Mastering the skill of endotracheal intubation to secure airway plays a critical role in many settings such as pre-hospital environments, emergency rooms, critical care units, and peri-operative medicine. In a rapidly deteriorating, critically ill patient, success rests on adequate preparation, experience and anticipated difficulty associated with airway, clinical condition, and intubation. Rapid sequence intubation involves the simultaneous rapid administration of a paralytic and an induction agent to create optimal conditions to provide rapid control of the airway with the placement of an endotracheal tube[1]. This article gives an overview of indications, mechanism of action of commonly used sedatives and paralytics, endotracheal tubes, the sequence of steps in rapid sequence intubation, adverse effects of intubations and medications, and important contraindications.

Usually, emergent endotracheal intubation is indicated in the following clinical scenarios[2]:

• Hypoxemic respiratory failure, especially when it is persistent despite 100% inspired oxygen or non-invasive positive pressure ventilator support
• Hypercapnic respiratory failure causing respiratory acidosis and increased work of breathing indicative of impending respiratory failure
• Upper airway obstruction or injury (e.g., burns or caustic inhalation) requiring early and rapid stabilization of airway.
• Shock/hemodynamic instability when associated with altered mentation and increased work of breathing
• Clinical conditions associated with risk for airway compromises such as stroke, drug overdose, or coma.

Regardless of the indications for endotracheal intubation, rapid sequence intubation is the standard of care for all intubations, which are not anticipated to be difficult[3]. The combination of administering a sedative with a neuromuscular blocking agent renders the patient unconscious and induces flaccid paralysis to facilitate placement of an endotracheal tube into the airway and also minimizes the risk of aspiration[4]. Common sedative agents used during rapid sequence intubation include etomidate, ketamine, and propofol. Commonly used neuromuscular blocking agents are succinylcholine and rocuronium. Certain induction agents and paralytics may be more beneficial than others in certain clinical situations.

Etomidate is the most commonly used induction agent for rapid sequence intubation. It is a nonbarbiturate-sedative, which depresses central nervous system function through activation of gamma-aminobutyric acid (GABA) receptors. Advantages are its short onset of action within 30 to 60 seconds and a short half-life of 3 to 5 minutes. It does not affect systemic blood pressure and also has central nervous system (CNS) protective effects such as reduced cerebral blood flow and cerebral oxygen uptake[5]. It is usually preferable in patients with pre-existing hypotension and trauma.

Ketamine, a phencyclidine derivative, is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, because of which it has analgesic, sympathomimetic and amnestic properties. Its bronchodilator properties make it a preferable agent in patients with acute severe asthma. It has a short onset of action of 1 to 2 minutes and a half-life of 5 to 15 minutes[6].

Propofol has multiple mechanisms of action, but primarily potentiates GABA receptors. Because it is highly lipid soluble, it induces sedation quickly within 9 to 50 seconds and has a short half-life of 3 to 10 minutes. It also has anti-convulsive, anti-emetic properties and reduces intracranial pressure, which is beneficial in patients with traumatic brain injury and status epilepticus. Because of such a quick onset of action and short half-life, it is also commonly used as a constinuous titratable infusion for sedating mechanically ventilated patients[7].

Neuromuscular blocking agents (NMBAs) cause skeletal muscle paralysis and facilitate laryngoscopy and rapid endotracheal intubation. NMBAs must always be used along with an induction (sedating) agent to ensure the patient is not aware of their environment since they will be unable to respond after paralysis. Succinylcholine is a depolarizing NMBA and blocks acetylcholine receptor synaptic signaling at the motor end plate. The initial depolarization leads to muscular fasciculation, in the beginning, followed rapidly by flaccid paralysis because of persistent depolarization that exhausts the receptor’s ability to respond. It has an onset of action of 30 to 60 seconds and lasts approximately 5 to 15 minutes. It is the most commonly used paralytic agent for rapid sequence intubation. Rocuronium is a non-depolarizing NMBA, that competitively blocks acetylcholine receptors with an onset of action of 1 to 2 minutes but lasts for a longer period approximately 45 to 70 minutes, because of which rocuronium is usually only used when succinylcholine is contraindicated or unavailable[8].

