Perioperative Medicine

ABSTRACT
Background: Anesthesia studies using high-flow, humidified, heated oxygen

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delivered via nasal cannulas at flow rates of more than 50 l ∙ min–1 postulated a

Carbon Dioxide Changes ventilatory effect because carbon dioxide increased at lower levels as reported
earlier. This study investigated the increase of arterial partial pressure of carbon

during High-flow Nasal

dioxide between different flow rates of 100% oxygen in elective anesthetized
and paralyzed surgical adults before intubation.

Oxygenation in Apneic Methods: After preoxygenation and standardized anesthesia induction with
nondepolarizing neuromuscular blockade, all patients received 100% oxygen

Patients: A Single-center (via high-flow nasal oxygenation system or circuit of the anesthesia machine),
and continuous jaw thrust/laryngoscopy was applied throughout the 15-min

Randomized Controlled period. In this single-center noninferiority trial, 25 patients each, were ran-
domized to five groups: (1) minimal flow: 0.25 l ∙ min–1, endotracheal tube;

Noninferiority Trial (2) low flow: 2 l ∙ min–1, continuous jaw thrust; (3) medium flow: 10 l ∙ min–1,
continuous jaw thrust; (4) high flow: 70 l ∙ min–1, continuous jaw thrust; and (5)
control: 70 l ∙ min–1, continuous laryngoscopy. Immediately after anesthesia
Thomas Riva, M.D., Robert Greif, M.D., induction, the 15-min apnea period started with oxygen delivered according
Heiko Kaiser, M.D., Thomas Riedel, M.D., to the randomized flow rate. Serial arterial blood gas analyses were drawn
Markus Huber, Ph.D., Lorenz Theiler, M.D., Sabine Nabecker, M.D. every 2 min. The study was terminated if either oxygen saturation measured
Anesthesiology 2021; XXX:00–00 by pulse oximetry was less than 92%, transcutaneous carbon dioxide was
greater than 100 mmHg, pH was less than 7.1, potassium level was greater
than 6 mmol ∙ l–1, or apnea time was 15 min. The primary outcome was
the linear rate of mean increase of arterial carbon dioxide during the 15-min
EDITOR’S PERSPECTIVE
apnea period computed from linear regressions.
What We Already Know about This Topic Results: In total, 125 patients completed the study. Noninferiority with a
• Apneic oxygenation during surgery may be required to facilitate surgical inter- predefined noninferiority margin of 0.3 mmHg ∙ min–1 could be declared for
ventions involving the airway or may occur during intubation or emergence all treatments with the following mean and 95% CI for the mean differences
• Controversy over the past 60 yr remains about the rate of rise of in the linear rate of arterial partial pressure of carbon dioxide with associ-
carbon dioxide during apneic oxygenation ated P values regarding noninferiority: high flow versus control, –0.0 mmHg ∙
• Initial studies with high-flow humidified nasal oxygen therapy min–1 (–0.3, 0.3 mmHg ∙ min–1, P = 0.030); medium flow versus control, –0.1
reported lesser than historical carbon dioxide increases during mmHg ∙ min–1 (–0.4, 0.2 mmHg ∙ min–1, P = 0.002); low flow versus control,
apnea, suggesting a ventilatory effect on carbon dioxide elimination –0.1 mmHg ∙ min–1 (–0.4, 0.2 mmHg ∙ min–1, P = 0.003); and minimal flow
• Subsequent randomized data in pediatric patients disputed these versus control, –0.1 mmHg ∙ min–1 (–0.4, 0.2 mmHg ∙ min–1, P = 0.004).
observations
Conclusions: Widely differing flow rates of humidified 100% oxygen during
What This Article Tells Us That Is New apnea resulted in comparable increases of arterial partial pressure of carbon
• Adults undergoing elective surgery underwent preoxygenation, dioxide, which does not support an additional ventilatory effect of high-flow
standardized anesthetic induction, and randomization to 15 min of nasal oxygenation.
apneic oxygenation via endotracheal tube (0.25 l/min), or high-flow (ANESTHESIOLOGY 2021; XXX:00–00)
nasal oxygen (2 to 70 l/min) with jaw thrust or with laryngoscopy
• The primary outcome was the linear rate of increase of arterial car-
bon dioxide, with a predetermined noninferiority margin of 0.3 mmHg
∙ min–1 between groups
• All groups met the noninferiority criteria and with comparable arterial par-
tial pressure of carbon dioxide increases between groups, suggesting an
I n 2015, the principle of apneic oxygenation was expanded
with the concept of high-flow nasal oxygenation1 by
administering heated humidified oxygen at high-flow rates
absence of ventilatory effects for high-flow humidified nasal oxygen therapy of up to 70 l ∙ min–1 in adults demonstrating an extended

