Pragmatic Trial Examining Oxygenation Prior to Intubation (PREOXI)

• ClinicalTrials.gov Identifier: NCT05267652
• Recruitment Status: Completed
• First Posted: March 4, 2022
• Last Update Posted: November 15, 2023
• Sponsor: Vanderbilt University Medical Center
• Collaborator: University of Colorado, Denver
• Information provided by (Responsible Party): Jonathan Casey, Vanderbilt University Medical Center

Study Description

Brief Summary:

Clinicians perform rapid sequence induction, laryngoscopy, and tracheal intubation for more than 5 million critically ill adults as a part of clinical care each year in the United States. One-in-ten emergency tracheal intubations is complicated by life-threatening hypoxemia. Administering supplemental oxygen prior to induction and intubation ("preoxygenation") decreases the risk of life-threatening hypoxemia. In current clinical practice, the most common methods for preoxygenation are non-invasive positive pressure ventilation and facemask oxygen. Prior trials comparing non-invasive positive pressure ventilation and facemask oxygen for preoxygenation have been small and have yielded conflicting results. A better understanding of the comparative effectiveness of these two common, standard-of-care approaches to preoxygenation could improve the care clinicians deliver and patient outcomes.

Condition or disease	Intervention/treatment	Phase
Acute Respiratory Failure	Other: Preoxygenation with Non-Invasive Positive Pressure Ventilation; Other: Facemask Oxygen	Not Applicable

Detailed Description:

BACKGROUND:

Clinicians frequently perform tracheal intubation of critically ill patients in the emergency department (ED) or intensive care unit (ICU). Complications of intubation, including hypoxemia and cardiovascular instability, occur in nearly half of intubations performed in these settings. Preventing complications during tracheal intubation is a key focus of clinical care and airway management research.

HYPOXEMIA DURING INTUBATION OF CRITICALLY ILL PATIENTS:

Life-threatening hypoxemia occurs in 1-in-10 cases of emergency tracheal intubation. Severe hypoxemia during intubation is associated with increased risk of cardiac arrest and death. Severe hypoxemia may be associated with worse outcomes in survivors. For example, neurologic recovery from traumatic brain injury may be worse after hypoxemia due to secondary ischemic insult.

ROLE OF PREOXYGENATION IN PREVENTING HYPOXEMIA DURING INTUBATION:

In current clinical practice, emergency tracheal intubation involves the nearly simultaneous administration of a sedative agent and a neuromuscular blocking agent to optimize the anatomic conditions for intubation. Following medication administration, patients rapidly become hypopneic and then apneic until invasive mechanical ventilation is initiated through the newly-placed endotracheal tube. The oxygen contained in the lungs at the time of neuromuscular blockade (i.e., the patient's functional residual capacity) is the reservoir of oxygen available to the patient's body to prevent hypoxemia and tissue hypoxia during the intubation procedure. For a patient breathing ambient air (i.e., room air), only 21% of the gas in the functional residual capacity is oxygen; 78% is nitrogen. Administering 100% oxygen to a patient prior to induction of anesthesia and tracheal intubation, referred to as "preoxygenation," can replace the nitrogen in the lung with oxygen, increasing up to five-fold the reservoir of oxygen available to the body during the procedure and prolonging the period during which intubation can be performed safely without encountering hypoxemia. In current clinical practice, the two most common methods of providing preoxygenation are:

1. Non-invasive positive pressure ventilation - a tight-fitting mask connected to either an invasive ventilator or non-invasive mechanical ventilator.
2. Facemask oxygen - with either a non-rebreather mask or a bag-mask device.

PREOXYGENATION WITH NON-INVASIVE POSITIVE PRESSURE VENTILATION:

Preoxygenation with non-invasive positive pressure ventilation is common during emergency tracheal intubation of critically ill adults in current clinical practice. During preoxygenation with non-invasive positive pressure ventilation, a tight-fitting mask is connected to a machine capable of providing positive pressure ventilation. Non-invasive positive pressure ventilation delivers up to 95-100% oxygen and can be provided by either a conventional invasive mechanical ventilator or a dedicated non-invasive ventilation machine, commonly referred to as a Bilevel Positive Airway Pressure (BiPAP) machine. In addition to providing high concentrations of oxygen, non-invasive positive pressure ventilation increases mean airway pressure and delivers breaths at a set rate during the period of hypopnea/apnea after induction. Because a mechanical ventilator is always required following intubation of a critically ill adult, no specialized equipment is required to use non-invasive positive pressure ventilation for preoxygenation of critically ill adults undergoing tracheal intubation.

