non-invasive ventilation: an update · surfactant administration in preterm infants (level of...

Non-invasive ventilation: An Update

Peter Davis The Royal Women’s Hospital

Melbourne Australia

Program

• What do we know?

– CPAP as primary therapy for RDS

– Post-extubation care

• CPAP

• NIPPV

• High flow subnasal cannulae

• What are the gaps?

And then...

• Better ventilators

• More expertise

• Surfactant

Roberton: “The baby under 1000g” 1989

“Intubation and IPPV should be used

routinely on all extremely low birth

weight neonates and should be

started as soon as the infant is on the

resuscitation trolley”

“Is chronic lung disease preventable” Avery 1987

0

20

40

60

80

100

1 2 3 4 5 6 7 8

Survival

CLD (28d)

Spontaneous effort in extremely preterm babies (2010)

Breathed Cried

Total (n=61) 80% 69%

<26 weeks 67% 56%

≥26 weeks 86% 74%

<750g 60% 44%

≥750g 94% 86%

CPAP in the Delivery Room

COIN, SUPPORT and VON

COIN (NEJM, 2008) • International, multicentre RCT

• n=610

• 25 to 28 weeks’ gestation

• Randomised after birth to CPAP or ETT intubation by 5 min

• Primary outcome: death or BPD

COIN: Results • Half CPAP group were never ventilated.

• Trend to less BPD at 36 weeks for CPAP group.

• CPAP group significantly less days on ETT.

• CPAP group more pneumothoraces.

• No differences in other major neonatal morbidities.

Infants of 25 to 28 weeks, who breathe at birth but need respiratory

support, can initially be managed with CPAP with improved

outcomes compared with those ventilated from birth

Support (NEJM, 2010)

• Multicentre RCT

• n= 1316

• 24.0-27.6 weeks’ gestation randomised before birth

• CPAP vs Intubation (and surfactant by 1 hr)

• Primary outcome: death or BPD

Support: Results

• No difference in death or BPD (trend favouring CPAP, p=0.07 for standard definition of BPD)

• CPAP:

– Less frequently intubated

– Less steroids for BPD

– Fewer days of mechanical ventilation

• No difference in air leak (6.8% vs 7.4%)

VON Trial (Pediatrics, 2011)

• Multicentre RCT

• 26.0-29.6 weeks’ gestation

• 3 groups:

– prophylactic surfactant [PS]

– intubate-surfactant-extubate [ISX]

– bubble CPAP (5 to 7 cm H2O) and selective surfactant [CPAP]

• Primary outcome: death or BPD at 36/40

VON Results

• Stopped early – declining enrolment, n=648

• No significant differences in primary or secondary outcomes

• Pneumothorax rates: 3.2% vs 5.4%

• CPAP group: 48% were not intubated and 54% not given surfactant

VON: Conclusions

• “Because there seems to be no negative effect to applying an elective early nCPAP approach to these infants, it may be recommended as a less invasive and potentially less expensive method”

Schmoelzer et al, BMJ 2013

Barrington, Neonatal Research, 2013

Death or BPD

My response to the current evidence

• For preterm babies breathing well at birth NCPAP is an appropriate first line treatment

• I “rescue” babies earlier than previously (COIN): 8 cm H20 pressure/40% oxygen

– Is this right?

• CPAP is not the “magic bullet” for BPD

– the search continues

Conclusions

1. Early use of CPAP with subsequent selective surfactant administration in extremely preterm infants results in lower rates of BPD/death when compared with treatment with prophylactic or early surfactant therapy (Level of Evidence: 1)

2. Preterm infants treated with early CPAP alone are not at increased risk of adverse outcomes if treatment with surfactant is delayed or not given (Level of Evidence: 1)

Conclusions

3. Early initiation of CPAP may lead to a reduction in duration of ventilation and postnatal steroid therapy (Level of Evidence: 1)

4. Infants with RDS are a heterogeneous population, it is necessary to individualize patient care. Care for these infants is provided in a variety of care settings, and thus the capabilities of the health care team need to be considered.

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)

Getting babies off an ETT

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

Can we do better than CPAP?

