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

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

“THE FACTS MA’AM, JUST THE FACTS”

CPAP The Gold Standard

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)

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 6/9 0.08 [0.00, 1.19] Higgins 1991 7/29 23/29 0.30 [0.16, 0.60] Chan 1993 19/60 22/60 0.86 [0.52, 1.42] Annibale 1994 15/40 17/42 0.93 [0.54, 1.59] So 1995 4/25 13/25 0.31 [0.12, 0.81] Tapia 1995 7/29 2/30 3.62 [0.82, 16.01] Davis 1998 16/47 27/45 0.57 [0.36, 0.90] Dimitriou 2000 15/75 25/75 0.60 [0.34, 1.04] Peake 2005 16/49 24/48 0.65 [0.40, 1.07] Total (95% CI) 363 363 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 < 0.00001) 0.1 0.2 0.5 1 2 5 10 Favours NCPAP Favours Headbox Treat 6 babies to prevent 1 failure

The Contender HFNC

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

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

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

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’

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

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

Parental Preference Klingenberg, ADC 2013

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

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

Popularity outstripped the evidence

High flow as primary therapy

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

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

High flow for Post extubation care

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

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

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

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

SUPERIOR

NON-INFERIOR

INCONCLUSIVE

INFERIOR

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

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

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

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

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

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

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

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

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

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) %

8 -2 19

NON-INFERIOR

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) %

INCONCLUSIVE

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) %

5 -5 15

NON-INFERIOR

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

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

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

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

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

HFNC vs CPAP/NIPPV as Primary Therapy Need for intubation

HFNC vs CPAP post-extubation Extubation failure

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)

Thank you to the Hipsters