PREOXYGENATION WITH FACEMASK OXYGEN:

In current clinical practice, preoxygenation with facemask oxygen is commonly performed using one of the following two types of facemask: [1] a non-rebreather mask or [2] a bag-mask device. Both a types of facemask (a non-rebreather and a compressed bag-mask device) deliver supplemental oxygen without increasing airway pressures or providing assistance with ventilation.

• A non-rebreather mask is a type of facemask with a loose-fitting mask that sits over a patient's nose and mouth and is connected to an oxygen reservoir. It delivers at least 15 liters per minute of 100% oxygen, but it may not reliably deliver flows of oxygen greater than 15 liters per minute and may allow entrainment of ambient air. Studies show that the while the oxygen content for healthy and calm volunteers may approach 100%, the oxygen content received by critically ill patients with tachypnea may be as low as 50%. It does not provide positive pressure.
• A bag mask device is a type of facemask with a mask that forms a tight seal over the mouth and nose when held in place by the operator, an exhalation port, and a self-inflating bag that serves as a reservoir for oxygen and can be compressed to provide positive pressure ventilation. If the bag of this device is compressed, this device delivers oxygen without providing positive pressure ventilation and can deliver more than 90% oxygen with an ideal mask seal. However, in the setting of emergency intubation leaks may result in the entrainment of ambient air and reduced oxygen delivery.

POTENTIAL ADVANTAGES OF PREOXYGENATION WITH NON-INVASIVE POSITIVE PRESSURE VENTILATION OR PREOXYGENATION WITH FACEMASK OXYGEN:

Preoxygenation with non-invasive positive pressure ventilation has been proposed to offer the following potential advantages compared to preoxygenation with facemask oxygen:

• Entrainment of ambient air: The tight-fitting mask used to deliver non-invasive ventilation entrains less ambient air than a non-rebreather or bag-mask device. The higher flow rates of oxygen gas with non-invasive ventilation may also help prevent entrainment of ambient air and increase the fraction of inspired oxygen.
• Atelectasis and alveolar recruitment: Preoxygenation and induction of anesthesia rapidly results in the development of atelectasis in both healthy patients and critically ill patients. This atelectasis increases shunt fraction and increases the risk of peri-procedural hypoxia. By delivering positive pressure during both inspiration and expiration, non-invasive ventilation raises mean airway pressure, recruiting alveoli and preventing the development of atelectasis.
• Hypopnea and Apnea. Administration of sedation and neuromuscular blocking agents reduces or eliminates spontaneous respiratory effort. This hypoventilation leads to accumulation of alveolar carbon dioxide and reductions in alveolar oxygen, contributing to hypoxemia. Use of non-invasive ventilation before induction and between induction and laryngoscopy provides continuous oxygen to the alveoli, increases the size of breaths taken in the setting of hypopnea, and delivers controlled breaths when patients are apneic.

Preoxygenation with facemask oxygen (via a non-rebreather or compressed bag-mask device) has been proposed to offer the following potential advantages compared with preoxygenation with non-invasive positive pressure ventilation:

• Simplicity of use: Preoxygenation with facemask oxygen (using either a non-rebreather or compressed bag-mask device) is simpler to set up than non-invasive positive pressure ventilation.
• Low risk of gastric insufflation: Although no clinical evidence exist to suggest that preoxygenation with non-invasive positive pressure ventilation increases the risk of gastric insufflation or aspiration of gastric contents, use of facemask oxygen (without any positive pressure) avoids this hypothetical concern.

PRIOR EVIDENCE FROM CLINICAL TRIALS:

Two small clinical trials have compared preoxygenation with non-invasive ventilation to preoxygenation with facemask oxygen during the tracheal intubation of critically ill adults. The first trial compared non-invasive ventilation to a facemask among 53 critically ill ICU patients in two hospitals and found that non-invasive ventilation increased the lowest oxygen saturation (93% vs. 81%, p<0.001) with no difference in incidence of aspiration (6% vs. 8%). The second trial compared non-invasive ventilation to a facemask oxygen with regard to severity of illness in the 7 days after intubation among 201 critically ill ICU patients. This trial found no significant difference in the severity of illness between groups and no significant difference in the rate of severe hypoxemia (18.4% vs 27.7%, p=0.10). This trial did not have adequate statistical power to detect clinically important differences between groups in the risk of hypoxemia. No large, multicenter trials have compared preoxygenation with non-invasive positive pressure ventilation to preoxygenation with facemask oxygen for critically ill adults undergoing tracheal intubation. Based on the available data from these small randomized clinical trials, preoxygenation with non-invasive positive pressure ventilation and preoxygenation with facemask oxygen both represent acceptable approaches to emergency tracheal intubation. Both approaches are considered standard-of-care and are used commonly in current clinical practice.