NIPPV

NIPPV Nasal Intermittent Positive Pressure Ventilation

• Cycling

• CPAP+BUR= back up rate

• SNIPPV = synchronised NIPPV

• NV = nasal ventilation

• N-SIMV = nasal synchronised IMV

• N-IMV = nasal IMV

• N-BiPAP = nasal bipap

• NI-PSV = non-invasive pressure support ventilation

Respiratory failure post-extubation (by synchronisation)

Respiratory failure post-extubation (by device)

BPD

Pneumothorax

The NIPPV International Randomized Controlled Trial

Haresh Kirpalani, David Millar, Brigitte Lemyre, Bradley Yoder, Aaron Chiu, Robin

Roberts

NEJM, 2013

METHODS

• Eligibility criteria: GA<30 weeks and BW<1000 g; requiring non-invasive support in first 7 days of life, or post-extubation within first 28 days.

• Manoeuvre: Randomized to either NIPPV (synchronized or not) or nCPAP.

• Primary Outcome : Composite of death or BPD.

Results

• 36 sites randomized 1009 infants.

• Key baseline characteristics were balanced

– Mean BW 801g vs 805g

– 92% vs 91% received steroids

Results

• No difference in rates of death or BPD

• Subgroup analyses:

– No differences - early vs later use of NIPPV

– No differences - synchronized or not

CONCLUSIONS

• For infants <1000 g BW who require non-invasive respiratory support, current devices for NIPPV do not confer additional benefit or risk

Strengths/Limitations

• Big trial, adequate power

• Pragmatic – large number of centres – “real life”

• Sound analysis

• Heterogeneous

– Subjects – preintubation/postextubation

– Interventions – SiPAP, “high pressure” NIPPV

Why the discrepancy?

• Is non-synchronised NIPPV effective?

NIPPV research at RWH

NIPPV research: mechanism of action…

Do NIPPV breaths inflate the chest?

Are they transmitted from nose to lungs?

Do non-synchronised inflations disrupt the infants

breathing?

A: During normal breathing

B: During periodic breathing or apnoea

NIPPV research: are breaths transmitted?

NIPPV research: Are breaths transmitted?

NIPPV research: Are breaths transmitted?

NIPPV research: Are breaths transmitted?

If inflation happens during inspiration (34%):

breath is 13% bigger

and

breath is 25% longer

NIPPV research: Apnoeas

NIPPV research: Apnoeas

2s

NIPPV research: Apnoeas

NIPPV research: apnoeas

Overall: inflations transmitted 5% of the time

during apnoea

When they are transmitted:

inflations produce a ‘breath’ 1/4 the size

of a spontaneous breath

My response to the current evidence

• NIPPV may offer advantages over CPAP

• Synchronisation and the device used may be important

• NIPPV does not appear to be associated with increased side effects

• The best combination of settings for NIPPV needs to be established in future trials

CPAP is difficult

Nasal septal erosion

Figure 3

Nasal septal erosion Nasal septal erosion

High Flow Subnasal Cannulae

A safe, effective alternative?

CPAP

CPAP

HFNC

Prongs hang loosely around cheeks

Prongs sit out slightly from nasal septum

There is a leak at the nostrils and mouth

Duoderm and tegaderm

HOW DOES HFNC WORK? • Positive distending pressure

– not ‘set’ or monitored like CPAP devices

• Oxygen delivery

– higher concentrations than ‘low flow’

• Heating and humidification

– better ‘conditioning’ of gases

• Supports inspiration with high flow of gas

– ?reduces ‘work of breathing’

• ‘Washout’: Reduces the ‘dead space’ re-breathing

– better/more efficient ventilation

Distending pressure • Concern about unpredictable distending pressures in

preterm infants

• Pressures generated by HFNC ≤ those commonly set with nasal CPAP

Wilkinson et al, J Perinatol 2008

WHO IS USING HFNC? International

• 2/3 of US academic units • Hochwald, J of Neonatal-Perinatal Medicine, 2010

• >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

Why are HFNC being used?