Standard endotracheal tubes (ETTs) are made of polyvinyl chloride (PVC), they can also be made from silicone, metal or rubber depending on intended use. ETTs have internal diameters ranging from 2.0 mm to 12.0 mm depending on pediatric or adult patients and the estimate of what size would be appropriate for a given patient based on their anthropometry and the presence or absence of co-existing pulmonary or airway disease. In general, for average adult males, 7.5 mm to 8.5 mm, and females, 7.0 mm to 7.5 mm are preferred. It is important to be prepared with multiple sizes of ETTs during intubation as anatomic variations of the upper airway can be unpredictable. While un-cuffed ETTs are used in the newborn, beyond this age group and for all adults, ETTs have an inflatable balloon at the distal end of the tube to form a seal when inflated against the tracheal wall that prevents air leaking around the tube to allow for adequate gas exchange. The cuff also maintains the ETT in proper position and prevents oropharyngeal and gastrointestinal secretions from entering the lower respiratory tract. A pilot balloon is present on the proximal end of the ETT outside of the patient and has a one-way valve to allow for monitoring the cuff pressure. A cuff pressure of 20 cm to 30 cm is usually recommended to provide an adequate seal without causing injury to tracheal wall. Another key feature of standard ETTs includes a radiopaque marking all along the length of the tube to allow for tip identification and tube location on plain chest radiographs. During intubation, an indwelling stylet must be present within the ETT before inserting the ETT into the airway. Oral intubation is the recommended route of choice for placing ETTs in emergent and rapid sequence intubation. Nasal intubation may only rarely be considered for those with oral or mandibular trauma or facial deformities[9]. 

Rapid sequence intubation involves sequential steps that lead to successful endotracheal intubation. These steps allow for adequate assessment of the choice, dose, timing, and sequence of administration of sedatives, analgesics, and paralytics while ensuring that all equipment is ready and the patient’s clinical status is optimized. Rapid sequence intubation using NMBAs is the standard of care and is associated with a reduction in complications when compared to using sedatives alone. The following steps make up rapid sequence intubation; preparation, pre-oxygenation, pretreatment, paralysis and induction, positioning, placement and confirmation and following these, post-intubation management. These are commonly called the “7Ps” of rapid sequence intubation and are described below[10].

Preparation includes assessment of the degree of difficulty of a patient’s airway and establishing adequate intravenous access and continuous monitoring (telemetry, blood pressure, and pulse oximetry). As mentioned prior, ETTs of multiple sizes should be available, and all tested for cuff leaks. Laryngoscopes, both curved and straight and in multiple sizes should be available. All laryngoscopes should be checked for a functioning light source. Bedside suction devices should be easily accessible. Of note, even if airway assessment does not reveal any obvious evidence of difficulty, a backup plan should be readily available. Adequate nursing staff and respiratory therapists must be present to assist with intubation, monitoring, administering drugs and to prepare the ventilator.

Pre-oxygenation involves providing the highest possible oxygen concentration at high flows for 3 to 5 minutes. This allows the patient to tolerate longer periods of apnea without causing hypoxia during rapid sequence intubation. The upper airway patency needs to be maintained with chin lift or jaw thrust maneuvers that facilitate oxygen entry into the airways. Patients in whom achieving high oxygen saturation is not possible, pre-oxygenation can be performed with non-invasive positive pressure ventilation masks or positive end-expiratory pressure (PEEP) valves that can be added to the bag-valve mask.

Pre-treatment is an additional step that involves administering medications which may optimize the clinical setting in which intubation is being done. For example, intravenous fluids, anxiolysis with benzodiazepines or opioid medications may be used before administrating sedatives and NMBAs. Typically a short-acting opioid such as intravenous fentanyl is administered for pre-treatment. In patients with reactive airway disease, short-acting beta agonist (albuterol) may be administered during this step to minimize airway resistance. Rarely, in patients with shock, pretreatment with alpha-adrenergic inotropic agents may circumvent further reduction in mean arterial pressure following intubation due to loss of sympathetic tone from the use of specific induction agents.

Paralysis with induction involves the simultaneous administration of the medications for sedation and paralysis that have been decided earlier in the preparation phase based on clinical status, allergies, and potential contraindications. During rapid sequence intubation, the dose of these drugs should be pre-calculated and administered intravenously as a bolus and never titrated. Onset and duration of action should all be taken into consideration. Etomidate should be given in a dose of 0.15 mg/kg to 0.3 mg/kg intravenously depending on the stability of the patient. Ketamine is to be given in a dose of 2 mg/kg intravenously. Propofol is given in doses of 0.5 mg/kg to 2 mg/kg intravenously depending on hemodynamic stability. Immediately after the induction agent, the paralytic of choice is administered intravenously. Succinylcholine is given in 1.5 mg/kg dose whereas rocuronium is given in a 1 mg/kg dose.

The protection and positioning phase is vital, as the patient is now paralyzed and it is important that the airway must be protected from aspiration. Minimal bag-mask ventilation should be used to keep oxygen saturations adequate; this will be possible only if pre-oxygenation was adequate. One can perform the Sellick maneuver, in other words, apply pressure over cricoid cartilage to occlude the esophagus if necessary.