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to
the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). This study was presented in part at the World Airway Management
Meeting 2019 in Amsterdam, The Netherlands, November 13 to 16, 2019; at the SwissAnaesthesia 2020 virtual meeting (where it was awarded second prize), October 29 to 30,
2020; and at the Euroanaesthesia 2020 virtual conference, November 28 to 30, 2020.
Submitted for publication December 11, 2020. Accepted for publication September 14, 2021. From the Department of Anaesthesiology and Pain Medicine, Inselspital, Bern
University Hospital, University of Bern, Bern, Switzerland (T. Riva, R.G., H.K., M.H., S.N.); the School of Medicine, Sigmund Freud University Vienna, Vienna, Austria (R.G.); the
Department of Paediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland (T. Riedel); the Division of Respiratory Medicine, Department of Paediatrics, Inselspital, University
Children’s Hospital, University of Bern, Bern, Switzerland (T. Riedel); the Department of Anaesthesia, Cantonal Hospital Aarau, Aarau, Switzerland (L.T.); and the Department of
Anesthesia and Pain Management, Sinai Health System, University of Toronto, Toronto, Ontario, Canada (S.N.).
Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved. Anesthesiology XXX; XXX:00–00. DOI: 10.1097/ALN.0000000000004025

ANESTHESIOLOGY, V XXX • NO XXX xxx 2021 1

Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.
<zdoi;. DOI: 10.1097/ALN.0000000000004025>
 PERIOPERATIVE MEDICINE

apnea period and a slower increase of carbon dioxide than clinic visit, and written informed consent was obtained by
previously described.2 This approach was named trans- the research team.
nasal humidified rapid insufflation ventilatory exchange Inclusion criteria were age more than 18 and less than

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(THRIVE).1 80 yr of age and had American Society of Anesthesiologists
The ventilatory effect obtained1 was reproduced by (ASA) physical status of I to III, the ability to speak German
another research group,3 and simulation models supported or French, and the ability to understand the purpose of the
the concept of improved carbon dioxide clearance during study. Exclusion criteria were the need for flexible optic
high-flow apneic oxygenation.4,5 A computer simulation intubation, expected difficult mask ventilation, known cor-
showed that a cascade vortex flow produced by turbulences onary heart disease, known heart failure with New York
continuously flowing down the trachea into the alveoli Heart Association classification of 2 or higher, arrhythmias
under high-flow nasal oxygenation with an open mouth requiring antiarrhythmic therapy (e.g., implanted cardio-
might lead to a carbon dioxide washout, explaining the verter defibrillator), peripheral occlusive arterial disease
ventilatory effect initially described.4 with a clinical classification higher than Fontaine 2b, treat-
Carbon dioxide clearance is important, as increased arte- ment with β-receptor antagonists, known stenosis of the
rial partial pressure of carbon dioxide (Paco2) causes acido- (common or internal) carotid or vertebral arteries, body
sis and increases blood pressure, heart rate, and/or cerebral mass index of more than 35 kg ∙ m–2 or less than 16 kg ∙
blood flow.6–8 Over time, increased carbon dioxide levels m–2, hyperkalemia (potassium level greater than 5.5 mmol
limit apneic oxygenation. During the first minute of apnea, ∙ l–1), known chronic obstructive pulmonary disease Gold
Paco2 increases rapidly by 12.0 to 13.0 mmHg; thereafter, it classification of 2 or higher, known systolic pulmonary
increases by ~3.0 to 5.0 mmHg ∙ min–1.2,7,9,10 Studies inves- arterial pressure greater than 35 mmHg, known obstructive
tigating THRIVE showed an end-expiratory carbon diox- sleep apnea syndrome requiring therapy, high risk of aspira-
ide increase of ~1.1 to 1.8 mmHg ∙ min–1 during apnea,1,3 tion requiring rapid sequence intubation, known increased
much lower than the historic controls investigating the intracranial pressure, neurosurgical patients scheduled for
increase in carbon dioxide during apnea.1–3,7 intracranial surgery, anemia with hemoglobin less than
Studies in pediatric patients described similar rates of 100 g ∙ l–1, pregnancy (a pregnancy test was performed in all
carbon dioxide increase during apneic oxygenation using fertile female patients before anesthesia), known neuromus-
high-flow nasal oxygenation but with different flow rates, cular disorders, known or suspected cervical spine instabil-
thus questioning the impact of flow on carbon dioxide ity, nasal obstruction with impossibility of nasal ventilation
clearance in children.11 The null hypothesis of this ran- (both nares had to be patent), and allergies to or contraindi-
domized controlled noninferiority trial was that there is a cations to use of one or more of the anesthesia agents used
detectable difference in the linear rates of mean increase in the study protocol.
of arterial carbon dioxide between different flow rates
(0.25/2/10 and 70 l ∙ min–1) during the apneic period after Study Procedures
induction of general anesthesia and neuromuscular block-
After arriving in the operating room, the patients were
ade in adults computed by a linear regression.
monitored according to the local standard of care, includ-
ing electrocardiogram, peripheral oxygen saturation (Spo2),
Materials and Methods noninvasive blood pressure, end-tidal carbon dioxide
(ETco2), and train of four (TOF-Watch; Organon Ltd.,
With approval from the Cantonal Ethics Committee of
Ireland). Intravenous and ultrasound-guided intraarte-
Bern (2018-00293) and registration at ClinicalTrials.
rial access was established. Additionally, two monitors for
gov (NCT NCT03478774, primary investigator: Lorenz
transcutaneous measurement of carbon dioxide and oxy-
Theiler, date of registration: March 27, 2018), we performed
gen (transcutaneous measurement monitors 4 and 5; both
this five-armed single-center randomized controlled non-
from Radiometer, Germany) were attached to the right
inferiority trial in the Department of Anaesthesiology and
anterior thorax at the third intercostal space. Furthermore,
Pain Medicine at the Bern University Hospital, University
thoracic electrical impedance tomography (PulmoVista
of Bern, Bern, Switzerland, between March 2018 and
500; Draeger, Germany) was used to monitor atelectasis
December 2019. The methods for this project have been
formation and absence of diaphragmatic movements. To
published12; however, some changes were necessary after its
measure the depth of anesthesia during the apneic period,
publication, which are explained in detail below.
we recorded processed frontal electroencephalography
(Narcotrend, Germany).
Study Participants After standard preoxygenation (to end-tidal oxygen
Eligible adult patients scheduled for elective surgery under greater than 90%), anesthesia was induced using a target-
general anesthesia were identified from operating room controlled infusion of propofol (plasma concentration, 2.5
lists. After screening for inclusion and exclusion criteria, the to 4 ng ∙ ml–1) and remifentanil (plasma concentration, 2.5
patients were recruited during the standard preadmission to 6.5 ng ∙ ml–1). The depth of anesthesia was targeted to

