1. The Golden Hour Debates
Giving High-risk Neonates the Best Possible Start
Michael S. Dunn, MD, FRCPC
Sunnybrook Health Sciences Centre
Toronto, Ontario, CANADA
Neil N. Finer, MD
UCSD
San Diego, CA

2. Prophylactic Surfactant or CPAP for ELBW Neonates
Resolved that:
Initial respiratory management of ELBW neonates should include intubation and prophylactic surfactant
Pro – Michael Dunn
Con – Neil Finer

3. Canadian Flag and map

6. Prophylactic Surfactant or CPAP for ELBW Neonates
Resolved that:
Initial respiratory management of ELBW neonates should include intubation and prophylactic surfactant
Pro – Michael Dunn
Con – Neil Finer

7. Outline RDS and surfactant The arguments for prophylactic surfactant
Guidelines and “Best Practices”
CPAP instead of prophylactic surfactant
When should we use prophylactic surfactant in 2011?

8. What do we Know?
RDS is the leading cause of mortality and morbidity in preterm infants
Surfactant deficiency is the major cause of RDS
The risk of RDS and related complications increases with decreasing gestational age
Surfactant replacement therapy is highly effective in reducing mortality and RDS related morbidity

9. Timing of Surfactant Treatment
Prophylactic
Treatment shortly after birth of a selected group of infants regardless of individual presentation
Delayed Selective
Treatment of infants only after a period of observation reveals evidence of “significant” RDS

11. RESPONSE TO SURFACTANT TREATMENT: PHYSIOLOGY

12. SURFACTANT THERAPY: EVIDENCE FROM TRIALS
EFFECT ON NEONATAL MORTALITY
Decreased
Risk
Increased
COMPARISONS
Number of Studies
0.2
0.5
1.0
2.0
4.0
DELIVERY ROOM SURFACTANT v. NO SURFACTANT
SYNTHETIC SURFACTANT 7
NATURAL SURFACTANT 8
SURFACTANT TREATMENT v. NO SURFACTANT
SYNTHETIC SURFACTANT 5
NATURAL SURFACTANT 12
0.2
0.5
1.0
2.0
4.0
Soll, 1997
Typical Relative Risk and 95% CI

13. SURFACTANT THERAPY: EVIDENCE FROM TRIALS
EFFECT ON PNEUMOTHORAX
Decreased
Risk
Increased
COMPARISONS
Number of Studies
0.2
0.5
1.0
2.0
4.0
DELIVERY ROOM SURFACTANT v. NO SURFACTANT
SYNTHETIC SURFACTANT 6
NATURAL SURFACTANT 8
SURFACTANT TREATMENT v. NO SURFACTANT
SYNTHETIC SURFACTANT 5
NATURAL SURFACTANT 12
0.2
0.5
1.0
2.0
4.0
Soll, 1997
Typical Relative Risk and 95% CI

14. SURFACTANT THERAPY: EVIDENCE FROM TRIALS
EFFECT ON BPD OR DEATH
Decreased
Risk
Increased
COMPARISONS
Number of Studies
0.2
0.5
1.0
2.0
4.0
DELIVERY ROOM SURFACTANT v. NO SURFACTANT
SYNTHETIC SURFACTANT 4
NATURAL SURFACTANT 7
SURFACTANT TREATMENT v. NO SURFACTANT
SYNTHETIC SURFACTANT 4
NATURAL SURFACTANT 10
0.2
0.5
1.0
2.0
4.0
Soll, 1997
Typical Relative Risk and 95% CI

15. What about Timing?
Is it better to provide surfactant to infants at high risk of RDS shortly after delivery rather that wait until they exhibit signs of significant disease?

16. Prophylactic Surfactant Therapy Potential Advantages
Facilitation of initial lung aeration and reabsorption of lung liquid
Decreased baro/volutrauma
Improved distribution of administered surfactant

17. Prophylactic Surfactant Advantages
Facilitation of initial lung aeration and reabsorption of lung liquid

18. Prophylactic Surfactant Advantages
Decreased baro/volutrauma

19. Prophylactic Surfactant Advantages
Improved distribution of administered surfactant

20. Prophylactic Surfactant Therapy Potential Disadvantages
Increased cost
Increased exposure
Destabilization at critical time
Necessitates endotracheal intubation
Adverse physiologic effects of laryngoscopy
Trauma to upper airway
Risk of barotrauma/volutrauma
Inadvertent hyperventilation

