Use of high flow nasal cannula in critically ill infants, children, and adults: A critical
review of the literature.
Online Supplement:
HFNC delivery systems (Pg 2-4)
Advantages and disadvantages of HFNC (Pg 5-6)
Table 3: On-going clinical trials or registered trials investigating the use of HFNC in infants,
children and adults (Pg 8-11)
Jan Hau Lee, Kyle J. Rehder, Lee Williford, Ira M. Cheifetz, David A. Turner
HFNC delivery systems.
Bubble humidification is the most common method for humidification of gas flow via standard
nasal cannula. However, this approach is generally not sufficient with higher gas flow rates due
to decreased hygrometric properties of the gas as well as decreased patient comfort
[1, 2]
. Newer
devices that can effectively handle high gas flows have been developed. The basic set-up
required for HFNC is a gas source to generate the necessary flow, a heated humidification
device that can handle high gas flow rates, often a pressure release valve, connection tubing
and an interface that will fit comfortably in the nares (Figure 1).
There are numerous high flow delivery systems commercially available [3-6]. These systems
share common characteristics. All can deliver flow rates greater than 30 lpm; some models can
deliver flow rates to up 60 lpm [2-5, 7]. They all achieve 95-100% relative humidity at 30-40oC by
mixing the inflow of gas with heated water vapor in the humidification systems. Some have a
proprietary semi-permeable membrane that separates inflowing gas from the heated water
allowing only heated vapor to mix with the gas, while others allow for a common chamber
between inflowing gas, heated water and vapor
[2, 3, 7]
. The various manufacturers have unique
compatible nasal cannula sizes and interfaces that fit their own humidifiers. Nasal cannulae are
available for sizes ranging from premature infants to adults.
One major difference between systems is the presence of a pressure release valve (Figure 1).
The need for such a valve is not universally accepted. Comparing two HFNC systems (up to 12
lpm) in an in-vitro lung model, Hasan and Habib [8] measured pressures generated in 3 different
locations in the HFNC setup at increasing distance from the flow source. Between the system
with and without a pressure release valve, there was a 15 cm H2O difference in positive
pressure measured at the device (most proximal to the flow source); however, a much lower
difference in pressure was found at the nasal prongs (6cm H2O) and the proximal upper
airway(3 cm H2O). The proximal upper airway pressure is most clinically relevant and such a
degree of difference is likely to be most important in smaller and younger patients. The pressure
release valve, allowing control of the maximal pressure generation at the device (below 35 cm
H2O) is considered by many to be a desirable safety feature to minimize the risk of a sudden
increase in airway pressure. This study showed that the presence of such a valve limited the
positive pressure at the proximal airways to < 6 cm H2O. Because of this finding, we
extrapolate that pressure release valve systems may be more useful when airleak syndrome is
of concern, such as the neonatal population. There are currently no in-vivo studies to allow us to
comment on the clinical significance of the presence of a release valve and whether such a
clinically significant difference in airway pressure is present in patients using different HFNC
systems.
Some HFNC systems have gas blenders for accurate and consistent blending of inspired
oxygen [3, 5, 7]. Gas titration is particularly important in premature infants in whom oxygen toxicity
is of concern, children with shunt-dependent congenital heart diseases, and in COPD patients in
whom respiratory drive is driven by relative hypoxemia. Therapeutic inhaled gases can also be
blended together with HFNC. For example, nitric oxide has been used with HFNC in patients
with pulmonary hypertension [9], while heliox with HFNC can be used in patients with airway
diseases [10]. Important considerations in this context are the impact of such high humidification
on the intrinsic properties (such as density and/or viscosity) of these gas mixtures and vice
versa. Intrinsic properties of gas mixtures such as high thermal conductivity of helium may affect
the heating mechanism in HFNC systems, but to our knowledge, there are no studies
addressing these potential issues. In addition, the very high flow rates used with HFNC limit the
duration in which these therapeutic gases can be utilized, necessitating frequent tank changes
and increasing costs.