Placement should occur once adequate sedation and paralysis have been obtained. Direct laryngoscopy should be performed, and once glottis is visualized definitively, an appropriate size endotracheal tube with stylet should be placed through the vocal cords under direct visualization. After that, the endotracheal tube cuff is inflated with 10 ml of air and the stylet removed. Placement should be confirmed by end tidal carbon dioxide detection, quantitative or colorimetric methods. Auscultation over both lung fields and the epigastric region should also be performed to ensure equal breath sounds on both sides in the chest and absent in epigastric region. A chest radiograph should be performed to determine the depth of airway intubation. Endotracheal tube tip should be located more than 2 cm but less than 5 cm from the carina on chest radiography.

Post-intubation management involves securing the endotracheal tube, connecting endotracheal tube to a mechanical ventilator and evaluating and managing potential post-intubation complications. Appropriate sedation agents should be initiated as discussed earlier. Most induction agents have short half-lives.

The goal of rapid sequence intubation is to intubate the trachea safely and as quick as possible without compromising oxygenation and hemodynamics[11]. During rapid sequence intubation, many complications can arise, some related to the clinical condition, some from adverse effects of medications and others from the placement of the endotracheal tube or incorrect confirmation[12].

During the preparation phase of rapid sequence intubation, tube size selection is important because attempting intubation with a larger endotracheal tube can cause vocal cord injury and laryngeal edema. 

Aspiration of gastric contents is a potential risk in all patients undergoing this procedure. Fasting is encouraged if clinical suspicion for anticipated intubation is high, but this cannot always be achieved in emergency settings. Although cricoid pressure can be employed, at times it can disrupt laryngoscopy view and can lead to esophageal rupture if active vomiting occurs. An aspiration event often results in a new infiltrate following endotracheal intubation on chest radiography[13].

Esophageal intubation can result in severe hypoxemia ultimately leading to cardiac arrest and death. Hence, end-tidal carbon dioxide detection (colorimetric or waveform capnography) is recommended to confirm tracheal placement. Pneumothorax is a rare but potential severe risk with endotracheal intubation; it is usually the result of a right or left mainstem intubation but can also occur in patients with severe reactive airway disease. Chest radiography following intubation is necessary not only to identify the depth of tube of tube placement but also a pneumothorax[13].

A key component of successful rapid sequence intubation is adequate sedation. Due to the many drugs, which are available the adverse effects of each sedative medication must be weighed against its potential benefits. Potential adverse effects of etomidate include myoclonus, nausea/vomiting, and adrenal suppression. It remains unclear whether single induction dose of etomidate causes reversible adreno-cortical suppression by reversibly inhibiting 11-beta-hydroxylase, a key enzyme in cortisol synthesis. When it occurs, it generally does not last more than 24 hours, and the level of cortisol usually does not fall below normal physiologic levels. Etomidate can also lower seizure threshold in patients who have a known seizure disorder[14].

Ketamine is known to cause disturbing dreams, hallucinations and emotional distress as its sedative properties wear off. This is often referred to as re-emergence phenomenon. This effect can be limited if concurrent benzodiazepine medications are used for sedation. As it increases cerebral blood flow, it should be avoided in patients with elevated intracranial pressures[6].

Propofol is contraindicated in those with soybean or egg allergies as current formulations may contain these products resulting in a potential allergic reaction. As it decreases sympathetic activity, peripheral vasodilation and myocardial depression occur, leading to hypotension. Often this resolves rapidly by replenishing intravascular volume by administered intravenous fluid bolus and sometimes with the transient use of inotropic agents. Propofol may also lead to potential worsening of an existing neurological injury, by reducing cerebral perfusion pressure[7].

Etomidate can lower seizure threshold in patients with seizure disorder and can also cause nausea and vomiting. Etomidate can cause dose-dependent inhibition of adrenal cortisol production for up to 12 hours. Hence, one should exercise caution in those with known adrenal insufficiency or seizure disorder[14].

Ketamine’s sympathomimetic effects can lead to an increased cardiac output and blood pressure, which can precipitate cardiac ischemia in patients with known coronary artery disease. Ketamine is also a cerebral vasodilator, which can cause increased intracranial pressures. Due to these side effects, ketamine is contraindicated in patients with closed intracranial trauma, raised intraocular pressures, coronary artery disease, and hypertension[6].

Propofol most commonly causes hypotension by reducing systemic vascular resistance. Usually, this is overcome by a bolus of intravenous fluids. Additionally, some patients may have hypersensitivity reactions if allergic to eggs or soy products. Propofol should be used cautiously or avoided in those patients with pre-existing hypotension[7].

A personal or family history of malignant hyperthermia and conditions predisposing to life-threatening hyperkalemia are absolute contraindications for the use of succinylcholine[8].