21. Prophylactic vs Selective Surfactant
EFFECT ON NEONATAL MORTALITY
Decreased
Risk
Increased
STUDY
0.2
0.5
1.0
2.0
4.0
Kendig 1991
Dunn 1991
Egberts 1993
Kattwinkel 1993
Walti 1995
Bevilacqua 1996
Bevilacqua 1997
TYPICAL ESTIMATE
0.2
0.5
1.0
2.0
4.0
Soll 2001
Relative Risk and 95% CI

22. Prophylactic vs Selective Surfactant EFFECT ON PNEUMOTHORAX
Decreased
Risk
Increased
STUDY
0.2
0.5
1.0
2.0
4.0
Kendig 1991
Dunn 1991
Egberts 1993
Kattwinkel 1993
Walti 1995
Bevilacqua 1996
TYPICAL ESTIMATE
0.2
0.5
1.0
2.0
4.0
Soll 2001
Relative Risk and 95% CI

23. Reviewers' Conclusions
Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge "at risk" infants who would require prophylactic surfactant administration.

24. Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics Feb;121(2):
Surfactant should be given to infants with respiratory distress syndrome as soon as possible after intubation irrespective of exposure to antenatal steroids or gestational age.
Prophylactic surfactant replacement should be considered for extremely preterm infants at high risk of respiratory distress syndrome, especially infants who have not been exposed to antenatal steroids.

26. PBP 4
Administer surfactant as soon as possible after birth for eligible infants
Develop guidelines and criteria for your unit for prophylactic surfactant administration
Ensure that surfactant is available in the delivery room or in a location close to the delivery room
When the delivery of an infant who is eligible for prophylactic surfactant is expected, start warming the surfactant before the infant is born
Do not wait for X-ray confirmation of endotracheal tube positioning before giving surfactant. Use the depth of endotracheal tube insertion, by palpation (Jain 2004) of the endotracheal tube, and symmetry of breath sounds to confirm that the tube is in the appropriate tracheal location
Do not wait to complete umbilical catheter placement and obtain radiographs before giving surfactant
Develop local guidelines for ‘rescue’ surfactant in infants who do not qualify for prophylactic surfactant
Educate staff about the importance of early administration of surfactant

27. “New” Evidence CPAP instead of prophylactic surfactant
Is there evidence to support a change to the guidelines?
Should we be using CPAP as our first line approach to the initial respiratory management of preterm babies?

28. Avery et al, Pediatrics 1987
Comparison of death and CLD (oxygen at 28 days) in babies g

29. Early Nasal CPAP What is the Evidence?
Inter-institutional benchmarking studies
Avery 1987
Van Marter 2000
Vanpee 2007
Descriptive, cohort or before/after studies
Jacobsen 1993
Kamper 1993
Gittermann 1997
Lindner 1999
DeKlerk 2001
Narendran 2003
Ammari 2005
Lopez Maestro 2006

30. NASAL CPAP and OUTCOME OF PRETERM INFANTS
Comparison of clinical outcome before (n=57) and after (n=59) introduction of nasal continuous positive airway pressure
De Klerk AM and De Klerk RK. J Paediatr Child Health 2001

31. Intriguing, but level of evidence is low…..

32. The CPAP vs Intubation RCTs
CPAP or Intubation (COIN) Trial
Surfactant, Positive Pressure, Oxygenation Randomized Trial (SUPPORT)
VON Delivery Room Management Trial

33. Clinical Trials nCPAP versus DR Intubation
Study
Patients N
Death / BPD
CPAP
ETT
Other Findings with CPAP
COIN
25-28 wk
Vigorous
610
.80 ( )
59 %
Inc. air leak
Inc. mort (NS) wk
75% of intubated babies given surf
SUPPORT
24-27 wk
1316
.91 ( )
83%
Dec. mort wk
Air leak similar
DRM
26-29 wk
Liveborn
648
.83 ( )
52%
Dec. mort (NS)

34. Conclusions COIN SUPPORT VON DRM
In infants born at 25 to 28 weeks’ gestation, early nasal CPAP did not significantly reduce the rate of death or BPD, as compared with intubation. Even though the CPAP group had more incidences of pneumothorax, fewer infants received oxygen at 28 days, and they had fewer days of ventilation.
SUPPORT
The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants.
VON DRM
Preterm neonates in this trial who were initially managed with either nCPAP or prophylactic surfactant with rapid extubation to nCPAP had similar clinical outcomes to those treated with prophylactic surfactant followed by a period of mechanical ventilation. An approach that utilizes early nCPAP leads to a reduction in the number of infants who are intubated and given surfactant.

