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Nasal High Flow

Therapy

in preterm infants

Anna Lavizzari, MD NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

University of Milan, Italy

Disclosures

I received travel grants from Vapotherm, Fisher&Pykel and

Chiesi S.p.A.

I have been consultant for Chiesi S.p.A.

Clin Perinat 2015

Hendrik S. Fischer and Christoph Bührer

Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy

REDUCTION INCIDENCE DEATH/BPD < 30 wks’ GA NNT 35

DOI: 10.1542/peds.2013-1880; originally published online October 21, 2013; 2013;132;e1351Pediatrics

Hendrik S. Fischer and Christoph BührerMeta-analysis

Avoiding Endotracheal Ventilation to Prevent Bronchopulmonary Dysplasia: A

Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy

REDUCTION INCIDENCE DEATH/BPD < 32wks’ GA NNT 25

Research on non-invasive

respiratory support

from 2000 to 2011

0

200

400

600

800

1000

1200

1400

1600

NCPAP HFNC BiPAP NIPPV/SNIPPV nHFV

Number of studies in the National Library of Medicine (PubMed)

from 2008 to 2019

The increasing clinical use of nHFT

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

%

0

10

20

30

40

50

60

Mangiagalli

Italia VON

Europa

Nasal High Flow Therapy (nHFT)

“Small, thin, tapered binasal tubes that deliver oxygen or blended oxygen/air at gas flows of more than 1 L/min.”

Wilkinson et al, Cochrane Database Syst Rev 2011

• Flow rates greater than 1 L/min

• The gas is heated to near body temperature and humidified

• The respiratory gas is delivered at a flow rates that meet or exceed the patient's inspiratory flow rate

• nHFT provides positive end-expiratory pressure

Locke 1993, Frey 2001, Sreenan 2001

High Flow Therapy

NCPAP High Flow NC Low Flow NC

Flow 0-14 L/min 1-8 L/min 1-2 L/min

Humidifier PASS Over

Humidifier

Membrane Humidifier/

PASS over Humidifier

Contact, bubbling

Humidifier

Interface prongs fit snugly into the

infant’s nostrils with minimal leakage

NC do not occlude

nostrils and have a large

leak around (preferred

cannula/nare ratio 0.5,

should be <0.8)

Standard nasal cannula

FiO2 0.21 - 1.0 0.21 -1.0 < 0.4

Nasal High Flow Therapy

Matching physiology!!

The ideal Non-Invasive Respiratory

Support should… Provide alveolar

recruitment,

maintain an adequate

end-expiratory volume

and airway patency

Enhance the wash out

Reduce the

Work of Breathing

Decrease the

metabolic cost

for gas conditioning

Positive distending

pressure

Adequate bias flow,

↓ the dead space

↓ the patient’s load

Optimal gas

conditioning

nCPAP

Matching Physiology

Provision of distending pressure

• Patient circuit with

inspiratory and

expiratory lines

• Pressure determined

by the resistance on

the expiratory line

Servo-controlled valve CPAP provided

by mechanical ventilator Water immersion Bubble CPAP

Respiratory flow Expiratory flow

Bias Flow

nHFT

Matching physiology


Flow out

Flow from the device Flow from the device

Flow out

Respiratory Flow Respiratory Flow

R = space between the cannula and the nares

Pressure = R * Flow out

nHFT

Matching physiology


Flow out

Flow from the device Flow from the device

Flow out

Respiratory Flow Respiratory Flow

P = R * Flow out

Flow out = Flow device – Resp flow Flow out = Flow device + Resp Flow

P = R * Flow out



Wilkinson DJ et al, J Perinat 2008

The distending pressure in

HHHFNC depends on :

• flow rate not linear!!

• infant size

• amount of leak around the

cannula

It is highly variable and not

easily to be monitored

Preterm infants receiving

HFNC at flow rates of 2 to 8 lpm

can receive clinically relevant

transmitted

pharyngeal pressures similar to

nCPAP

P phar (cmH2O) = 0.7 + 1.1 F

(F = flow per kg in l min -1 kg -1)

1

2

3



Pressure delivered may be affected by

different devices, in particular for higher

flow rates

Collins et al. J Pediatr Child Health 2013

4

Lavizzari et al,

Arch Dis Child Fetal Neonat 2014

5 In addition to the intersubject and

intrasubject variability in the

amount of pressure developed,

there may also be large between-

centre variability.

