant Chiesi Farmaceutici Reseach grants Laerdal Medical Interventions in term or near term newborn in the delivery room

INTERVENTION FREQUENCY

130 mill Assess baby’s response to birth 100/100 Dry, keep baby warm, position correctly B Stimulate to breathe by drying A 20 mill Clear airways – only if needed 15/100 S I Establish effective bag & mask ventilation C 4-6 mill Start with air 3 – 5/100 2 mill Endotracheal intubation 2/100 A Provide chest compressions 0.8 mill D with oxygen < 1/1000 Adrenaline 6/10 000 V 0.8 mill A Volume N 0.1 mill expansion 1/12000 C E D

Saugstad OD 2016 29-34 w

Variable Routine O2/CPAP Bag/Mask ET CPR Level % 24 32.5 26.1 14.7 2.7 GA w OR 0.55 (0.51-0.59) 0.52 (0.48-0.55 0.37 (0.34-0.41) 0.41 (0.35-0.48 Multiples OR 1.29 (1.05-1.59) 0.95 (0.79-1.13) 0.69 (0.55-0.86) 0.40 (0.22-0.73) ANS OR 0.69 (0.53-0.89) 0.77 (0.58-1.01) 0.56 (0.41 -0.77) 0.22 (0.12-0.34) Death % 0.6 1.0 1.6 7.2 21.0

Bajaj M et al J Pediatr 2018;195:33-8

Need of CPR in 500-1500 g

6% with survival 63% Vs 89% not needing CPR Finer NN et al Pediatrics1999;104:428-34 eNewborn

Summary of Data 2014-16 eNewborn: Networking with Modern Technology

Dominique Haumont Brussels Decomposition of Infant Mortality

GA Early Neonatal Late Neonatal Early Postneonatal Late Postneonatal Infant mortality

Died Total Died Total Died Total Died Total Died Total

22 16 37 7 21 2 14 1 12 26 37

23 205 698 103 493 60 390 3 330 371 698

24 316 1700 167 1384 104 1217 4 1113 591 1700

25 235 2138 142 1903 93 1761 3 1668 473 2138

26 172 2602 115 2430 84 2315 5 2231 376 2602

27 119 3179 60 3060 56 3000 1 2944 236 3179

28 115 4049 62 3934 53 3872 2 3819 232 4049

29 91 4743 44 4652 25 4608 1 4583 161 4743

30 84 6111 38 6027 13 5989 1 5976 136 6111

31 78 7818 24 7740 24 7716 0 7692 126 7818

32 41 5272 34 5231 25 5197 0 5172 100 5272

Total 1472 38347 796 36875 539 36079 21 35540 2828 38347 D i s t r i b u t i o n p e r G e s t a t i o n a l W e e k

1 0 0 0 0

8 0 0 0 r

e 6 0 0 0

b m

u 4 0 0 0 n

2 0 0 0

0

2 2 2 3 2 4 2 5 2 6 2 7 2 8 2 9 3 0 3 1 3 2

G e s t a t i o n a l a g e w e e k s eNewborn: Total 38347 infants 22-32 Weeks Gestational Age 2014-16 European Data base – E newborn N e o n a t a l M o r t a l i t y

8 0

6 0

4 0 %

2 0

0

2 3 4 5 6 7 8 9 0 1 2 2 2 2 2 2 2 2 2 3 3 3

G e s t a t i o n a l a g e w e e k s R i s k o f N e o n a t a l M o r t a l i t y

6 0 )

I 4 0

C

%

5 9

( 2 0

R O

0

2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

G e s t a t i o n a l a g e w e e k s I n f a n t M o r t a l i t y

8 0

6 0

4 0 %

2 0

0

2 3 4 5 6 7 8 9 0 1 2 2 2 2 2 2 2 2 2 3 3 3

G e s t a t i o n a l a g e w e e k s M o r t a l i t y

8 0 N e o n a t a l

I n f a n t 6 0

4 0 %

2 0

0

2 3 4 5 6 7 8 9 0 1 2 2 2 2 2 2 2 2 2 3 3 3

G e s t a t i o n a l a g e w e e k s R e s u s c i t a t i o n p e r g e s t a t i o n a l w e e k