In addition to the administration of therapeutic gases (such as helium [10] and nitric oxide [9]) via
HFNC, aerosol delivery of drugs can be administered via HFNC. However, the increased flow
rates may substantially affect medication delivery. Ari et al. [11] studied the in-vitro effect of heliox
and oxygen in the delivery of albuterol using HFNC. Their finding showed that with 100%
oxygen, increasing gas flow from 3 to 6 lpm, resulted in less albuterol delivered (11% to 2%),
but this marked decreased in albuterol delivery was improved with the introduction of 80%
helium (11% to 5%). This interesting finding should be kept in mind for clinical application and
future studies looking at administration of aerosolized drugs with HFNC. A higher dose of
medication or the addition of helium may be required to ensure adequate medication delivery.
Based on the available data, it seems reasonable to recommend that if an aerosolized
medication is deemed necessary in a patient supported with HFNC, it should likely be delivered
using conventional mask techniques. Additional investigations are needed before more
definitive recommendations can be made.
There are no studies to date to show superiority of one HFNC system over another. The
decision on which HFNC system to acquire for clinical use is likely to be driven by the overall
cost of the systems, clinical preference on the need for a pressure release valve, the allied
health and engineering support available, and the local availability of the respective humidifiers
and HFNC systems in different countries and clinical settings. Of note, newer designs have
also allowed HFNC to be adapted for use in lower-acuity clinical environments, including the
home setting [7]. In clinical scenarios where superiority of HFNC is not well demonstrated, due
consideration should be given to the costs of the overall setup for HFNC (including
consumables such as vapor cartridges) relative to standard nasal cannula and NIV apparatus
before deciding on the best mode of respiratory support.
Advantages and disadvantages of HFNC.
The importance of warming and humidifying gas to support respiration has long been
established [12]. Humidification optimizes mucociliary clearance, improves secretion quality, and
maintains normal mucosal function [13, 14]. Infants ventilated with ambient air that is not warmed
or humidified have significantly decreased pulmonary compliance and airway conductance. [15]
HFNC systems have the distinct advantage of being able to “decouple” the need to achieve high
humidity with high flow. These systems maintain high humidity despite using relatively lower
flow rates, in contrast to bubble humidifiers which lose effectiveness at high flow rates. The
proposed advantage of HFNC reducing the metabolic cost of warming and humidifying
inspiratory air is a theoretical one which has not been shown in any bench or clinical study [16].
Despite proper humidification, patients may still experience discomfort with HFNC, albeit much
less often than with less-highly humidified delivery. [1, 17, 18] This subjective sensation of
improvement of dryness on HFNC was supported by blinded assessment of the upper airway
mucosa by otorhinolaryngologists [18]. However, to our knowledge, there are no studies
comparing patient comfort and tolerance with HFNC versus mask-based NIV devices. Such
studies would provide valuable information for clinicians in an attempt to optimize patient
comfort and cooperation.
In any water-based humidification system, there is always a risk of nosocomial infection. In
2005, a HFNC device was associated with increased Ralstonia pickettii bacteremia [19] and was
recalled briefly from the market. After redesign of the humidifiers, there have been no further
reports of associated infections.
Given that HFNC can potentially generate positive pressure in the airway, airleak syndromes
are a theoretical risk associated with use of these devices. A single case report describes a 26
week gestational age premature infant who developed subcutaneous scalp emphysema with
pneumo-orbitis and pneumocephalus after being supported with HFNC of 4 lpm
[20]
. It is likely
that the very low birth weight, premature infant population is at most risk of air leak with HFNC.
The lack of pressure monitoring available in HFNC systems and inconsistency of pressure
generated may further compound this issue, however, we are not aware of additional reports of
air leak syndromes associated with HFNC.
REFERENCES.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Chanques G, Constantin JM, Sauter M, Jung B, Sebbane M, Verzilli D, Lefrant JY, and Jaber S
(2009) Discomfort associated with underhumidified high-flow oxygen therapy in critically ill
patients. Intensive Care Med 35(6): 996-1003.
Waugh JB and Granger WM (2004) An evaluation of 2 new devices for nasal high-flow gas
therapy. Respir Care 49(8): 902-6.
Fisher & Paykel (2012). [cited 2012 February 22nd]; Available from: http://www.fphcare.com/.
