An interventional study of Intubation with a sedative medication only and Intubation with a sedative medication and neuromuscular blockade agent in Acute Respiratory Failure, sponsored by Vanderbilt University Medical Center. Not yet recruiting at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-28.
Sponsored by Vanderbilt University Medical Center · Not applicable, Interventional, and Treatment
The INtubation with Sedation Only to Preserve Independent Respiratory Effort (INSPIRE) trial is a pragmatic, non-blinded, parallel-group, randomized clinical trial comparing the effect of intubation with sedation only (intervention group) versus intubation with sedation plus neuromuscular blockade (control group) among adults undergoing emergency tracheal intubation in the ED and ICU with regard to the outcomes of: (1) hypoxemia during intubation, (2) successful intubation on the first attempt, and (3) awake immobility and PTSD symptoms. Patients who are determined by treating clinicians to require emergency tracheal intubation and who meet eligibility criteria will be enrolled and randomly assigned to either intubation with sedation only or intubation with sedation plus neuromuscular blockade.
Each year more than 1.5 million critically ill patients undergo emergency tracheal intubation in the United States (US). Unlike intubation in an operating room (during which less than 1% of patients experience a serious complication), 20% of patients intubated in an emergency department (ED) or intensive care unit (ICU) experience hypoxemia, and 2.5% of patients experience a cardiac arrest.
The most common approach to emergency tracheal intubation in current clinical care involves rapid administration of a sedative followed by a neuromuscular blocking agent (i.e. a paralytic). This technique is referred to by some as, "rapid sequence intubation." Neuromuscular blockade is intended to relax the muscles of the upper airway and make it easier for a clinician to visualize the vocal cords and advance an endotracheal tube into the trachea. However, neuromuscular blockade exposes patients to numerous risks including medication reactions and prolonged apnea, which increases the risk of hypoxemia.
Until recently, tracheal intubation was nearly always performed with a direct laryngoscope. When using a direct laryngoscope, clinicians must displace the tongue and epiglottis with the blade and lift the jaw anteriorly to visualize the vocal cords and pass an endotracheal tube. The most common reason for failure to intubate using a direct laryngoscope was an inadequate view of the vocal cords. Neuromuscular blockade gained widespread use because completely relaxing the muscles surrounding the upper airway optimizes the view of the vocal cords during direct laryngoscopy. In recent years, video laryngoscopes, which include a camera near the tip of the blade, have replaced direct laryngoscopes for intubation of critically ill patients in most settings. Video laryngoscopes provide better visualization of the vocal cords and allow placement of an endotracheal tube without requiring the anatomic manipulation required with a direct laryngoscope to obtain a direct line of sight from the mouth to the trachea. A recent randomized trial demonstrated that use of a video laryngoscope, compared with a direct laryngoscope, cut in half the chance of failing to place an endotracheal tube on the first attempt (from 30% to 15%). Use of a video laryngoscope, rather than a direct laryngoscope, is now recommended for intubation of critically ill adults in international guidelines and used for nearly 100% of intubations in many EDs and ICUs.
Whether neuromuscular blockade is needed to facilitate successful intubation when a video laryngoscope is used (rather than a direct laryngoscope) is unknown. It is possible that intubation can be routinely performed with video laryngoscopy without neuromuscular blockade. If neuromuscular blockade is not necessary, millions of patients each year in the US could avoid exposure to neuromuscular blockade during emergency tracheal intubation and the potential associated toxicities and complications.
Hypoxemia is one of the most common complications during intubation and is the strongest risk factor for cardiac arrest and death. Because neuromuscular blockade causes apnea, receipt of neuromuscular blockade could increase the likelihood of hypoxemia during intubation. When intubation is performed with neuromuscular blockade, clinicians hope that intubation and initiation of ventilation through an endotracheal tube can take place before hypoxemia develops. However, patients undergoing intubation in the ED or ICU commonly have underlying lung disease that may lead to hypoxemia within seconds of the onset of apnea. Intubation using sedation only (without neuromuscular blockade) may allow patients to continue to breathe spontaneously throughout the intubation procedure, potentially avoiding apnea and decreasing the likelihood of hypoxemia during intubation. Observational data, generated prior to the routine use of video laryngoscopy, suggested that intubation with sedation only and intubation with sedation plus neuromuscular blockade resulted in similar rates of hypoxemia when direct laryngoscopy was used. Whether intubation with sedation only would result in a lower incidence of hypoxemia than intubation with sedation and neuromuscular blockade when intubation is performed using video laryngoscopy (where the benefits of neuromuscular blockade in facilitating view of the vocal cords may be less relevant) remains unknown.