1 0 0 B a s i c R e s u s c i t a t i o n

8 0

6 0 % 4 0

2 0

0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

w e e k s G A R e s u s c i t a t i o n p e r g e s t a t i o n a l w e e k

1 0 0 A d v a n c e d R e s u s c i t a t i o n

8 0 B a s i c R e s u s c i t a t i o n

6 0 % 4 0

2 0

0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

w e e k s G A R e s u s c i t a t i o n p e r g e s t a t i o n a l w e e k

1 0 0 9 1 % A d v a n c e d R e s u s c i t a t i o n

8 0 B a s i c R e s u s c i t a t i o n 5 9 %

6 0

4 9 % % 4 0

2 0 5 % 8 %

0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

w e e k s G A R e s u s c i t a t i o n p e r g e s t a t i o n a l w e e k

1 0 0

8 0

6 0 % 4 0

2 0

0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

w e e k s G A R e s u s c i t a t i o n p e r g e s t a t i o n a l w e e k

1 0 0

8 0

6 0 % 4 0

2 0 9 2 9 6 9 7 9 6 9 5 9 2 8 8 8 2 7 3 5 7

0 2 2 2 4 2 6 2 8 3 0 3 2 3 4

w e e k s G A R i s k o f D e a t h : R e s u s c i t a t i o n

3 ) I O R : 1 . 9 5 9 5 % C I ( 2 . 4 3 - 1 . 5 7 )

C 2

%

5

9

(

R 1 O

A d v a n c e d B a s i c

0 ILCOR 2015 ILCOR changes 2010 -2015

1.Support of transition, not automatically resuscitation

2.Cord clamping For uncompromised infants, a delay of cord clamping ≥ 1 min

3. Body temperature For non-asphyxiated infants 36.5-37.5oC

4.Maintenance of temperature < 32 wk 36.5-37.5oC maintained by warmed humidified resp gases, increased room temperature (< 28 wk >25oC, plastic wrapping, cap, thermal mattress )

5. Optimal assessment of heart rate Suggest use of ECG in resuscitation

6. Meconium stained amniotic fluid –non-vigerous infant Intubation only for suspected tracheal obstruction

7. Air/Oxygen Term infants start with 21%. Preterm 21- 30%

8. Continuous Positive Airways Pressure (CPAP) CPAP rather than intubation for spontaneously breathing preterm infants

9. Hypothermia therapy in low income settings cooling with ice packs

Saugstad OD, 2016 The Premature Infant CPAP and IPPV Treatment Recommendation For spontaneously breathing preterm infants with respiratory distress requiring respiratory support in the delivery room, we suggest initial use of CPAP rather than intubation and IPPV weak recommendation, moderate-quality evidence.

ILCOR 2015 Ventilation Strategies in the Delivery Room

Treatment Recommendation • We suggest against the routine use of initial sustained inflation (greater than 5 seconds duration) for preterm infants without spontaneous respirations immediately after birth, but an SI may be considered in individual clinical circumstances or research settings weak recommendation, low-quality evidence.

ILCOR 2015 Oxygen Concentration for Resuscitating Premature Newborns

Treatment Recommendations • We recommend against initiating resuscitation of preterm newborns (less than 35 weeks of gestation) with high supplementary oxygen concentrations (65%–100%).

• We recommend initiating resuscitation with a low-oxygen concentration (21%–30%) strong recommendation, moderate-quality evidence.

