Published February 28, 2023

NEJM Evid 2023; 2 (3)

DOI: 10.1056/EVIDtt2200305

TOMORROW’S TRIAL

When Should We Intubate in Hypoxemic

Respiratory Failure?
Christopher J. Yarnell, M.D.,1 and Bhakti K. Patel, M.D.2

Abstract C. Corey Hardin, M.D., Ph.D.,

There is little evidence to guide the common and high-stakes decision to initiate invasive Editor
ventilation in hypoxemic respiratory failure. In this Tomorrow’s Trial, Yarnell and Patel pro-
pose a randomized trial of different physiological thresholds for the initiation of invasive
ventilation.

The Problem

A
64-year-old woman is admitted to the intensive care unit (ICU) with hypoxemic
respiratory failure as a result of pneumonia. She is alert, hemodynamically sta-
ble, and tachypneic, with a respiratory rate of 28 breaths per minute. Peripheral
oxygen saturation is 95% while receiving inspired oxygen at a fraction of 1.0 through a
high-flow nasal cannula at 60 liters per minute. She rates her dyspnea as 4 on a scale
of 0–10, where higher numbers indicate more severe dyspnea. Should she receive intuba-
tion and invasive ventilation or ongoing noninvasive oxygen support?

Respiratory support is an essential component of the management of hypoxemic respira-

tory failure. Whereas randomized trials have investigated noninvasive support strategies,1,2
there is little evidence to guide the common and high-stakes decision to initiate invasive
ventilation. The coronavirus 2019 pandemic has highlighted the uncertainty and urgency
of this question.

The Pros and Cons of Early Invasive Ventilation

Although intubation for invasive ventilation is often framed in terms of time, such as “early The author affiliations are listed
versus late,”3 this comparison cannot be operationalized in a randomized trial. Intubations at the end of the article.

that occur earlier with respect to ICU admission or time from a particular physiological Dr. Yarnell can be contacted at
state result from strategies with lower-severity physiological thresholds for invasive venti- christopher.yarnell@uhn.ca or at
lation such that patients reach those thresholds faster and more patients reach them. This University of Toronto, Critical
Care Medicine, 585 University
means that the question of when we should intubate can be reframed as “What physiologi- Ave., 10MB ICU, Toronto, ON,
cal thresholds identify patients who benefit from invasive ventilation?” Canada M5G2C4.

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Choosing a lower-severity physiological threshold for
invasive ventilation would result in more invasive ventila-
tion and has both benefits and risks. Proposed benefits
include the avoidance of catastrophic deteriorations,
emergency intubations, and patient self-inflicted lung
injury.4 Patient self-inflicted lung injury is a hypothesized
mechanism by which large spontaneous patient efforts,
stimulated by dyspnea and hypoxemia, worsen the under-
lying lung injury and increase the chance of death5; how-
ever, invasive ventilation is resource intensive and carries
risks of harm, including peri-intubation shock and cardiac
arrest, laryngeal trauma, ventilator-associated pneumonia,
delirium, and ICU-acquired weakness.6,7
What We Know
The fraction of patients that receive invasive ventilation is
known to vary over time and by health care facility.8,9
Current clinical practice is not consistent with any particu-
lar physiological threshold.10 More concerning is that the
use of invasive ventilation may vary by patient race,10
underscoring the need for objective thresholds to attenu-
ate the impact of bias on decision-making.
Randomized trials of noninvasive respiratory strategies often
use invasive ventilation as an outcome and incorporate pre-
specified criteria for its use.11 Similar criteria have been used
in multiple studies since the 1990s; however, it is unknown
if these criteria are appropriate with respect to patient out-
comes or if they are followed in clinical practice.8,10
Observational research suggests potential physiological
thresholds to identify patients who will experience benefit
from invasive ventilation. A large cohort study of patients
with acute respiratory distress syndrome showed that mor-
tality among patients with an arterial-to-inspired oxygen
(PaO2/FIO2) ratio less than 150 mm Hg was lower if patients
were managed with invasive as opposed to noninvasive ven-
tilation.12 Validated indices to predict invasive ventilation
use exist for patients on high-flow nasal cannula (Respira-
tory rate and OXygenation [ROX] index) or noninvasive
ventilation (Heart rate, Acidosis, Coma, Oxygenation, and
Respiratory rate [HACOR] score).13,14 The ROX index is the
ratio of oxygen saturation measured by pulse oximetry/FIO2
to respiratory rate. The HACOR score is a composite score
composed of heart rate in beats per minute, pH, conscious-
ness Glasgow coma score, oxygenation, and respiratory
rate. Using esophageal pressures, reduction in patient work
of breathing after initiating noninvasive ventilation was
NEJM EVIDENCE
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highly predictive of avoiding invasive ventilation.15 Clinical
trajectory, including the duration and degree of hypoxemia
or work of breathing, could be used to identify patients who
will experience benefit from invasive ventilation.
What We Need
We need a randomized superiority trial of different physio-
logical thresholds for the initiation of invasive ventilation
in hypoxemic respiratory failure. An initial trial could
enroll patients who are receiving oxygen through high-flow
nasal cannula or noninvasive positive pressure ventilation
and who do not have emergency indications for invasive
ventilation, such as cardiac arrest, coma, or urgent surgery.
Patients would be randomly assigned to usual care or one
of two or more potential physiological thresholds for inva-
sive ventilation. The physiological thresholds would com-
bine measures of hypoxemia and measures of work of
breathing or its proxies (Table 1). Including a usual care
arm increases external validity, whereas incorporating two
or more physiological thresholds helps clarify which thresh-
olds lead to the best outcomes. In all arms, intubation would
be performed if clinicians perceived that cardiorespiratory
arrest or upper airway obstruction was imminent.
Patients would be reassessed at regular 2-hour intervals to
evaluate whether or not they meet their assigned thresh-
old. Patients would undergo invasive ventilation promptly
after reaching their threshold and be otherwise managed
with noninvasive oxygen support. Care during invasive
ventilation would be encouraged to follow guidelines for
lung-protective ventilation, sedation, and weaning. The
primary outcome would be 90-day mortality. Secondary
outcomes measured at 90 days would include the propor-
tion receiving invasive ventilation, ventilator-free days,
and hospital-free days. Secondary outcomes measured at
12 months would include pulmonary function, cognition,
quality of life, and activities of daily living. A sample size of
at least 500 patients per arm would be needed to reliably
detect a reduction in 90-day mortality from 25% to 18%.
This trial would face many barriers. Clinicians may be
uncomfortable allowing randomization to dictate the deci-
sion for invasive ventilation. Recruitment of patients would
have to be prompt after ICU admission. Patient crossover
would be frequent but could be minimized by thoughtful
thresholds. Reasons for crossover would be recorded, espe-
cially in the case where emergency intubation occurs without
a patient meeting their assigned threshold. Heterogeneity of
2
 Table 1. Proposed Thresholds For Evaluation in a Randomized Controlled Trial.*