Smiths Medical (2012). [cited 2012 28th March]; Available from: http://www.smithsmedical.com/.
Hydrate Inc (2010). [cited March 28th 2012]; Available from: http://hydrateinc.com/index.php.
Vapotherm (2012) [cited February 18th 2012]; Available from: http://www.vtherm.com/.
DeLay PD, Stone SS, Karzon DT, Katz S, and Enders J (1965) Clinical and immune response of
alien hosts to inoculation with measles, rinderpest, and canine distemper viruses. Am J Vet Res
26(115): 1359-73.
Hasan RA and Habib RH (2011) Effects of flow rate and airleak at the nares and mouth opening
on positive distending pressure delivery using commercially available high-flow nasal cannula
systems: a lung model study. Pediatr Crit Care Med 12(1): e29-33.
Huang J and Fridman D (2011) High flow oxygen and low dose inhaled nitric oxide in a case of
severe pulmonary hypertension and obstructive shock. Chest 140(4).
Kim IK, Phrampus E, Sikes K, Pendleton J, Saville A, Corcoran T, Gracely E, and Venkataraman S
(2011) Helium-oxygen therapy for infants with bronchiolitis: a randomized controlled trial. Arch
Pediatr Adolesc Med 165(12): 1115-22.
Ari A, Harwood R, Sheard M, Dailey P, and Fink JB (2011) In vitro comparison of heliox and
oxygen in aerosol delivery using pediatric high flow nasal cannula. Pediatr Pulmonol 46(8): 795801.
Williams R, Rankin N, Smith T, Galler D, and Seakins P (1996) Relationship between the humidity
and temperature of inspired gas and the function of the airway mucosa. Crit Care Med 24(11):
1920-9.
Kilgour E, Rankin N, Ryan S, and Pack R (2004) Mucociliary function deteriorates in the clinical
range of inspired air temperature and humidity. Intensive Care Med 30(7): 1491-4.
Nakagawa NK, Macchione M, Petrolino HMS, Guimaraes ET, King M, Saldiva PHN, and Lorenzi G
(2000) Effects of a heat and moisture exchanger and a heated humidifier on respiratory mucus
in patients undergoing mechanical ventilation. Crit Care Med 28(2): 312-317.
Greenspan JS, Wolfson MR, and Shaffer TH (1991) Airway responsiveness to low inspired gas
temperature in preterm neonates. J Pediatr 118(3): 443-5.
Dysart K, Miller TL, Wolfson MR, and Shaffer TH (2009) Research in high flow therapy:
mechanisms of action. Respir Med 103(10): 1400-5.
Roca O, Riera J, Torres F, and Masclans JR (2010) High-flow oxygen therapy in acute respiratory
failure. Respir Care 55(4): 408-13.
Cuquemelle E, Pham T, Papon JF, Louis B, Danin PE, and Brochard L (2012) Heated and
Humidified High-Flow Oxygen Therapy Reduces Discomfort During Hypoxemic Respiratory
Failure. Respir Care.
Jhung MA, Sunenshine RH, Noble-Wang J, Coffin SE, St John K, Lewis FM, Jensen B, Peterson A,
LiPuma J, Arduino MJ, Holzmann-Pazgal G, Atkins JT, and Srinivasan A (2007) A national
outbreak of Ralstonia mannitolilytica associated with use of a contaminated oxygen-delivery
device among pediatric patients. Pediatrics 119(6): 1061-8.
20.
Jasin LR, Kern S, Thompson S, Walter C, Rone JM, and Yohannan MD (2008) Subcutaneous scalp
emphysema, pneumo-orbitis and pneumocephalus in a neonate on high humidity high flow
nasal cannula. J Perinatol 28(11): 779-81.
Table 3: On-going clinical trials or registered trials investigating the use of HFNC in infants, children and adults
Investigators
(Trial identifier
number)
Neonates
Yoder et al.
(NCT 00609882)*
Study design
Sites
Number and type of
patients
Start date
Outcomes
Randomized
comparing HFNC
and CPAP
United States
and China
December
2007
Primary: Extubation rate
Secondary: Apnea, ventilation days
oxygen days, adverse events, weight
gain and time to full feeds
Kugelman et al.