In addition to effects on short-term outcomes like hypoxemia during intubation, the choice to administer or not administer neuromuscular blockade during intubation may affect longer-term, patient-centered outcomes. Receipt of a neuromuscular blocking agent can cause awake immobility (also referred to as "awareness of paralysis" or "awareness with paralysis"). Awake immobility occurs when a patient is awake and aware but unable to move. Awake immobility has been shown to occur in 3-7% of emergency tracheal intubations, affecting 25,000-111,000 patients annually in the United States. Awake immobility is a traumatic and stressful experience for patients. Patients who experience awake immobility during intubation or mechanical ventilation are more likely to experience symptoms of post-traumatic stress disorder (PTSD) for months or even years after the critical illness. Symptoms of PTSD may impair patients' physical functioning and quality of life.
No randomized trials have compared intubation with sedation only versus intubation with sedation and neuromuscular blockade among critically ill adults undergoing emergency tracheal intubation in the ED and ICU. The only previous randomized trial directly comparing tracheal intubation with sedation only versus sedation plus neuromuscular blockade was an 1150-patient non-inferiority trial conducted among patients being intubated in the operating room for elective surgery. The trial found successful intubation on the first attempt without major complications occurred in 374 patients (66.2%) in the sedation only group and 403 (71.6%) patients in the neuromuscular blockade group (adjusted between group difference -5.7%; 95% CI -11.3% to -0.1%; p=0.32 for noninferiority). However, approximately 80% of the intubations were performed with a direct laryngoscope (rather than a video laryngoscope, with which neuromuscular blockade may not be required for successful intubation on the first attempt). Because the trial was limited to patients without critical illness undergoing elective intubation, it was unable to evaluate whether maintaining spontaneous breathing prevents hypoxemia. The results, therefore, do not directly apply to intubations of critically ill adults in the ED or ICU, for whom the most common indication for intubation is respiratory failure.
As a result of the lack of rigorous evidence on the effects of use of neuromuscular blockade on outcomes during emergency tracheal intubation, variation exists in current clinical care. Many EDs and ICUs administer neuromuscular blockade for all intubations, some administer neuromuscular blockade in select cases, and some perform all intubations with sedation only. Because millions of critically ill adults undergo emergency tracheal intubation in an ED or ICU each year and no prior randomized trial has compared intubation with sedation only versus intubation with sedation and neuromuscular blockade, a randomized trial is needed to compare the effectiveness and safety of intubation with sedation only versus intubation with sedation and neuromuscular blockade with regard to: (1) hypoxemia during intubation, (2) successful intubation on the first attempt, (3) awake immobility during intubation and mechanical ventilation, and (4) symptoms of PTSD after critical illness.
Exclusion Criteria:
Other: Intubation with a sedative medication only
Other: Intubation with a sedative medication and neuromuscular blockade agent
Patients in the sedation only group will undergo emergency tracheal intubation with sedation only (without receiving neuromuscular blockade) on the first attempt. The choice and dose of the sedative agent(s) (e.g., etomidate, ketamine, propofol, or other) will will be at the discretion of the operator and in accordance with usual clinical practice in the participating unit.
Patients in the sedation plus neuromuscular blockade group will receive sedation plus neuromuscular blockade prior to the first attempt at intubation. The choice and dose of the sedative agent(s)) (e.g., etomidate, ketamine, propofol, or other) and neuromuscular blockade agent(s) (e.g., succinylcholine, rocuronium, or other) will be at the discretion of the operator and in accordance with usual clinical practice in the participating unit.
Incidence of Hypoxemia
Primary Effectiveness Outcome: Incidence of hypoxemia (SpO2 \<88%) during the interval between induction and 2 minutes after tracheal intubation
Time frame: During the interval between induction and 2 minutes after tracheal intubation
Incidence of Successful intubation on the first attempt
Primary Safety Outcome: Incidence of successful intubation on the first attempt is defined as the 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 over the bougie into the mouth.
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes
Cormack-Lehane grade of glottic view
Cormack-Lehane grade of glottic view on the first laryngoscopy attempt
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes
Time from induction to successful tracheal intubation
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Operator-assessed difficulty of intubation
(Easy, Moderate, Difficult)
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Lowest oxygen saturation between induction and two minutes after tracheal intubation
Time frame: Between induction and 2 minutes after intubation
Oxygen saturation < 80% between induction to two minutes after tracheal intubation
Time frame: Between induction and 2 minutes after intubation.