Matching physiology Washout of nasopharyngeal dead space

Matching physiology

Washout of nasopharyngeal dead space

pCO2

pO2

Pediatric Pulmonology, 2017

Large prongs/large nares Small prongs/small nares


Nasopharingeal End-Expiratory CO2 - pEECO2 • Crossover, CPAP 6 cmH2O vs HFNC 8-2 lpm,

in 44 infants of 3 groups: <1000 g, 1000–1500 g and >1500 g

• pEECO2 was markedly attenuated at higher

flows with a strong, negative correlation

between pEECO2 and weight-corrected flow

rate (rs=−0.323, p<0.0001). • Open mouth state was associated with

greater washout effect, not statistically

significant

• The reduction of pEECO2 was greatest in

infants weighing <1000 g,

• The mean nCPAP pEECO2 was higher than

HFNC across all flows, but only achieved

significance at 6–8 L/min (p<0.05).

The ideal Non-Invasive Respiratory

Support should… Provide alveolar

recruitment,

maintain an adequate

end-expiratory volume

and airway patency

Enhance the wash out

Reduce the

Work of Breathing

Decrease the

metabolic cost

for gas conditioning

Providing an adequate

positive distending

pressure

Adequate bias flow,

↓ the dead space

↓ the patient’s load,

pressure stability,

synchronization

Adequate gas

conditioning

Matching physiology

Reduction of WOB

INCLUSION CRITERIA

• GA between 28+0 and 32+6

weeks

• Postnatal age < 96 h

• Receiving either NCPAP or

HHHFNC for mild to

moderate RDS

• Parental consent

EXCLUSION CRITERIA

• Intraventricular haemorrhage

• Major congenital abnormalities

Study objective: To compare the effect of HHHFNC and NCPAP on lung function and

mechanics in preterm infants with respiratory distress syndrome at the same level of

retropharyngeal pressure (Prp)


Work of breathing

at equal distending pressure

NCPAP

2 cmH20

4 cmH20

6 cmH20

HHHFNC

2 l/min

4 l/min

6 l/min

Cross-

over trial

Face mask

pneumotachography

Oesophageal

balloon

Retropharyngeal

catheter + pressure

transducer

PtcO2 , PtcCO2

SpO2

RIP bands

Lavizzari et al, Arch Dis Child Fetal Neonat 2014

Breathing pattern, lung mechanics, gas exchange, WOB at equal Prp

Breathing pattern

Mechanical properties

Gas Exchange

WOB

Prp of 2 cmH2O Prp 4 cmH2O

Lavizzari et al, Arch Dis Child Fetal Neonat 2014

WOB associated with upper airways

Cross-over trial,

20 preterm infants

HHHFNC at 6-8 lpm

versus

NCPAP at 6 cmH2O

Shetty et al, Arch Dis Child Fetal Neonat 2017

Pediatr Pulmonol. 2015

De Waal et al, Arch Dis Child Fet Neonatal 2017

Williams et al, Crit Care Med 1996

Humidity, temperature of inspired gas and

function of airway mucosa

MTV= mucus transport velocity

BTPS= body temperature, atmospheric pressure and saturation with water vapor

ACQUA CALDA

ACQUA CALDA

GAS RISCALDATO & UMIDIFICATO

Gas flow

Circuit

Vapor transfer

cartridge Flow Temperature

> 5 lpm 37-38°C

< 5 lpm 35-36°

Setting


Clinical Efficacy!!

nCPAP or nHFT

Post- extubation

N.

Patients

GA, BW Study type and design Devices, NHFT flow

rates

Primary

outcome

Collins

132 preemies

< 32 wks

RCT of NCPAP vs HFNC

post-extubation

8 L/min to 4 L/min,

Vapotherm

Extubation

failure

within 7 days

Yoder 432 28-42

wks


either as primary therapy

for RDS or post-extubation

3-5 L/min wt-based;

Comfort Flo, Fisher and

Paykel, and

Vapotherm

Intubation

within 72 hrs

of applied

NIV mode

Manley 300 preemies

< 32 wks

Non-inferiority RCT of

NCPAP vs HFNC exclusively

as primary therapy for RDS

5-6 L/min;

Intubation

within 7 days

HFNC versus CPAP to prevent

extubation failure HFNC versus CPAP to prevent extubation failure, Death

HFNC versus CPAP to prevent extubation failure, CLD

Wilkinson et al.