2 Anesthesiology 2021; XXX:00–00 Riva et al.

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 Flow Effects of High-flow Nasal Oxygenation

Narcotrend index values between 35 and 55. Rocuronium United Kingdom) was inserted.13 If airway patency still
(0.6 to 0.9 mg ∙ kg–1) was used for neuromuscular blockade; was not achieved, the study intervention would have been
adequacy was verified with a train-of-four value of 0 before terminated.

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the onset of apnea and every 5 min throughout the proce- The predefined study termination criteria were: Spo2 less
dure and by visual absence of diaphragmatic movements in than 92%, transcutaneous carbon dioxide greater than 100
the electrical impedance tomography. Hypotension (defined mmHg, pH less than 7.1, potassium greater than 6 mmol ∙
as reduction of 20% from the baseline value, measured pre- l–1, and apneic period reaching 15 min. If any of these cri-
operatively on the ward) due to anesthetic drugs was coun- teria were attained, apnea was terminated (termination of
teracted with a continuous infusion of norepinephrine. study period), and bag-mask ventilation was commenced.
After successful facemask ventilation was established, a Airway management was then performed according to the
sealed opaque envelope was opened. Patients were randomly discretion of the attending anesthesiologist. After intuba-
allocated to one of five study groups, and the apneic period tion, a standardized manual airway recruitment maneuver
was started. Randomization was computer generated (www. was performed.The recruitment maneuver consisted of sus-
randomization.com, accessed October 7, 2021), and patients tained manual inflations of the anesthesia reservoir bag to a
were stratified in blocks of five according to body mass index peak inspiratory pressure of 40 cm H2O for 15 s.14
(16 to 25 kg ∙ m–2, 25.1 to 30 kg ∙ m–2, and 30.1 to 35 kg ∙ Throughout the study, serial arterial blood samples for
m–2) and smoking status (nonsmoker, former smoker, daily blood gas analysis (ABL 800, Radiometer) were drawn and
smoker 40 yr of age or less, and daily smoker of greater than analyzed in our central laboratory: awake, immediately after
40 yr of age). Patients were blinded to their group allocation; apnea start and 1 min later, then every 2 min, and 10 min
blinding of study personnel was not feasible due to the study after the end of the study period. A safety interview was
setup. Randomization was kept in sequentially numbered conducted on the first postoperative day to evaluate side
opaque envelopes, which were opened just before anesthesia effects and possible injuries during airway management.
induction by the research team.
Inspired oxygen concentration was 1.0 in all patients. Measurements
High-flow humidified oxygen was delivered via a high-flow The recorded patient baseline characteristics included
nasal cannula of adequate size (small to large, occlusion of sex, age, height, weight, body mass index, smoking status
maximum 50% of nostrils; Optiflow MR 850 system, Fisher (smoker, ex-smoker, pack years), ASA physical status, dental
& Paykel, New Zealand). The medium-flow and low-flow prosthesis, and the surgical discipline (visceral, orthopedics,
humidified oxygen was delivered using Aquapak Hudson thoracic/neuro).Vital signs (invasive continuous blood pres-
RCI (Teleflex, USA) and a flow-meter (Carbamed digi- sure, heart rate, Spo2, ETco2, transcutaneous carbon dioxide,
flow, Switzerland) using a standard nasal cannula (O2-Star and blood gas parameters (pH, Paco2, Pao2, and potassium)
curved nasal cannula, Dräger, Germany). We delivered min- were recorded. The amount of the drug delivered was
imal-flow oxygen via a standard endotracheal tube, using recorded, as well as any side effects (e.g., sore throat, hoarse-
the circuit of a Dräger Primus anesthesia machine to ensure ness, pain, postoperative nausea and vomiting) on the first
the delivery of exactly 0.25 l ∙ min–1. postoperative day.
The five study groups included four experimental In our published methods article, we defined the increase
groups and one control group: in transcutaneous carbon dioxide as the primary outcome
parameter and Paco2 as a secondary outcome parameter.12
(i)  Minimal-flow group: 0.25 l ∙ min–1 oxygen via endo-
However, very early in the experiment, we realized that
tracheal tube (additional study arm, which was added
there were discrepancies in the values of transcutaneous
after publication of the initial study protocol)
carbon dioxide measurements. This was confirmed when
(ii) Low-flow group: 2 l ∙ min–1 oxygen + continuous jaw
we installed a second system for transcutaneous measure-
thrust
ment, distributed by the same manufacturer. Because it was
(iii) Medium-flow group: 10 l ∙ min–1 oxygen + continu-
impossible to determine which transcutaneous measure-
ous jaw thrust
ment was the correct one, we decided to rely on Paco2
(iv) High-flow group: 70 l ∙ min–1 oxygen + continuous
measurements instead, using them as the primary outcome.
jaw thrust
The results of the transcutaneous carbon dioxide values
(v) Control group: 70 l ∙ min–1 oxygen + continuous laryn-
are provided in the Supplemental Digital Content (http://
goscopy with a McGrath MAC video laryngoscope
links.lww.com/ALN/C735).
(Medtronic, Ireland)
The primary outcome parameter was therefore the mean
Upper airway patency was visually confirmed using a naso- increase in Paco2 in mmHg ∙ min–1 during the 15-min
pharyngeal fiberscope (EF-N slim, Acutronic, Switzerland) apnea period. Secondary outcomes were the number of
directly after the start of apnea and at 7 min and 14 min patients who desaturated before the end of the predefined
into the apnea period. If airway patency was not achieved, apnea period and the time (in minutes) until desaturation
an oropharyngeal tube (Guedel airway, Intersurgical, from Spo2 100 to 92% (measured by pulse oximetry).

