INtubation With Sedation Only to Preserve Independent Respiratory Effort Trial

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.