Cochrane Database of Systematic Review 2016

HFNC versus CPAP to prevent extubation failure, Treatment failure

HFNC versus CPAP to prevent extubation failure, Nasal Trauma

HFNC versus CPAP to prevent extubation failure, Pneumothorax

NNTB 50


extubation failure,

GI performation or NEC

NNTB 50

HFNC versus CPAP to prevent extubation failure, ROP

HFNC versus CPAP to prevent extubation failure, IVH

HFNC versus CPAP to prevent extubation failure, Sepsis


extubation failure

nCPAP or nHFT - Primary treatment

for respiratory distress

N.

Patients

GA, BW Study type and design Devices, NHFT flow

rates

Primary

outcome

Iranpour [Arabic]

70 30-35

wks

RCT of NCPAP vs HFNC after

prophylactic surfactant

and early extubation to

NCPAP

HFNC F&P;

Flow (L/min) = 0.92 +

0.68x, X = weight in Kg

[Sreenan’s formula]

Intubation

within 7 days

Yoder 432 28-42

wks


either as primary therapy

for RDS or post-extubation

3-5 L/min wt-based;

Comfort Flo, Fisher and

Paykel, and

Vapotherm

Intubation

within 72 hrs

Kugelman 76 <35 wks,

>1,000 g

Pilot, RCT for CT of NIPPV vs

HFNC as primary therapy

for RDS

1-5 L/min;

Vapotherm

Mechanical

ventilation

within 72 hrs

Lavizzari 316 29-36

wks

Non-inferiority RCT of

NCPAP vs HFNC exclusively

as primary therapy for RDS

4-6 L/min;

Vapotherm

Intubation

within 72 hrs

nCPAP or nHFT - Primary treatment

for respiratory distress

N.

Patient

s

GA, BW Study type and design Devices, NHFT

flow rates

Primary

outcome

Roberts

750 ≥28 wks

Non-inferiority RCT on NCPAP

vs HFNC without prior

surfactant

treatment

6-8 L/min Intubation

within 72 hrs

Chen [chinese]

66 VLBW, GA not

specified in

abstract


after prophylactic

surfactant

not specified in

abstract

Intubation

within 7 days

Shin 87 30-35 wks

> 1250 g

Non-inferiority RCT on NCPAP

vs HFNC

Fisher & Paykel

Optiflow, 3-7L/min

Intubation and

mechanical

ventilation

Murki ≥28 wks

≥ 1000 g Non-inferiority RCT on NCPAP

vs HFNC

Optiflow Junior or

AIRVO 2, Fisher

and Paykel, 5-7

L/min

Intubation

within 72 hrs

HFNC versus CPAP for for primary

respiratory support after birth –

Secondary outcomes:

- nasal trauma,

- supplemental oxygen

- hospitalisation

- pneumothorax

- sepsis

HFNC versus CPAP for primary

respiratory support after birth HFNC versus CPAP for for primary


Treatment failure

HFNC versus CPAP for for primary respiratory support after birth - CLD

HFNC versus CPAP for for primary


Death

EXCLUSION CRITERIA

1) severe RDS

requiring early

intubation in DR

2) major congenital

anomalies

3) no parental

consent

INCLUSION CRITERIA

1) GA ≥ 29+0 and

< 37+0 weeks

1) inborn

2) parental consent

RDS with

Silverman score ≥ 5 or

FIO2 > 0.3 for target

SpO2 88-93%

Study enrollment

Methods – Intervention

Mechanical ventilation

1) FIO2 > 0.40 for SpO286-

93% after surfactant

2) Severe apnea (apnea

episodes > 4 in 1 hour or

> 2 in 1 hour requiring

PPV)

3) PaCO2>70 mmHg and pH

< 7.20

Chest XR, BG

Surfactant (INSURE)

(Curosurf, 200 mg/kg) if:

