2. High flow nasal cannulae: Evidence base in preterm infants
Peter Davis
Melbourne
Australia

3. Where does HFNC fit in the spectrum of non-invasive ventilation?OR
Where does HFNC fit in the spectrum of non-invasive ventilation?

4. “THE FACTS MA’AM, JUST THE FACTS”

5. CPAP
The Gold Standard

7. RECOMMENDATION
CPAP immediately after birth with later selective surfactant administration is an alternative to routine intubation and surfactant administration in preterm infants (Level of Evidence: 1, Strong Recommendation)
If it is likely that respiratory support with a ventilator will be needed, early administration of surfactant followed by rapid extubation is preferable to prolonged ventilation (Level of
Evidence: 1, Strong Recommendation)

8. NCPAP immediately after extubation for preventing morbidity in preterm infants
Outcome:
Failure
Study
NCPAP
Headbox
RR (fixed)
RR (fixed)
or sub-category
n/N
n/N
95% CI
95% CI
Engelke 1982
0/ /9
0.08 [0.00, 1.19]
Higgins 1991
7/ /29
0.30 [0.16, 0.60]
Chan 1993
19/ /60
0.86 [0.52, 1.42]
Annibale 1994
15/ /42
0.93 [0.54, 1.59]
So 1995
4/ /25
0.31 [0.12, 0.81]
Tapia 1995
7/ /30
3.62 [0.82, 16.01]
Davis 1998
16/ /45
0.57 [0.36, 0.90]
Dimitriou 2000
15/ /75
0.60 [0.34, 1.04]
Peake 2005
16/ /48
0.65 [0.40, 1.07]
Total (95% CI)
0.62 [0.51, 0.76]
Total events: 99 (NCPAP), 159 (Headbox)
Test for heterogeneity: Chi² = 17.93, df = 8 (P = 0.02), I² = 55.4%
Test for overall effect: Z = 4.58 (P < )
0.1
0.2
0.5 1 2 5 10
Favours NCPAP
Favours Headbox
Treat 6 babies to prevent 1 failure

9. The Contender
HFNC

10. The battleground Primary therapy: prophylaxis/treatment of RDS
Post-extubation care
(Apnea)
(Weaning from CPAP)

11. Some tertiary NICUs have stopped using nasal CPAP as routine therapy
WHO IS USING HFNC?
2/3 of US academic units
Hochwald, J of Neonatal-Perinatal Medicine, 2010
2/3 of Australia and NZ NICUs
Hough, J Paediatr Child Health, 2012
>80% of UK NICUs
Nath, Pediatrics International, 2010
50% of level 2 and 33% of level 1 SCNs in the UK use HFNC (either humidified or not)
Nath, Pediatrics International, 2010
Some tertiary NICUs have stopped using nasal CPAP as routine therapy

12. Australia NZ Neonatal Network
First included data on HFNC use in 2009
Blended air and oxygen, >1 L/min, ≥4 hours

13. Why are HFNC being used? ‘easy to use’ ‘babies more settled’ ‘safe’
‘less “CPAP belly”’
‘decreases WOB’
‘less nasal trauma’
‘nurses love it’
‘no pneumothoraces’

14. Perceptions of HFNC in comparison to NCPAP
Nursing Perceptions
Perceptions of HFNC in comparison to NCPAP
Roberts, Journal of Paediatrics and Child Health, 2014

15. Nursing Perceptions
Which mode of post-extubation support would you rather use for these infants?
Chosen support: 24 weeks 91% CPAP, 26 weeks 79% CPAP, 28 weeks 77% HFNC, 30 weeks 93% HFNC

16. Parental Preference
Klingenberg, ADC 2013

17. COCHRANE REVIEW (2011) Wilkinson, Andersen, O’Donnell and De Paoli
“Insufficient evidence to establish the safety or effectiveness of HFNC… in preterm infants”

18. COCHRANE REVIEW (2011) Wilkinson, Andersen, O’Donnell and De Paoli
“Further adequately powered RCTs should be undertaken in preterm infants comparing HFNC with NCPAP…”