RATIONALE FOR A LARGE MULTICENTER TRIAL OF PREOXYGENATION:

Because of the imperative to optimize emergency tracheal intubation in clinical care, the common use of both preoxygenation with non-invasive positive pressure ventilation and preoxygenation with facemask oxygen in current clinical practice, and the lack of existing data from randomized trials to definitively inform whether preoxygenation strategy effects the rate of hypoxemia, examining the approach to preoxygenation during emergency tracheal intubation represents an urgent research priority. To address this knowledge gap, the investigators propose to conduct a large, multicenter, randomized clinical trial comparing preoxygenation with non-invasive positive pressure ventilation versus preoxygenation with facemask oxygen with regard to hypoxemic during tracheal intubation of critically ill adults in the ED or ICU.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1301 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pragmatic Trial Examining Oxygenation Prior to Intubation
• Actual Study Start Date: March 10, 2022
• Actual Primary Completion Date: October 14, 2023
• Actual Study Completion Date: November 11, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Preoxygenation with Non-Invasive Positive Pressure Ventilation Group; Patients assigned to preoxygenation with non-invasive positive pressure ventilation will receive non-invasive mechanical ventilation via a tight-fitting mask from the initiation of preoxygenation until the initiation of laryngoscopy. Trial protocol will not dictate the brand or type of mechanical ventilator that will be used to deliver non-invasive ventilation.	Other: Preoxygenation with Non-Invasive Positive Pressure Ventilation; The delivery of oxygen and ventilation by non-invasive mechanical ventilation via a tight-fitting mask from the initiation of preoxygenation until the initiation of laryngoscopy. Trial protocol will not dictate the brand or type of mechanical ventilator that will be used to deliver non-invasive ventilation.
Active Comparator: Preoxygenation with Facemask Oxygen Group; For patients randomized to preoxygenation with facemask oxygen, supplemental oxygen will be administered via a non-rebreather mask or bag-mask device without manual ventilation from the initiation of preoxygenation until induction. Trial protocol will not dictate the brand or type of facemask. The decision between use of a non-rebreather mask and use of a bag-mask device will be made by treating clinicians. The decision of whether to provide manual ventilation with a bag-mask device between induction and laryngoscopy will be made by treating clinicians.	Other: Facemask Oxygen; The delivery of supplemental oxygen via a non-rebreather mask or bag-mask device without manual ventilation from the initiation of preoxygenation until induction. Trial protocol will not dictate the brand or type of facemask. The decision between use of a non-rebreather mask and use of a bag-mask device will be made by treating clinicians. The decision of whether to provide manual ventilation with a bag-mask device between induction and laryngoscopy will be made by treating clinicians.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Hypoxemia [ Time Frame: from induction to 2 minutes following tracheal intubation ]
   A peripheral oxygen saturation < 85% during the interval between induction and 2 minutes after tracheal intubation

Secondary Outcome Measures :

1. Lowest oxygen saturation [ Time Frame: from induction to 2 minutes following tracheal intubation ]
   Lowest oxygen saturation during the interval between induction and 2 minutes after tracheal intubation

Other Outcome Measures:

1. Incidence of operator-reported aspiration [ Time Frame: from induction to 2 minutes following tracheal intubation ]
2. Fraction of inspired oxygen at 24 hours after induction [ Time Frame: 24 hours after induction ]
3. Oxygen saturation at 24 hours after induction [ Time Frame: 24 hours after induction ]
4. Incidence of pneumothorax [ Time Frame: from induction to 24 hours after induction ]
   Radiology report of new pneumothorax on chest x-ray in the 24 hours after induction
5. Incidence of new infiltrate [ Time Frame: from induction to 24 hours after induction ]
   Radiology report of new infiltrate on chest imaging in the 24 hours after intubation
6. Incidence of severe hypoxemia [ Time Frame: from induction to 2 minutes following tracheal intubation ]
   Lowest oxygen saturation of <80% between induction and two minutes after tracheal intubation
7. Incidence of very severe hypoxemia [ Time Frame: from induction to 2 minutes following tracheal intubation ]
   Lowest oxygen saturation of <70% between induction and two minutes after tracheal intubation
8. Oxygen saturation at induction [ Time Frame: from enrollment to induction ]
9. Systolic blood pressure at induction [ Time Frame: from enrollment to induction ]
10. Duration from induction to successful intubation [ Time Frame: Duration of procedure (minutes) ]
11. Cormack-Lehane grade of glottic view on first attempt [ Time Frame: Duration of procedure (minutes) ]
    Grade 1: Full view of glottis Grade 2: Partial view of glottis Grade 3: Only epiglottis seen (none of glottis) Grade 4: Neither glottis nor epiglottis seen
12. Incidence of successful intubation on the first attempt [ Time Frame: Duration of procedure (minutes) ]
    Placement of an endotracheal tube in the trachea with a single insertion of a laryngoscope blade into the mouth and either a single insertion of an endotracheal tube into the mouth or a single insertion of a bougie into the mouth followed by a single insertion of an endotracheal tube into the mouth
13. Number of laryngoscopy attempts [ Time Frame: Duration of procedure (minutes) ]
14. Number of attempts at passing a bougie [ Time Frame: Duration of procedure (minutes) ]
15. Number of attempts at passing an endotracheal tube [ Time Frame: Duration of procedure (minutes) ]
16. Incidence of cardiovascular collapse [ Time Frame: from induction to 2 minutes following tracheal intubation ]