ILCOR 2015 Changes in the international recommendations on neonatal stabilisation and resuscitation (2015)

Sarrato GZ, García ES,Maldonado JA, Robles CG, Thió Lluch M, Iriondo M, Grupo de Reanimación Neonatal de la Sociedad Española de Neonatología Anales de Pediatria 2016

Neonatology.2018;114:112-123. Neonatology.2018;114:112-123. Need of Resuscitation 22-32 weeks Preterm Newborn Resuscitation

What about oxygen? High versus low initial FiO2

Updated Review & Meta-analysis for Preterm Infants

High FiO2: 60-100% O2

Low FiO2: 21-30% O2 Initial FiO2 Level Does not Influence Death in Preterm Infants

Hospital Death RR 0.99 95% CI 0.52-1.91) Oei JL, Vento M, Rabi Y, Wright I, Finer N, Rich W, Kapadia V, Aune D, Rook D, Tarnow-Mordi W, Saugstad OD. Arch Dis Child Fetal Neonatal Ed 2017;102:F24-F30 Secondary outcomes: low Vs high initial FiO2

NB! Study not powered For 2nd outcomes

Oei JL, Vento M, Rabi Y, Wright I, Finer N, Rich W, Kapadia V, Aune D, Rook D, Tarnow-Mordi W, Saugstad OD. Arch Dis Child Fetal Neonatal Ed 2017;102:F24-F30 Secondary outcomes: low Vs high initial FiO2

NB! Study not powered For 2nd outcomes

Oei JL, Vento M, Rabi Y, Wright I, Finer N, Rich W, Kapadia V, Aune D, Rook D, Tarnow-Mordi W, Saugstad OD. Arch Dis Child Fetal Neonatal Ed 2017;102:F24-F30 TORPIDO Patient recruitment.

Infants <32 w GA Randomized to Air or 100% O2 No difference in mortality for all babies < 28 w Mortality RA: 17% 100% O2: 6% RR 3.9 (95% CI 1.1-13.4)

Oei JL, Saugstad OD et al. 2017;139:e20161452 Recommendations of FiO2 and Resuscitation of Newborns

Term and near term infants Start with air - adjust according to SpO2 OR for mortality 0.69 ( 0.54-0.88) in favour of air Preterm 28-31 weeks GA Start with 21-30% - adjust according to SpO2 OR for mortality 1.9 (0.33- 11.1) Preterm < 28 weeks GA Don’t start with 21% Start with 30% - adjust according to SpO2 OR for mortality 5.3 (1.35-20)

OD Saugstad 2017 JL Oei et al 2018 Datakindly provided by B. Arjan te Pas B. Hooper Stuart and Breathing rate (bpm) % of time glottis open Why doimmature infants needinitial oxygen? Pretermrabbit kittens (29d GA ) Development of SpO2 8 studies N=768 GA < 32 w

Outcomes of oxygen saturation targets during delivery room stabilisation of preterm infants Oei, J L, Finer N, Saugstad OD, Wright I, Rabi Y, Tarnow-Mordi W, Rich, W, Kapadia V, Rook D, Vento M. Arch Dis Child Fetal Neonatal ed 2017;F1-F9 The Impact of 5 min SpO2

05:00 Torpido Trial Non-randomised exploratory analyses in the cohort

Association of clinical variables with death or disability aOR 95% CI p

FiO2 1.0 0.71 0.36-1.37 0.31 5 minute SpO2 0.50 0.26-0.98 0.04 >80% Male 1.69 0.93-3.09 0.08 28-31+6 weeks 0.44 0.23-0.86 0.01 IVH >/= grade3 2.84 1.32-6.12 0.008 BPD 1.08 0.53-2.12 0.84

Oei, J L, Finer N, Saugstad OD, Wright I, Rabi Y, Tarnow-Mordi W, Rich, W, Kapadia V, Rook D, Vento M. Arch Dis Child Fetal Neonatal ed 2017; Torpido Trial Non-randomised exploratory analyses in the cohort