(NCT 01189162)*
Randomized
comparing HFNC
and NIMV
Haifa, Israel
January 2010
Primary: Treatment failure (intubation or
change from allocated treatment)
Secondary: Vital signs measurements,
ABG, IVH, BPD, oxygen days, LOS and
adverse effects
Weintraub et al.
(NCT 01270581)*
Randomized
comparing HFNC
and CPAP
New York,
United States
Neonates > 1000 g BW
and > 27 weeks GA
with early respiratory
distress within 24 hours
of birth or as mode of
respiratory support after
extubation.
420 patients
Neonates between 25
and 35 weeks
gestational age and >
1000 g BW with RDS,
apnea of prematurity
and post-extubation
support .
Neonates ≥ 35 weeks
GA with TTNB.
66 patients
July 2010
Buckmaster et al.
(ACTRN
12611000233921)+
Randomized
comparing HFNC
and headbox
oxygen
Newcastle,
Australia
May 2011
Klingenberg et al.
(NCT 01526226)*
Randomized
cross-over study
comparing HFNC
and CPAP
Randomized
comparing HFNC
and CPAP
Tromso,
Norway
Neonates ≥ 32 weeks
GA with respiratory
distress within 1st 24
hours of life.
520 patients
Neonates between 25
and 34 weeks GA.
20 patients
Intubated neonates <
32 weeks GA who are
ready for extubation.
300 patients
May 2012
Primary: duration of respiratory support
Secondary: esophageal pressure, time
to feeding, need for intubation, adverse
effects, LOS
Primary: Treatment failure (CO2
retention, pH < 7.25 and oxygen
requirement > 40%)
Secondary: Oxygen days, LOS,
pneumothorax, parental satisfaction
Primary: Patient comfort (EDIN score)
Secondary: Noise, parental satisfaction,
salivary cortisol as marker of stress
hormone response
Primary: Treatment failure within 7 days
(ABG, oxygen requirements, apnea and
reintubation)
Secondary: Duration of mechanical
ventilation, BPD, adverse events.
Davis et al.
(ACTRN
12610000166077)+
Victoria.
Australia
February
2012
Children
Kelly et al. (ACTRN
Nonrandomized
cross-over
New Zealand
Children (0-16 years)
with respiratory distress
on HFNC, CPAP or
oxygen
supplementation.
50 patients
Infants up to 6 months
whom are on HFNC 3 –
5 lpm or nasal CPAP 5
-6 cm H2O.
60 patients
July 2010
Primary: Pharyngeal pressure
Secondary outcome: Work of breathing
De Jongh et al.
(NCT01531465)*
Non-randomized,
observational
study comparing
HFNC and nasal
CPAP
Delaware,
United States
June 2011
Primary: Lung compliance
Secondary: Nil
Chisti et al.
(NCT01396759)*
Randomized
three group
design comparing
HFNC 2 lpm/kg,
bubble CPAP
and standard
nasal cannula
(0.5-2 lpm)
Bangladesh
Children up to 5 years
old with severe
pneumonia and SpO2 <
90%.
975 patients
July 2011
Primary: Treatment failure (SpO2 < 85%
after 1 hour and clinical signs of
exhaustion)
Secondary: Intubation, infection rates,
LOS, mortality
Wensley et al.
(NCT01498094)*
Randomized
comparing HFNC
8 lpm with
standard low flow
oxygen
British
Columbia,
Canada
Infants up to 18 months
with clinical diagnosis
of bronchiolitis.
100 patients
December
2011
Primary: LOS
Secondary: ICU admission, respiratory
parameters
Randomized
comparing HFNC
and BiPAP
Texas, United
States
August 2009
Primary: Edmonton symptom
assessment scale, dyspnea score
Wolfson et al.
(NCT00990119)*
Randomized
comparing HFNC
with current
standard of care
Pennsylvania,
United States
Adults with advanced
cancer and persistent
dyspnea.
50 patients
Adults > 50 years with
history of COPD.