19. Popularity outstripped the evidence

20. High flow as primary therapy

21. Yoder, Pediatrics 2013 Multicentre RCT
141 infants (primary therapy) ≥28 weeks and ≥1000g
Randomized in 1st 24 hrs
HFNC: Comfort Flo, Vapotherm, F&P
NCPAP: Bubble, ventilator, SiPAP
No significant difference in intubation <72 hours: 9/75 for NCPAP, 6/66 for HFNC

22. Kugelman, Pediatr Pulmonol 2014
Single centre RCT
76 infants <35 weeks’ gestation
Randomised to HFNC or NIPPV from birth
No significant difference in intubation
13/38 (34.2%) for NIPPV, 11/38 (28.9%) for HFNC

23. High flow for Post extubation care

24. Collins, J Pediatr 2012 Single centre RCT
Device: Vapotherm vs Hudson binasal prongs
Subjects: 132 infants <32 weeks, post-extubation
Primary outcome: No significant difference in extubation failure within 7 days
HFNC caused less nasal trauma

25. Yoder, Pediatrics 2013
Devices: Comfort Flo, Fisher and Paykel, Vapotherm vs Bubble CPAP, Infant Flow, Ventilator
Subjects: 432 infants 28 weeks – term, primary therapy or post-extubation
Primary outcome: No significant difference in intubation <72 hours
HFNC caused less nasal trauma

26. NON-INFERIORITY TRIALS
Most RCTs are superiority trials
Non-inferiority trials: does the new treatment (eg. HFNC) have efficacy that is similar to or no worse than an established therapy (eg. NCPAP)
The premise: the new treatment has some other benefit and might be favoured over the standard treatment, even if the efficacy is the same or lower
Piaggio et al, JAMA 2006

27. NON-INFERIORITY TRIALS
Non-inferiority is based on the risk difference (95% CI) for the primary outcome between the two treatments
‘Margin of non-inferiority’ is defined
We defined the margin as 20%
If the risk difference for treatment failure and upper limit of its 95% CI is ≤20%, then HFNC is ‘non-inferior’
Piaggio et al, JAMA 2006

29. SUPERIOR

30. NON-INFERIOR

31. INCONCLUSIVE

32. INFERIOR

33. A multicenter, randomized, non-inferiority trial
The HIPERSPACE Trial
High-Flow Nasal Cannulae as Post-Extubation Respiratory Support in Premature Infants:
A CPAP Equivalent?
A multicenter, randomized, non-inferiority trial
NEJM 2013

34. INTERVENTION NCPAP Caffeine <24 hours prior to extubation HFNC
Fisher & Paykel ‘Optiflow’ circuit
Ventilator or ‘Bubble’ CPAP
Fisher & Paykel prongs
Hudson/midline binasal prongs
Extubated 5-6 L/min
Extubated 7 cm H2O
Max 6-8 L/min
Max 8 cm H2O
Min 2 L/min
Min 5 cm H2O
+/- Non-synchronised NIPPV
Could use NCPAP only if
Discouraged any use of HFNC
already failed HFNC
during the admission

35. INTERVENTION NCPAP Caffeine <24 hours prior to extubation HFNC
Fisher & Paykel ‘Optiflow’ circuit
Ventilator or ‘Bubble’ CPAP
Fisher & Paykel prongs
Hudson/midline binasal prongs
Extubated 5-6 L/min
Extubated 7 cm H2O
Max 6-8 L/min
Max 8 cm H2O
Min 2 L/min
Min 5 cm H2O
+/- Non-synchronised NIPPV
Could use NCPAP only if
Discouraged any use of HFNC
already failed HFNC
during the admission

36. INTERVENTION NCPAP Caffeine <24 hours prior to extubation HFNC
Fisher & Paykel ‘Optiflow’ circuit
Ventilator or ‘Bubble’ CPAP
Fisher & Paykel prongs
Hudson/midline binasal prongs
Extubated 5-6 L/min
Extubated 7 cm H2O
Max 6-8 L/min
Max 8 cm H2O
Min 2 L/min
Min 5 cm H2O
+/- Non-synchronized NIPPV
Could use NCPAP only if
Discouraged any use of HFNC
already failed HFNC
during the admission