35. So we can do whatever we want!
WooHoo!

36. But……
Are there any circumstances in which surfactant prophylaxis is likely to be the preferred approach?

37. Reviewers' Conclusions
Prophylactic surfactant administration to infants judged to be at risk of developing respiratory distress syndrome (infants less than weeks gestation), compared to selective use of surfactant in infants with established RDS, has been demonstrated to improve clinical outcome. Infants who receive prophylactic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, it remains unclear exactly which criteria should be used to judge "at risk" infants who would require prophylactic surfactant administration.

38. Questions What about the highest-risk babies?
If an elective nCPAP approach is taken, might some infants be disadvantaged by a delay in delivery of surfactant?
How do we decide who might benefit from intubation and prophylactic surfactant versus a trial of CPAP?

39. Let’s look at the smallest, most immature babies…..

40. Surfactant Treatment and Endotracheal Intubation by Gestation Age
Gestational Age (weeks)

42. Initial Stabilization
Columbia weeks GA 87
Initial Stabilization 27 60
Intubation
CPAP 33 27
Failure
Success
Ammari et al. J Pediatr 2005

44. Outcome at 36 weeks percent Dead or oxygen Died Oxygen 25/26 27/28

45. PULMONARY AIR LEAK
P=0.001

47. Clinical Trials nCPAP versus DR Intubation
Study
Patients N
Death / BPD
CPAP
ETT
Other Findings with CPAP
COIN
25-28 wk
Vigorous
610
.80 ( )
59 %
Inc. air leak
Inc. mort (NS) wk
75% of intubated babies given surf
SUPPORT
24-27 wk
1316
.91 ( )
83%
Dec. mort wk
Air leak similar
DRM
26-29 wk
Liveborn
648
.83 ( )
52%
Dec. mort (NS)

48. The Surfactant Positive Airway Pressure And Pulse Oximetry Trial In ELBW Infants (SUPPORT) - NICHD
RR (95% CI)
0.74 (0.57, 0.98)
P = 0.03
percent
P <
Finer. NEJM 2010 48

49. So, what are the arguments?
Surfactant administration as soon after birth as is feasible and safe provides the best opportunity to evenly expand and stabilize the surfactant deficient lung
This can be achieved by intubation and administration of prophylactic surfactant shortly after birth
Most preterm infants born at less than 26 weeks’ require intubation at some point in their clinical course anyway

50. Conclusions
Although often successful in allowing preterm neonates to avoid intubation, initial management with nCPAP will result in a delay in the administration of surfactant to many surfactant deficient infants
This delay can result in an increased risk of air leak and other complications of prematurity
Intubation with surfactant prophylaxis should remain the preferred approach to the initial respiratory management of the highest-risk preterm neonates (ie. those born at less than 26 weeks’ gestation)

52. CPAP and Surfactant
Should very preterm infants be treated with elective intubation, surfactant and a period of ongoing MV or stabilized on nCPAP with later selective surfactant?
Should very preterm infants be treated with elective intubation, surfactant and rapid extubation to nCPAP or stablilized on nCPAP with later selective surfactant?
If an infant is initially stabilized on nCPAP, what criteria should be used for selective surfactant treatment?

53. Clinical Trials ISX versus nCPAP
Study
Patients N
Death / BPD MV
Other Findings
Rojas et al
27-31 wk
RDS
279
.86 ( )
.69 ( )
No diff in MV, BPD in lower GA group.
Very high BPD rate
CURPAP
25-28 wk
Vigorous
208
1.03 ( )
.95 ( )
Dec. air leak with nCPAP (NS).
Very low BPD rate
DRM
26-29 wk
Liveborn
648
.94 ( )
1.14 ( )
ISX similar to CPAP
Air leak similar
?Conclusion:

54. Angela Kribs MD Cologne, Germany
Combining the Art of Gentle Resuscitation and Surfactant Administration
Angela Kribs MD
Cologne, Germany

55. Respiratory management of RDS (n=155)%
They observed an increase of the use of CPAP as primary respiratory support over time from 65 on 95% and at the same time a decrease of mechanical ventilation as primary respiratory support and also during the course of RDS in the first 72 hrs of live.

56. Outcome of preterm infants < 1000 g and < 27 weeks%
With the use of the new method we could reach a survival rate of 80% of all live born infants for infants with a GA 23 to 25 weeks and of 90 % for infants of 26 weeks. Survival without neonatal complications increased with increasing GA.
Gestational Ages