Riva et al. Anesthesiology 2021; XXX:00–00 3

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 PERIOPERATIVE MEDICINE

Statistical Analysis time points. The “complete data” sensitivity test consid-
ers only those patients for whom blood sample measure-
The linear increase in Paco2 over 15 min (mmHg ∙ min–1)
ments are available for each time point. The sensitivity test
was computed via linear regression for each patient, result-

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denoted as “imputed data” is based on imputed missing
ing in a distribution for the linear Paco2 increase for each
values computed with the predictive mean matching as
treatment group. For the noninferiority test, the null
imputation method.To allow for an adjustment period after
hypothesis stated that the difference of mean linear increase
the induction of apnea, the sensitivity test “complete data
of Paco2 between any of the four experimental groups and
+ adjustment” considers only blood sample measurements
the control group rates of 100% oxygen in apneic, anes-
from the second half of the apnea period (minutes 7 to 15).
thetized, and paralyzed adults after induction of anesthesia
The Supplemental Digital Content (http://links.lww.
before intubation was at least δ = 0.3 mmHg ∙ min–1 (non-
com/ALN/C735) shows the detailed analysis as outlined
inferiority margin).
in the published study protocol using a linear mixed-effect
Data from published literature suggest that patients in
model and the outcome parameter of transcutaneous car-
the control group should have a low linear increase in Paco2
bon dioxide for transcutaneous measurement monitors 4
of 0.9 mmHg ∙ min–1. A value of 0.3 mmHg ∙ min–1 would
and 5 (Supplemental Digital Content figs. I through VI and
result in a total increase of 4.5 mmHg over a 15-min apnea
tables I through VIII, http://links.lww.com/ALN/C735).
period. We defined this as clinically acceptable, because the
To calculate the necessary sample size, a difference in linear
normal range of Paco2 is 35.0 to 46.0 mmHg.
group means a Paco2 of 3 mmHg ∙ min–1 was necessary;
To test the noninferiority hypothesis, a 0.025 α-level
assuming a SD of 0.353 mmHg ∙ min–1, 22 patients were
was used, which corresponds to a two-sided 95% (100 ×
required per group (based on a one-sided α-value of 0.025
{1 – 2α}) CI. We declared noninferiority if the upper limit
and a power of 80%). We therefore decided to include 25
of the 95% CI of the difference in mean linear increase of
patients/group.
Paco2 was below the predefined noninferiority margin of
The data are reported as means ± SD or percentage; a
δ = 0.3 mmHg ∙ min–1. Normality of the individual linear
probability of less than 0.05 was considered significant. All
rates in Paco2 was assessed using a Shapiro–Wilk test. To
statistical analyses were performed with R (R Core Team,
account for multiple testing across the four noninferiority
R Foundation for Statistical Computing, Austria).
tests for each comparison of a treatment group with the
control group, the noninferiority declarations and the asso-
ciated P values were based on simultaneous CI computed Results
with the single-step Dunnett procedure.15 All patients were included in the analysis. The apnea period
Three sensitivity tests to assess the robustness and depen- of 15 min was completed by 95% of all patients, irrespective
dence of the declaration of noninferiority on the under- of the treatment group. Baseline characteristics of the 125
lying blood sample measurements were performed. The participants were comparable (25 per group) and are sum-
reference case is denoted as “raw data” and includes missing marized in table 1. Figure 1 shows the study consort flow
blood sample measurements for some patients at varying diagram.