    A composite of one or more of the following between induction and 2 minutes after intubation:

    • Systolic blood pressure < 65 mmHg
    • New or increased vasopressor
    • Cardiac arrest not resulting in death within 1 hour of induction
    • Cardiac arrest resulting in death within 1 hour of induction
17. 28-day in-hospital mortality [ Time Frame: 28 days ]
18. Ventilator-free days to 28 days [ Time Frame: 28 days ]
19. ICU-free days to 28 days [ Time Frame: 28 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patient is located in a participating unit
• Planned procedure is tracheal intubation using a laryngoscope and sedation
• Planned operator is a clinician expected to routinely perform tracheal intubation in the participating unit.

Exclusion Criteria:

• Patient is receiving positive pressure ventilation by a mechanical ventilator, bag-mask device, or laryngeal mask airway
• Patient is known to be less than 18 years old
• Patient is known to be pregnant
• Patient is known to be a prisoner
• Immediate need for tracheal intubation precludes safe performance of study procedures
• Patient is apneic, hypopneic, or has another condition requiring positive pressure ventilation between enrollment and induction
• Operator has determined that preoxygenation with non-invasive positive pressure ventilation or preoxygenation with a facemask is required or contraindicated for optimal care of the patient

Contacts and Locations

Locations

United States, Alabama

UAB Hospital

Birmingham, Alabama, United States, 35233

United States, Colorado

University of Colorado Denver

Aurora, Colorado, United States, 80045

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Louisiana

Our Lady of the Lake Regional Medical Center

Baton Rouge, Louisiana, United States, 70808

Ochsner Medical Center | Ochsner Health System

New Orleans, Louisiana, United States, 70112

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

The Lahey Hospital & Medical Center

Burlington, Massachusetts, United States, 01805

United States, Minnesota

Hennepin County Medical Center

Minneapolis, Minnesota, United States, 55415

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

United States, North Carolina

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

Brooke Army Medical Center

Fort Sam Houston, Texas, United States, 78234

Baylor Scott & White Health

Temple, Texas, United States, 76508

United States, Wisconsin

University of Wisconsin-Madison

Madison, Wisconsin, United States, 53705

Sponsors and Collaborators

Vanderbilt University Medical Center

University of Colorado, Denver

Investigators

• Principal Investigator: Jonathan D Casey, MD, MSc; Vanderbilt University Medical Center
• Principal Investigator: Adit A Ginde, MD, MPH; University of Colorado, Denver
• Study Director: Matthew W Semler, MD, MSc; Vanderbilt University Medical Center
• Study Chair: Kevin W Gibbs, MD; Wake Forest University Health Sciences

More Information

• Responsible Party: Jonathan Casey, Assistant Professor, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT05267652
• Other Study ID Numbers: 211271
• First Posted: March 4, 2022
• Last Update Posted: November 15, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Following publication, individual patient data will be made available for sharing to researchers with 1) a signed data access agreement, 2) research testing a hypothesis, 3) a protocol that has been approved by an institutional review board, and 4) a proposal that has received approval from the principal investigator.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Following publication. No end date

Access Criteria

1. a signed data access agreement
2. research testing a hypothesis
3. a protocol that has been approved by an institutional review board
4. a proposal that has received approval from the principal investigator

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jonathan Casey, Vanderbilt University Medical Center:

Critical illness; Emergency airway management; Tracheal intubation; Non-invasive ventilation; Facemask oxygen

Additional relevant MeSH terms:

Respiratory Insufficiency; Respiration Disorders; Respiratory Tract Diseases