Bayley III scores in infants not reaching SpO2 > 80% at 5 mins Survivors SpO2 <80% SpO2 > 80% OR (95% CI) p BSID Scores - Survivors 28-31+6 weeks N= 26 N= 31 gestation Cognitive 95.4 (12.4) 100.8 (12.5) 0.02

Language 93.2 (15.4) 96.7 (14.5) 0.22

Motor 94.3 (11.0) 96.4 (13.3) 0.38

Age of test 38.6 (6.9) 26.1 (7.3) 0.06 (months) Any BSID >1SD 15/44 (34%) 14/67 (21%) 1.33 (0.89-2.01) 0.13 below mean Outcomes of Babies Who Do Not Reach SpO2 80% at 5 minutes

OR 2.4 (1.3-4.4) OR 4.5 (2.1-9.8)

Oei JL et al Saturation at 5 minutes •Almost 50% of infants < 32 weeks do not

reach SpO2 study targets at 5 minutes of age

•Those who do not reach SpO2 80% by 5 minutes are at increased risk of death and IVH

•Randomized studies to test signifcance of saturation at 5 min of age highly needed Oei, J L, Finer N, Saugstad OD, Wright I, Rabi Y, Tarnow-Mordi W, Rich, W, Kapadia V, Rook D, Vento M. Arch Dis Child Fetal Neonatal ed 2017; The Impact of Heart Rate at 5 min

05:00 Impact of Bradycardia after Birth on Neonatal Morbidity and Mortality in Preterm Infants BradyPrem Study Objective: To study the incidence of bradycardia in preterm infants < 32 weeks GA in the delivery room and its impact on neonatal morbidity and mortality. Non-randomized data

.No Bradycardia: No HR value recorded < 100 bpm .Transient Bradycardia: HR < 100 bpm for ≤ 1 minute .Prolonged Bradycardia: HR < 100 bpm for ≥ 2 minutes

Vishal Kapadia, MD University of Texas Southwestern Medical Ctr Neonatal Resuscitation Tuesday May 8th 12.15-2.15 # 107 Prolonged Bradycardia and Initial FiO2

Kapadia V et al in preparation Impact of Prolonged Bradycardia on Mortality

Kapadia V et al in preparation Duration of Bradycardia and Mortality Heart rate at 5 minutes •Those who did not reach HR of 100 bpm by 5 minutes were at increased risk of death (observational data)

•Randomized studies to test significance of heart rate at 5 min of age highly needed

Khapadia et al in preparation HEAT LOSS! ILCOR 2015 HEAT LOSS PREVENTION Placing or covering infants with an occlusive wrap immediately after birth will reduce the incidence of hypothermia and result in decreased morbidity and mortality. Prevention of hypothermia at birth – Plastic wrap versus routine care

Death within hospital stay

McCall EM, Alderdice F, Halliday HL, Jenkins JG, Vohra S. Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004210. do Prevention of hypothermia at birth – Plastic wrap versus routine care

Major brain injury

McCall EM, Alderdice F, Halliday HL, Jenkins JG, Vohra S. Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004210. do Randomized Trial of Occlusive Wrap for Heat Loss Prevention in Preterm Infants

36.3 Vs 35.7 oC 36.6 Vs 36.2 oC

Mortality rates of all infants according to baseline and poststabilization temperature. No effect on mortality of wrapping! OR 1.0 (95% CI 0.7-1.5) Less pulmonary hemorrhage

Maureen C. Reilly , .et al The Journal of Pediatrics, Volume 166, Issue 2, 2015, 262 - 268.e2 Thermal care for preterm newborns 7.0: Kangaroo mother care is recommended for the routine care of neonates weighing ≤2000g at birth as soon as they are clinically stable. 7.1 Neonates weighing ≤2000g at birth should be provided as close to continuous Kangaroo mother care as possible. 7.2 Intermittent Kangaroo mother care, rather than conventional care is recommended for newborns weighing ≤2000g at birth, if continuous Kangaroo mother care is not possible.

2015 Thank you so much for your attention!