Table 1. Patient Baseline Characteristics

Characteristic Minimal Flow (n = 25) Low Flow (n = 25) Medium Flow (n = 25) High Flow (n = 25) High Flow (Control; n = 25)

Female, n (%) 10 (40) 10 (40) 14 (56) 9 (36) 17 (68)

Age, yr 46 ± 15 47 ± 17 48 ± 19 48 ± 19 46 ± 18
Height, cm 174 ± 7 172 ± 9 170 ± 8 173 ± 10 170 ± 8
Weight, kg 78 ± 13 76 ± 14 71 ± 14 75 ± 18 70 ± 12
Body mass index, kg ∙ m–2 26 ± 3.5 25 ± 3.3 24 ± 3.3 25 ± 4.5 24 ± 3.7
Smoking status*
Smoker, n (%) 8 (32) 11 (44) 6 (24) 6 (24) 10 (40)
Ex-smoker, n (%) 0 (0) 1 (4) 1 (4) 0 (0) 1 (4)
Pack years, yr 18 ± 3 23 ± 15 9±7 2 15 ± 20
ASA physical status, n (%)
I 10 (42) 6 (24) 3 (12) 6 (24) 7 (28)
II 13 (54) 16 (64) 21 (84) 18 (72) 15 (60)
III 1 (4) 3 (12) 1 (4) 1 (4) 3 (12)
Dental prosthesis, n (%) 0 (0) 3 (12) 2 (8) 4 (16) 2 (8)

The values are number (proportion) or mean ± SD.

*Smoking status, missing for two patients in the medium-flow group.
ASA, American Society of Anesthesiologists.

4 Anesthesiology 2021; XXX:00–00 Riva et al.

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 Flow Effects of High-flow Nasal Oxygenation

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Fig. 1. Consolidated Standards of Reporting Trials flow diagram.

Figure 2A shows the trajectories of Paco2 for all study of a two-sided 95% CI for the mean difference in the linear
groups. Figure 2B shows the mean rate of changes in Paco2 rate of Paco2 increase was below the predefined noninfe-
over the observation period. Absolute Paco2 increases over riority margin of 0.3 mmHg ∙ min–1 in all experimental
time (means ± SD), and associated linear increase rates groups. Means and 95% CIs for the mean differences in
were: minimal flow, 32.0 ± 5.6 mmHg (2.0 ± 0.3 mmHg the linear rate of Paco2 with associated P values regard-
∙ min–1); low flow, 31.2 ± 5.5 mmHg (2.0±0.4 mmHg ∙ ing noninferiority are as follows: high flow versus control,
min–1); medium flow, 29.6 ± 5.8 mmHg (2.0 ± 0.4 mmHg –0.0 mmHg ∙ min–1 (–0.3, 0.3 mmHg ∙ min–1, P = 0.030);
∙ min–1); high flow, 32.0 ± 7.6 mmHg (2.1 ± 0.5 mmHg medium flow versus control, –0.1 mmHg ∙ min–1 (–0.4, 0.2
∙ min–1); and high flow (control), 33.2 ± 7.0 mmHg (2.1 mmHg ∙ min–1, P = 0.002); low flow versus control, –0.1
± 0.4 mmHg ∙ min–1). The Supplemental Digital Content mmHg ∙ min–1 (–0.4, 0.2 mmHg ∙ min–1, P = 0.003); and
table XII (http://links.lww.com/ALN/C735) shows the minimal flow versus control, –0.1 mmHg ∙ min–1 (–0.4, 0.2
sensitivity testing of the linear rates of changes in arterial mmHg ∙ min–1, P = 0.004).
carbon dioxide. Three sensitivity tests assessed and confirmed the overall
Figure 3 shows the noninferiority of all four experimen- noninferiority of the four experimental groups compared to
tal groups compared to the control group. The upper limit the control group. All but one upper limit of the two-sided

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 PERIOPERATIVE MEDICINE

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Fig. 2. (A) Time series of arterial partial pressure of carbon dioxide (Paco2) for each patient in the five groups. The number of patients in each
treatment group is indicated at the top of each. (B) Linear rates in Paco2 for the five groups. The units are mmHg ∙ min–1. Group means and
their 95% CI values are indicated for each group, and solid black points correspond to the linear rates in Paco2 for each patient.

95% CI for the mean difference in the linear rate of Paco2 As a further sensitivity test, the entire noninferiority
in all sensitivity tests over all group comparisons was below analysis was additionally computed with a mixed-effects
the predefined noninferiority margin of 0.3 mmHg ∙ min–1. regression model. The same conclusions regarding the non-
Only when high flow was compared with the control did inferiority were found, which highlights the robustness of
the 95% CI of the sensitivity analysis using the complete our findings (compare Supplemental Digital Content figs. I
data + adjustment exceed the noninferiority margin by 0.0 through VI and tables I through VII, http://links.lww.com/
mmHg ∙ min–1 (P = 0.060). The complete data + adjust- ALN/C735).
ment approach considers only blood sample measurements Table 2 shows the means ± SD linear rates of increase
from the second half of the apnea period (minutes 7 to in transcutaneous measurement of carbon dioxide over time
15) to allow for an adjustment period after the induction with transcutaneous measurement monitor 4, and table 3
of apnea. It is noteworthy that the additional constraints shows the results with transcutaneous measurement monitor
on data availability in these sensitivity tests may reduce the 5. No one met the study termination criterion of an increase
number of available patients, which reduces the power to in transcutaneous carbon dioxide above 100 mmHg. In six
detect a statistically significant noninferiority difference. patients (5%), the Spo2 level decreased less than 92% (one in