30 patients
September
2009
Vargas et al.
Randomized
cross-over study
France
Adults with evidence of
acute lung injury
January 2010
Primary: NIV or intubation
Secondary: Dyspnea score, respiratory
parameters, ABGs, ICU admission,
LOS, total duration of respiratory
support
Primary: esophageal pressure and
esophageal time product
1261000549022)+
Adults
Hui et al.
(NCT00934128)*
(NCT01056952)*
Lim et al.
(NCT01166256)*
Jones et al. (ACTRN
12610000964011)+
of HFNC 40 lpm
and CPAP 7.5
cm H2O
Randomized
comparing HFNC
with BiPAP
(PaO2/FiO2 < 300).
15 patients
Korea
Secondary: ABG, comfort and dyspnea
scale
Adult patients with
acute hypoxemic
respiratory failure
74 patients
Adults presenting at
emergency department
with respiratory distress
requiring oxygen
therapy.
390 patients
July 2010
Primary: Intubation rates; ABG results
Secondary: Compliance, adverse
events, length of stay and mortality
January 2011
Primary: Hospital’s LOS
Secondary: Need for NIV or intubation,
air leaks, patient satisfaction, mortality
Adults postcardiopulmonary
bypass cardiac surgery
who are ready for
extubation and with
BMI ≥ 30.
162 patients
Post-operative adult
patients in the
cardiothoracic intensive
care unit.
340 patients.
January 2011
Primary: Atelectasis on CXR
Secondary: PaO2/FiO2 ratio, dyspnea
score, RR
March 2011
Primary: SpO2/FiO2 ratio on postoperative Day 3.
Secondary: oxygenation indices, need
for adjunct respiratory support, CXR
changes, spirometry, comfort score,
adverse events, ICU readmissions,
LOS, mortality
Randomized
comparing HFNC
40 lpm and
standard oxygen
therapy (nasal
prongs, face
mask or Venturi
mask)
Randomized
comparing HFNC
35 – 50 lpm and
nasal prongs or
face mask
New Zealand
Parke et al.
(ACTRN
12610000973011)+
Randomized
comparing HFNC
with standard
oxygen therapy
(via nasal
cannula or face
mask)
New Zealand
Frat et al.
(NCT01320384)*
Randomized 3
arms trial
comparing HFNC
30 – 50 lpm with
HFNC & NIV and
standard low flow
nasal cannula
Randomized 4
arms trial
comparing HFNC
France
Adults with hypoxemic
respiratory failure
(PaO2/FiO2 < 300). 300
patients
March 2011
Primary: Intubation
Secondary: Ventilator free days and
morbidity
Italy
High risk :
Adults > 65 years old
post-extubation with:
November
2011
Primary: Post-extubation respiratory
failure and reintubation
Secondary: Nosocomial infection,
Corley et al.
(ACTRN
12610000942055)+
Hernandez et al.
(NCT01191489)*
Australia
with BiPAP in
“high risk”
patients and
HFNC with
conventional
nasal cannula in
“low risk” patients
1. Cardiac failure as
main reason for
intubation
2. COPD
3. APACHE II score >
12 at intubation
4. BMI > 30
5. evidence of inability
to handle secretions
Low risk: Adults > 18
years who are ready for
extubation.
990 patients
+ Australian New Zealand Clinical Trials registry; * ClinicalTrials.gov registry
tracheobronchitis, ICU LOS and
mortality, hospital LOS and mortality
ABG – arterial blood gas, BiPAP - bilevel positive airway pressure, BMI – body mass index, BPD – bronchopulmonary dysplasia, BW – birth
weight, COPD – chronic obstructive pulmonary disease, CO2- carbon dioxide, CPAP – continuous positive airway pressure, CXR – chest
radiograph, FiO2 – fraction of inspired oxygen, GA- gestational age, ICU – intensive care unit, IVH – intraventricular hemorrhage, LOS – length of
stay, NIMV – nasal intermittent mechanical ventilation, NIV – non-invasive ventilation, RDS – respiratory distress syndrome, RR – respiratory rate,
SpO2 – pulse oximetry, TTNB – transient tachypnea of the newborn