Lowest systolic blood pressure between induction and 2 minutes after tracheal intubation
Time frame: Between induction and 2 minutes after intubation.
Cardiovascular collapse
Cardiovascular collapse, defined as the occurrence of any of the following between induction and 2 minutes after tracheal intubation: Systolic blood pressure \< 80 mmHg, new or increased vasopressors, or cardiac arrest.
Time frame: Between induction and 2 minutes after intubation.
Highest systolic blood pressure between induction and two minutes after intubation
Time frame: Between induction and 2 minutes after intubation.
Systolic blood pressure > 180 mmHg between induction and two minutes after intubation
Time frame: Between induction and 2 minutes after intubation.
Operator-reported aspiration
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Injury to teeth
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Injury to oropharynx or pharynx
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Injury to the vocal cords or trachea
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Receipt of tracheostomy, receipt of cricothyroidotomy, or failed intubation
Time frame: Duration of placement of the endotracheal tube, an average duration of 4 minutes.
Possible effects of neuromuscular blockade
Possible effects of neuromuscular blockade, defined as the occurrence of any of the following: * Ventricular arrhythmia between induction to two minutes after intubation * Malignant hyperthermia between induction and 24 hours after intubation * Hyperkalemia defined as \>6.0meq/L between induction and 1 hour after intubation * Anaphylaxis between induction and 1 hour after intubation
Time frame: Between induction and 24 hours after intubation
In-hospital death by 1 hour
Time frame: 1 hour after enrollment
In-hospital death by 28 days
Time frame: In the first 28 days after enrollment
Ventilator-free days through day 28
Defined as the number of calendar days, between enrollment and 28 days after enrollment, on which the patient is alive and free of invasive mechanical ventilation. If a patient is liberated from invasive mechanical ventilation, returns to invasive mechanical ventilation and subsequently is liberated from invasive mechanical ventilation again prior to day 28, the number of VFDs will be counted from the end of the last period of invasive mechanical ventilation to day 28. If the patient is receiving invasive mechanical ventilation at day 28 or dies prior to day 28, VFDs are 0. If a patient is discharged while receiving invasive mechanical ventilation, VFDs are 0. Outcome ascertainment ends at 28 days or hospital discharge, whichever occurs first.
Time frame: In the first 28 days after enrollment
ICU-free days through day 28
Defined as the number of calendar days, between enrollment and 28 days after enrollment, on which the patient is alive and not admitted to an intensive care unit after the patient's final transfer out of the intensive care unit. Patients who are never transferred out of the intensive care unit receive a value of 0. Patients who die before day 28 receive a value of 0. For patients who are transferred out of the ICU, return to an ICU, and are subsequently transferred out of the ICU again prior to day 28, ICU-free days are counted from the date of final transfer out of the ICU. Outcome ascertainment ends at 28 days or hospital discharge, whichever occurs first.
Time frame: In the first 28 days after enrollment
Incidence of Awake Immobility
Among participants who provide prospective consent, awake immobility will be determined by the AWP and Perceived Threat Questionnaire
Time frame: Between extubation and 90 days following intubation.
PTSD symptoms at 90 days after intubation
Among participants who provide prospective consent, PTSD symptoms at 90 days will be measured using the Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (PCL-5). The PCL-5 is a widely used 5-10 minute patient survey validated to characterize severity of symptoms of PTSD. Patients rate 20 items corresponding to the DSM-5 criteria for PTSD on a 5-point Likert scale ranging from 0 (not bothersome) to 4 (extremely bothersome). Total scores range from 0 to 80, with higher scores indicating more severe symptoms of PTSD.
Time frame: Between extubation and 90 days following intubation.
Breathlessness at 90 days after intubation.
Among participants who provide prospective consent, breathlessness will be measured using the Clinical COPD Questionnaire (CCQ). Scores range from 0 (least severe) to 6 (most severe). The CCQ symptom score has been used as a patient-reported outcome measure in more than 40 studies evaluating breathlessness among patients with respiratory disease, and it has been validated as an outcome measure in adults with the types of airway disease that occur following invasive mechanical ventilation through an endotracheal tube.
Time frame: Between extubation and 90 days following intubation.
All-cause, all-location death by 90 days
Time frame: At 90 days after enrollment.
Plan to share: Yes
Supporting information: Study protocol, Sap
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Vanderbilt University Medical Center