‘easy to use’

‘safe’

‘decreases WOB’

‘nurses love it’

‘babies more settled’

‘less “CPAP belly”’

‘less nasal trauma’

‘no pneumothoraces’

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…”

High-Flow Nasal Cannulae as Post-Extubation Respiratory Support in Premature Infants:

A CPAP Equivalent?

A multicenter, randomized, non-inferiority trial

Manley BJ, Owen LS, Doyle LW, Andersen CC, Cartwright DW, Pritchard MA, Donath SM, Davis PG. N Engl J Med. 2013

PRIMARY OUTCOME: FAILURE WITHIN 7 DAYS

FOLLOWED TO DISCHARGE FROM HOSPITAL

VS HFNC 5-6 L/min NCPAP 7 cm H2O

PRETERM INFANTS <32 WEEKS’ GA

FIRST EXTUBATION

NON-INFERIORITY TRIALS

• Most RCTs are superiority trials

• Non-inferiority trials aim to determine if a new treatment (eg. HFNC) has efficacy that is similar to or no worse than an established therapy (eg. NCPAP)

• The premise is usually that the new treatment has some other benefit and might be favored 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

SAMPLE SIZE

• Based on local data for previous 2 years, expected NCPAP failure rate in very preterm infants was 25%

• 300 infants (150 in each group) were required to demonstrate non-inferiority of HFNC with ≈90% power

INTERVENTION

Fisher & Paykel ‘Optiflow’ circuit Fisher & Paykel prongs

Extubated 5-6 L/min

Max 6-8 L/min

Min 2 L/min

Could use NCPAP only if already failed HFNC

NCPAP

Ventilator or ‘Bubble’ CPAP Hudson/midline binasal prongs

Extubated 7 cm H2O

Max 8 cm H2O Min 5 cm H2O

+/- Non-synchronised NIPPV

Discouraged any use of HFNC during the admission

Caffeine <24 hours prior to extubation

INTERVENTION

Fisher & Paykel ‘Optiflow’ circuit Fisher & Paykel prongs

Extubated 5-6 L/min

Max 6-8 L/min

Min 2 L/min

Could use NCPAP only if already failed HFNC

NCPAP

Ventilator or ‘Bubble’ CPAP Hudson/midline binasal prongs

Extubated 7 cm H2O

Max 8 cm H2O Min 5 cm H2O

+/- Non-synchronised NIPPV

Discouraged any use of HFNC during the admission

Caffeine <24 hours prior to extubation

INTERVENTION

Fisher & Paykel ‘Optiflow’ circuit Fisher & Paykel prongs

Extubated 5-6 L/min

Max 6-8 L/min

Min 2 L/min

Could use NCPAP only if already failed HFNC

NCPAP

Ventilator or ‘Bubble’ CPAP Hudson/midline binasal prongs

Extubated 7 cm H2O

Max 8 cm H2O Min 5 cm H2O

+/- Non-synchronized NIPPV

Discouraged any use of HFNC during the admission

Caffeine <24 hours prior to extubation

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. 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

PRIMARY OUTCOME (N=303) FAILURE OF THE ASSIGNED TREATMENT WITHIN 7 DAYS

HFNC

NCPAP

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

8 19 -2

NON-INFERIOR

<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

<26 weeks’ GA

Primary

outcome

≥26 weeks’ GA

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

NASAL TRAUMA

HFNC NCPAP P value

Nasal trauma - Any recorded - Due to assigned treatment

39% 19%

55% 53%

0.008

<0.001

SECONDARY OUTCOMES:

INFANT COMFORT SCORES

HFNC NCPAP P value

No. scores 305 334 0.46

Mean (SD) score 10.9 (2.0) 12.0 (2.0) <0.001

CONCLUSIONS

HFNC was non-inferior to NCPAP as post-extubation support in very preterm infants (risk difference 8%)

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

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)

The Gaps

• CPAP + Surfactant without ETT

– MIST/LISA

– Nebulised surfactant

• NIPPV

– Can we deliver more effectively/synchronisation

• HFNC

– Higher flows: safety and efficacy

– Use as primary support