6 Anesthesiology 2021; XXX:00–00 Riva et al.

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 Flow Effects of High-flow Nasal Oxygenation

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Fig. 3. Noninferiority tests comparing four experimental groups with the control group. The null hypothesis states that the linear rates in
arterial partial pressure of carbon dioxide (Paco2) is at least 0.3 mmHg ∙ min–1 (noninferiority margin) larger than the linear trend of the control
group. The differences of the group means and the corresponding 95% simultaneous CI values are shown. Different colors refer to the sensi-
tivity tests considered in this study. The reference case is denoted as Raw Data and includes missing blood sample measurements for some
patients at varying time points. The Complete Data sensitivity test considers only those patients for whom blood sample measurements are
available for each time point. The sensitivity test denoted as Imputed Data is based on imputed missing values computed with the predictive
mean matching as an imputation method. To allow for an adjustment period after the induction of apnea, the sensitivity test Complete Data +
Adjustment considers only blood sample measurements from the second half of the apnea period (minutes 7 to 15).

the minimal-flow group, two in the low-flow group, one in Discussion

the medium-flow group, and two in the high-flow [control] This single-center randomized controlled noninferiority
group). One patient in the minimal-flow group and one in trial demonstrates that the rate of carbon dioxide increase
the high-flow (control) group desaturated after 7 min. The during apneic oxygenation is noninferior to high-flow
two patients in the low-flow group desaturated after 9 min, nasal oxygenation at 70 l ∙ min–1 flow with continuous
while one patient in the medium-flow group and one patient laryngoscopy to ensure a patent airway. Flow rates for
in the high-flow (control) group desaturated after 13 min. In 100% oxygen varied between 0.25 and 70 l ∙ min–1, and
patients who met a termination criterion, bag-mask venti- carbon dioxide accumulation was comparable in all con-
lation was commenced immediately. All patients reached an ditions; therefore, our results suggest the absence of an
Spo2 level of greater than 92% before airway management. additional ventilatory effect attributed to high-flow nasal
There was no difference in the incidence of hoarseness, oxygenation in adults.
sore throat, headache, or nausea and vomiting between the There was a marked discrepancy between the val-
treatment groups. The next day, 21 patients reported a dry ues measured with the two transcutaneous carbon
nose (minimal flow, 1; low flow, 5; medium flow, 1; high dioxide monitoring devices of the same manufacturer.
flow, 4; and high flow [control], 10). This made it difficult to decide which monitor would
During the postoperative safety interview, one patient provide the correct data. To base our primary outcome
reported suffering from eye lacrimation and nasal irritation (rate of carbon dioxide increase) on solid, verifiable
caused by inadvertent drying of water in the humidifying measurements, only the analyses of Paco2 increase (mea-
systems. The symptoms disappeared within 3 days after sur- sured every 2 min by arterial sampling) were used in the
gery. No other adverse events were recorded. model calculations.

Riva et al. Anesthesiology 2021; XXX:00–00 7

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 PERIOPERATIVE MEDICINE

Table 2. Linear Rates in Increase of Transcutaneous Carbon Dioxide per Minute with Transcutaneous Measurement Monitor 4

Data Minimal Flow (n = 23) Low Flow (n = 24) Medium Flow (n = 23) High Flow (n = 22) High Flow (Control; n = 22)

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Raw data 2.1 ± 0.5 1.9 ± 0.5 1.6 ± 0.4 1.9 ± 0.7 2.0 ± 0.5
Complete data 2.1 ± 0.5 1.9 ± 0.5 1.6 ± 0.4 1.9 ± 0.7 1.9 ± 0.5
Complete data + adjustment 1.9 ± 0.4 1.7 ± 0.4 1.5 ± 0.4 1.7 ± 0.7 1.9 ± 0.5
Imputed data 2.0 ± 0.5 1.8 ± 0.6 1.6 ± 0.4 1.9 ± 0.7 1.9 ± 0.5

The data are means ± SD. The units are in mmHg ∙ min–1. The number of patients in each group may differ across the sensitivity tests due to missing data measurements. The reference
case is denoted as raw data and includes missing blood sample measurements for some patients at varying time points. The complete data sensitivity test considers only those patients
for whom blood sample measurements are available for each time point. The sensitivity test denoted as imputed data is based on imputed missing values computed with the predictive
mean matching as imputation method. To allow for an adjustment period after the induction of apnea, the sensitivity test complete data + adjustment considers only blood sample
measurements from the second half of the apnea period (minutes 7 to 15). (Transcutaneous measurement monitor 4 [Radiometer, Germany].)