37. Failure of the assigned treatment within 7 days
PRIMARY OUTCOME
Failure of the assigned treatment within 7 days
Defined as receiving maximal support and satisfying
one or more of the following criteria:
1. Increased oxygen: increase of 20% (0.2) above pre-extubation baseline
2. Apnea: more than 6 requiring stimulation in 6 hours or 2 episodes of positive pressure ventilation in 24 hours
3. Respiratory acidosis: pH <7.2 and pCO2 >60 mm Hg
4. Emergency intubation: at physician discretion

38. NCPAP 7 cm H2O (+/- nsNIPPV)
FAILURE
HFNC
FAIL
NCPAP 7 cm H2O (+/- nsNIPPV)
RE-INTUBATED

39. NCPAP 7 cm H2O (+/- nsNIPPV)
FAILURE
HFNC
FAIL
NCPAP 7 cm H2O (+/- nsNIPPV)
RE-INTUBATED
‘Rescue CPAP’

40. NCPAP 7 cm H2O (+/- nsNIPPV)
FAILURE
HFNC
NCPAP
FAIL
NCPAP 7 cm H2O (+/- nsNIPPV)
RE-INTUBATED

41. INFANT DEMOGRAPHICS HFNC N=152 NCPAP N=151 GA, weeks, mean (SD)
27.7 (2.1)
27.5 (1.9)
Birth weight, grams, mean (SD)
1041 (338)
1044 (327)
Antenatal corticosteroids
93%
95%
Surfactant treatment
Median age at extubation, hours 43 38
Mean FiO2 prior to extubation
0.23

42. HFNC NCPAP 52/152 39/151 34% 26% Risk difference 8%
PRIMARY OUTCOME (N=303) FAILURE OF THE ASSIGNED TREATMENT WITHIN 7 DAYS
HFNC
52/152
34%
NCPAP
39/151
26%
Risk difference 8%
95% CI (-2, 19) %

43. 8 -2 19

44. NON-INFERIOR

45. HFNC NCPAP 26/32 19/31 81% 61% Risk difference 20%
<26 WEEKS’ GA (N=63) FAILURE OF THE ASSIGNED TREATMENT WITHIN 7 DAYS
HFNC
26/32
81%
NCPAP
19/31
61%
Risk difference 20%
95% CI (-2, 42) %

46. INCONCLUSIVE

47. 26 WEEKS’ GA (N=240) FAILURE OF THE ASSIGNED TREATMENT WITHIN 7 DAYS
HFNC
26/120
22%
NCPAP
20/120
17%
Risk difference 5%
95% CI (-5, 15) %

48. 5 -5 15

49. NON-INFERIOR

50. SECONDARY OUTCOMES: RE-INTUBATION WITHIN 7 DAYS
HFNC
27/152
18%
NCPAP
38/151
25%
Risk difference -7%
95% CI (-17, 2) %

51. SECONDARY OUTCOMES: RE-INTUBATION WITHIN 7 DAYS
HFNC
27/152
18%
NCPAP
38/151
25%
HALF OF INFANTS IN WHOM HFNC FAILED WERE ‘RESCUED’ BY NCPAP

52. No difference in: Death or BPD Time on resp support Steroids for BPD
Days in oxygen
Pneumothorax
Laser for ROP
Proven sepsis
NEC stage 2 or 3
IVH grade 3 or 4
Cystic PVL
Days in hospital

53. NASAL TRAUMA HFNC NCPAP P value Nasal trauma Any recorded
Due to assigned treatment
39%
19%
55%
53%
0.008
<0.001

54. CONCLUSIONS
HFNC was non-inferior to NCPAP as post-extubation support in very preterm infants
About half of very preterm infants in whom HFNC therapy failed were ‘rescued’ from re-intubation by NCPAP
HFNC is feasible, but should be used with caution in infants born <26 weeks’ GA
HFNC was not associated with any increased risk of morbidity, and caused less nasal trauma than NCPAP

55. HFNC vs CPAP/NIPPV as Primary Therapy Need for intubation

56. HFNC vs CPAP post-extubation Extubation failure

57. But what does it mean for us?
Moved from sceptics to cautious adopters
More mature babies
CPAP back up
We like it for
Kangaroo care (from week 1)
Establishment of breast feeding (and boosting maternal supply) from 32 weeks
We like it enough to start a trial of HFNC for initial therapy of RDS in babies >28 weeks (HipsterTrial)

58. Thank you
to the
Hipsters