Threshold Respiratory Criteria Safety Criteria Rationale

Reduce self-inflicted Sustained for 15 minutes despite Hemodynamic failure: Identifies patients at risk of the
lung injury optimized HFNC or NIV: Requirement for vasopressors proposed harm of self-inflicted lung
Hypoxemia: FIO2≥0.8 required to maintain with norepinephrine injury. Hypoxemia is included as a
oxygen saturation≥92% dose>0.1 lg/kg/min marker of lung injury, whereas
Tachypnea: Respiratory rate≥25 breaths Neurologic failure: tachypnea and the additional criteria
per minute GCS<12 points focused on dyspnea, chest wall
AND at least one of the following: motion, or tidal volume capture
 Dyspnea: Self-reported dyspnea≥4 by potentially injurious breathing
visual analogue scale patterns.
 Altered chest wall ventilatory patterns
during breathing: Accessory muscle use,
abdominal paradoxical breathing
 Excessive tidal volume on NIV: Tidal
volume>9 ml/kg of ideal body weight
Failure to improve Despite ≥4 hours of optimized HFNC or Identifies patients who are
NIV: worsening or not improving and
Hypoxemia: Oxygen saturation<92% may be at high risk of additional
despite FIO2 1.0 deterioration or decompensation.
Tachypnea: Respiratory rate≥30 breaths
per minute
Usual care No specific thresholds provided to the clinical team Inclusion of a usual care arm allows
for comparison of outcomes
between novel thresholds and
current clinical practice.
* This table shows potential thresholds for invasive ventilation for evaluation in the proposed trial, which would enroll patients requiring high-flow
nasal cannula or noninvasive ventilation for treatment of acute hypoxemic respiratory failure. The thresholds include respiratory criteria that vary
across the interventional thresholds, and safety criteria that remain constant across the interventional thresholds. The usual care arm includes no
specific thresholds. Oxygen saturation can be measured by peripheral oximeter or arterial blood gas. FIO2 denotes inspired oxygen fraction; GCS,
Glasgow Coma Scale; HFNC, high-flow nasal cannula; and NIV, noninvasive ventilation.

treatment effect across underlying disease processes will 3. Sklar MC, Yarnell CJ. Always say never: why studies of timing of

have to be addressed through biomarker measurement invasive ventilation should compare “early versus late/never” as
opposed to “early versus late”. Am J Respir Crit Care Med 2021;
and preplanned secondary analyses. Despite these chal-
204:737-738. DOI: 10.1164/rccm.202104-0860LE.
lenges, this trial would provide valuable information for
4. The Difficult Airway Society. 4th National Audit Project of The
patients, clinicians, and families faced with the life- and
Royal College of Anaesthetists. Major complications of airway
independence-threatening problem of hypoxemic respira-
management in the United Kingdom: report and findings. March
tory failure. 2011 (https://www.nationalauditprojects.org.uk/downloads/NAP4%
20Full%20Report.pdf).
Disclosures
5. Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to mini-
Author disclosures are available at evidence.nejm.org. mize progression of lung injury in acute respiratory failure. Am J
Respir Crit Care Med 2017;195:438-442. DOI: 10.1164/rccm.201605-
Author Affiliations 1081CP.
1
University of Toronto, Toronto
2 6. Devlin JW, Skrobik Y, G
elinas C, et al. Clinical practice guidelines
University of Chicago, Department of Medicine, Chicago
for the prevention and management of pain, agitation/sedation,
delirium, immobility, and sleep disruption in adult patients in
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