High-flow nasal oxygenation is an established method Further studies have shown improved carbon dioxide
used to improve alveolar oxygen concentration during elimination in adults.3,26 In apneic patients undergoing
intubation,16–19 preoxygenation,17,20 awake flexible optic laryngeal surgery, one research group reported an increase
intubation,18 intubation of morbidly obese patients,19 and of 0.9 mmHg ∙ min–1 in ETco2 using the same method;
endoscopic airway surgery in adults.21 Additionally, high- however, the same study showed an increase in Paco2 of 1.8
flow nasal oxygenation was successfully used during pediat- mmHg ∙ min–1.3 In the initial study of the concept of high-
ric airway surgery where an endotracheal tube would have flow nasal oxygenation, the rise in ETco2 was compared
blocked the surgical field22 and during induction of anes- to the rise in the Paco2 of historical controls.1 It may not
thesia for healthy children.23 account for the increasing arterial-to-alveolar gradient with
The main limitation of apneic oxygenation is carbon progressive apnea.27
dioxide accumulation, which causes cardiovascular com- A further potential reason that our results differ might
plications and respiratory acidosis caused by hypercap- be that the authors used historical controls from the 1950s
nia.7,24 Previous studies reported a carbon dioxide increase rather than performing a prospective randomized controlled
of 1.1 to 3.4 mmHg ∙ min–1 during apneic oxygenation trial. The effects of high carbon dioxide levels on the sym-
under general anesthesia.1,7,10,24 Another group reported pathetic nervous system was hard to control in early stud-
a high mean increase in Paco2 of 12 mmHg in the first ies. We therefore meticulously followed a protocol to keep
minute and after that a slower increase of 3.4 mmHg ∙ blood pressure, heart rate, and depth of anesthesia in a tight
min–1 in the ensuing 5 min.10 Others observed a transcu- range of values. That way, we tried to rule out the influence
taneous carbon dioxide rise of 2.3 mmHg ∙ min–1 during of different levels of depth of anesthesia resulting in different
apneic oxygenation using buccal oxygen with flows of 10 activation of the sympathetic system. Our results showed a
l ∙ min–1.25 mean increase in Paco2 between 2.0 and 2.1 mmHg ∙ min–1
Upon first publication of the concept of high-flow nasal for all study groups, well within the difference of our pre-
oxygenation, the study authors reported an increase of only defined noninferiority margin. These values are comparable
1.1 mmHg ∙ min–1 for ETco2 with high-flow nasal oxygen- to the 1.8 mmHg ∙ min–1 reported previously.3 One possible
ation—only one third of the rate observed with historical explanation that these values are lower than those of earlier
controls. Therefore, the study authors postulated that high- reports is that modern anesthesia might reduce metabolism
flow nasal oxygenation has a ventilatory effect and created substantially, resulting in far less carbon dioxide production,
the acronym THRIVE.1 which in turn results in less carbon dioxide increase, leading

Table 3. Linear Rates in Increase of Transcutaneous Carbon Dioxide per Minute with Transcutaneous Measurement Monitor 5

Data Minimal Flow (n = 25) Low Flow (n = 25) Medium Flow (n = 25) High Flow (n = 24) High Flow (Control; n = 25)

Raw data 1.7 ± 0.8 1.7 ± 0.4 1.4 ± 0.5 1.7 ± 0.6 1.7 ± 0.5
Complete data 1.7 ± 0.8 1.7 ± 0.3 1.4 ± 0.5 1.7 ± 0.6 1.7 ± 0.5
Complete data + adjustment 1.4 ± 0.6 1.5 ± 0.4 1.3 ± 0.5 1.5 ± 0.7 1.5 ± 0.5
Imputed data 1.7 ± 0.8 1.5 ± 0.6 1.4 ± 0.5 1.7 ± 0.6 1.7 ± 0.6

The data are means ± SD. The units are in mmHg ∙ min–1. The number of patients in each group may differ across the sensitivity tests due to missing data measurements. The refer-
ence case is denoted as raw data and includes missing blood sample measurements for some patients at varying time points. Please refer to table 2 for a detailed description of the
three sensitivity studies (complete data, complete data + adjustment, and imputed data). (Transcutaneous measurement monitor 5 [Radiometer, Germany].)

8 Anesthesiology 2021; XXX:00–00 Riva et al.

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 Flow Effects of High-flow Nasal Oxygenation

to a substantially prolonged apneic oxygenation period. is responsible for minor gas transport; it is independent of
However, future studies need to confirm this. nasal oxygen flow rates.
None of these high-flow nasal oxygenation studies com-
Limitations