FIO2 > 0.35

to target SpO2 86-93%,

RDS with

Silverman score ≥ 5 or

FIO2 > 0.3 for target

SpO2 88-93%

HHHFNC

4-6 l/min

NCPAP (or

BiPAP)

4-6 cmH2O

Block-randomization;

stratification for GA

29+0-32+6 / 33+0-34+6

/35+0 36+6 weeks

Results - Primary outcome

Results – Primary outcome

Results – Secondary outcomes

Study design, primary outcome: same as HISTER trial

Study setting: non-tertiary centers

Inclusion: GA ≥31 weeks, birth weight >1200g

Patients enrolled n 754

Treatment failure intubation within 72h

ITT HFNC 78 of 381 infants (20.5%) vs CPAP 38 of 373 infants (10.2%)

(risk difference, 10.3 percentage points; 95%CI, 5.2 to 15.4).

Per protocol

HFNC 49 of 339 infants (14.5%) vs CPAP 27 of 338 infants (8.0%)

(risk difference, 6.5 percentage points; 95% CI, 1.7 to 11.2).

NEJM 2019

Objective: to identify clinical and demographic variables that predict nasal

high-flow (nHF) treatment failure when used as a primary respiratory support for preterm infants.

Secondary analysis from the data of the HIPSTER trial on 278 infants

A multivariable logistic regression model was applied, where the dependent variable was nHF treatment failure within 72 hours of randomization.

J Pediatr 2017

Nasal HF treatment success was more likely in infants born at ≥ 30 weeks GA and with

prerandomization FiO2 <0.30 the “30/30” rule!

However, CPAP remains superior to nHF (without no rescue CPAP) in preventing

treatment failure, even when the 30/30 rule is applied.


User friendly!!

2018

Nasal injury is common in preterm

infants born <30 weeks’ gestational age, receiving CPAP via binasal

prongs.

nurses

J Pediatrics and Child Health 2014

Infant Comfort & Parents Preference

Arch Dis Child Fet Neonat 2013

Does nHFT really improve comfort?

Salivary cortisol Premature Infant Pain Profile (PIPP)

Does nHFT improve feeding ability?

• RCT of 44 infants BW < 1500g and

GA <30 weeks with evolving BPD

• Randomization at 32 weeks, if still requiring CPAP

• Primary outcome: days taken to establish full oral feeds (oral

intake ≥120 mL/kg/day), aiming to demonstrate demonstrate a 7-day difference

Arch Dis Child Fet Neonat 2016


In practice…

Journal of Perinatology 2017

Yoder BA et al, J Perinat 2017

Why do we need practice Guidelines?

• HHHFNC is widely used in high-resource countries

• Expanding international use

• Guidelines generally improve outcomes

• Assist in identifying areas to improve

Practice Guidelines on Nasal High-Flow Therapy

in newborn infants

Arch Did Child Fetal Neonat 2018

Ped Pulmonology 2019

Conclusions

• Even though nasal CPAP is the most widely used form non-

invasive respiratory support in neonates, nasal HFT has been

increasingly applied to this population worldwide.

• The clinical use of nHFT has been supported by different

mechanisms of action, which has been evaluated both in

animal and human studies.

• Recent meta-analysis support the use of nHFT as an

alternative to nCPAP for post-extubation in infants ⩾28 weeks

of gestation in preventing treatment failure, death, and BPD.

Conclusions

• By contrast, HFNC is associated with higher failure rates than

NCPAP as primary support in premature infants, even though

it is not associated to increased rate of intubation.

• Infants > 30 wks of gestation and with FiO2 < 0.30 are more

likely to succeed with NHFT (30/30 rule)

• NHFT was safe and it was clearly associated with reduced

rates of nasal trauma compared to nasal CPAP. There may

also be a reduced incidence of pneumothorax.

Future Research

Agenda

Optimization of NHFT and nasal CPAP Best strategy for weaning Bed-side, non-invasive tools to individualize respiratory

management Implementation (O2-closed loop, high frequency,

heliox…) To assess the efficacy of NHFT in other neonatal lung

disorders (MAS, CDH…) To compare different devices and interfaces NHFT for delivery room stabilization, neonatal

transport, post-discharge… NHFT in resource-limited countries

Thank you!

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