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pared different flow rates. Our study compared an increase
in carbon dioxide at different flow rates, thus showing the
The post hoc change of the primary outcome parame-
absence of a relevant ventilatory effect caused by a higher flow
ter (as explained under “Materials and Methods”) could
of nasal oxygen. Because there was no significant difference
be regarded as a limitation of our study; however, the
between the high-, medium-, low-, and minimal-flow study
Supplemental Digital Content (http://links.lww.com/
groups, a ventilatory carbon dioxide clearance caused by the
ALN/C735) shows the results of this originally planned
high flow of high-flow nasal oxygenation can be excluded.
analysis. Other limitations are the single-center study design
Only three randomized controlled trials on high-flow
and the inability to blind the study team to the interven-
nasal oxygenation report Paco2 or transcutaneous carbon
tion, although it seems difficult to imagine how this could
dioxide measurements, and they are all pediatric studies. have influenced patients’ Paco2 levels. Another limitation of
One study found no difference with or without high- this study are the extensive exclusion criteria, which need
flow nasal oxygenation and reported an increase in carbon to be considered while judging our results and their trans-
dioxide of 2.4 (range, 0.2 to 3.9) mmHg ∙ min–1 for both ferability to other patients and/or settings.
groups.28 Another study reported a comparable carbon
dioxide rate increase of 4.3 (interquartile range, 3.8 to 4.7) Conclusions
mmHg ∙ min–1 without and 4.1 (interquartile range, 3.2
to 4.6) mmHg ∙ min–1 with high-flow nasal oxygenation.23 This study provides evidence that the increase in Paco2 in
These studies also failed to show a flow-dependent venti- apneic, anesthetized, and paralyzed adults during apneic
latory effect at flow rates of up to 2 l ∙ kg–1 ∙ min–1.23,28 In oxygenation with 100% oxygen is similar using different
response to criticism that 2 l ∙ kg–1 ∙ min–1 might be not flow rates between 0.25 and 70 l ∙ min–1. All experimental
equivalent to the adult rate of 70 l ∙ kg–1 considered to be groups were noninferior to the accepted standard technique
high flow, a recent study even confirmed the absence of a of high-flow nasal oxygenation with a flow of 70 l ∙ min–1
flow-dependent ventilatory effect of high-flow nasal oxy- and continuous laryngoscopy. This study demonstrates the
genation in small children at flow rates of 4 l ∙ kg–1 ∙ min–1.11 absence of the proposed ventilatory effect of high gas flows
The lungs are oxygenated during apnea, when oxy- while performing nasal apneic oxygenation.
gen reaches the alveoli after passing through the upper
airways. There is a ventilatory mass flow of oxygen from Acknowledgments
the unobstructed upper airways in the direction of the The authors thank the following (both from the Department
alveoli3 generated by higher alveolar oxygen extraction of Anaesthesiology and Pain Medicine, Inselspital, Bern
from the alveoli and lower carbon dioxide diffusion into University Hospital, University of Bern, Bern, Switzerland):
the alveoli. This creates a subatmospheric alveolar pressure Maren Loosli, anesthesia study nurse, for her help in con-
that triggers the oxygen flow into the alveoli. This leads to ducting the study and Jeannie Wurz, B.A., research assistant,
the substantially prolonged safe apnea period observed by for review of the English in the article.
the application of high-flow nasal oxygenation. Applying
humidified instead of dry oxygen over longer apneic peri- Research Support
ods preserves the integrity and function of the respiratory Supported by a departmental research grant from the
mucosa.29,30 Department of Anaesthesiology and Pain Medicine,
When a mouth is open, the turbulent supraglottic gas Inselspital, Bern University Hospital, University of Bern,
flow of high-flow nasal oxygenation loops around the soft Bern, Switzerland.
palate, exits the mouth,8 and is responsible for a continu-
ous flushing of the oral and pharyngeal cavity with fresh Competing Interests
oxygen from the cannula. A recently published study by
our research group dismissed the purported mechanism Dr. Riedel holds a consultancy contract with the com-
of positive airway pressure generation by high-flow nasal pany Sentec AG, Landquart, Switzerland, and has received a
grant from the Swiss Foundation for Research on Muscle
oxygenation in the trachea and bronchi when the mouth
Diseases, Colombier, Switzerland, for a different research
is open.31
project. Both have no association with the current research
Cardiogenic oscillations remain the only physiologic
project. The other authors declare no competing interests.
mechanism explaining carbon dioxide elimination during
apneic oxygenation. Cardiac contractions in the thoracic
cavity compress and expand the small airways, causing Reproducible Science
these cardiogenic oscillations with a gas movement of 10 Full protocol available at: [email protected]. Raw
to –30 ml/heartbeat.32,33 This bidirectional air movement data available at: [email protected].

Riva et al. Anesthesiology 2021; XXX:00–00 9

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 PERIOPERATIVE MEDICINE

Correspondence different oxygen flow rates: A randomised controlled

trial. Anaesthesia 2021; 76:924–32
Address correspondence to Dr. Nabecker: Inselspital, Bern
12. Theiler L, Schneeberg F, Riedel T, Kaiser H, Riva T,
University Hospital, University of Bern, Freiburgstrasse,

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Greif R: Apnoeic oxygenation with nasal cannula oxy-
3010 Bern, Switzerland. [email protected].
gen at different flow rates in anaesthetised patients: A
Anesthesiology’s articles are made freely accessible to all
study protocol for a non-inferiority randomised con-
readers, for personal use only, 6 months from the cover date
trolled trial. BMJ Open 2019; 9:e025442
of the issue.
13. Uzun L, Ugur MB, Altunkaya H, Ozer Y, Ozkocak I,
Demirel CB: Effectiveness of the jaw-thrust maneuver
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