Rapid sequence intubation (RSI) in children for emergency medicine: Medications for sedation and paralysis

INTRODUCTION — This topic will discuss medications commonly used for sedation and paralysis outside of the operating room during RSI in children. The approach to RSI outside of the operating room in children, including the steps involved in performing RSI and the selection of sedative and paralytic agents according to patient characteristics, is discussed separately. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach".)

RAPID SEQUENCE INTUBATION — RSI describes a sequential process of preparation, sedation, and paralysis to facilitate safe, emergency tracheal intubation. Pharmacologic sedation and paralysis are induced in rapid succession to perform laryngoscopy and tracheal intubation with the goal of preventing aspiration. A simple, systematic approach to preparation and execution of the procedure is necessary in order to perform RSI successfully (table 1 and figure 1). This approach is discussed in detail separately. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Approach'.)

SEDATION (INDUCTION) AGENTS — Sedation (induction) agents are integral to the performance of RSI. They provide amnesia, unconsciousness, blunt sympathetic responses, and can improve intubating conditions.

Each of the major induction agents in common use in children is discussed below and provided in the rapid overview (table 1). Further information about selection of sedatives and paralytics for RSI in children according to serious underlying conditions (eg, hemodynamic instability, increased intracranial pressure, status asthmaticus, or status epilepticus) is provided separately. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent' and "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of paralytic agent'.)

Additional discussion of pathophysiology and use of these agents for RSI outside of the operating room in adults is provided elsewhere. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)

Etomidate — Etomidate is an ultra-short-acting, imidazole derivative that produces reliable sedation and induction for RSI without causing significant hemodynamic compromise. It is an effective induction agent for most children undergoing RSI and is especially useful for patients with hypovolemic shock (eg, pediatric trauma patients), hypotensive patients with status epilepticus, and those with increased intracranial pressure (ICP). (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent' and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Etomidate'.)

The dose of etomidate used in RSI is 0.3 mg/kg intravenous (IV) with a time to effect of approximately 15 to 45 seconds and a duration of effect at this dose of 10 to 12 minutes. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Etomidate'.)

Etomidate reliably decreases ICP and cerebral metabolic rate, suggesting that it has a neuroprotective effect. Etomidate also has a protective effect similar to thiopental for generalized seizure activity, although regional neuro-excitation has been described in adults. Myoclonus has been reported as an adverse effect associated with etomidate. It does not generally interfere with intubation in children when paralytics are also used [1]. Such myoclonus has been misidentified as seizure activity, leading to incorrect recommendations that etomidate be avoided in patients with seizure disorders. If neuro-excitation is a concern, then benzodiazepine sedation (eg, midazolam) may be provided after intubation. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'General use'.)

Because of its adrenocortical suppression, the 2010 Advanced Life Support recommendations provided by the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) suggest that etomidate not be used routinely in children with septic shock. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Airway and breathing'.)

Etomidate has undergone increasing use for RSI in children and observational studies and case series indicate that it produces good intubating conditions with minimal hemodynamic changes and a low frequency of adverse events, even in hypovolemic patients or those with limited cardiac reserve [1-8].

Ketamine — Ketamine is a dissociative anesthetic that is derived from phencyclidine. It produces rapid sedation (induction), amnesia, and analgesia while preserving protective airway reflexes. The dose of ketamine used in RSI is 1 to 2 mg/kg IV with a time to effect of 45 to 60 seconds and a duration of action of 10 to 20 minutes, depending upon dose. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Ketamine'.)

Ketamine is generally considered the preferred agent in children with septic shock because, unlike etomidate, it does not cause adrenocortical suppression and, compared with other options (eg, midazolam, propofol, or thiopental) it does not cause hypotension. In addition, ketamine causes endogenous catecholamine release, thus augmenting heart rate and blood pressure in patients who are not catecholamine depleted. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Airway and breathing'.)

However, the physician should make every effort to reverse hypovolemia and to provide direct-acting vasopressors to counteract hypotension prior to ketamine administration because ketamine also has a direct negative inotropic effect. When given to patients in septic shock with exhausted endogenous catecholamine stores, it has rarely been associated with cardiac arrest that has been attributed to negative inotropic effect that is not overcome by release of endogenous catecholamines [9]. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent'.)

Catecholamine release associated with ketamine also results in bronchodilation in animal studies. Although direct evidence is lacking in children, it is suggested as the preferred agent for RSI in patients with status asthmaticus [10]. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent' and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'General use'.)

Ketamine may elevate ICP and theoretically has the potential for worsening ICP in patients with head injury, although evidence for adverse clinical effects in this population is weak. On the other hand, ketamine has anticonvulsant properties and may benefit patients with neurologic injury by increasing cerebral perfusion, particularly those who are hypotensive. Thus, it may still be appropriate for RSI in patients with increased ICP associated with low or normal blood pressure. However, we generally avoid it in patients who are hypertensive. The use of ketamine for patients with head injury is discussed in greater detail separately. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Elevated intracranial pressure'.)

The ketamine dose for RSI is well below doses associated with increased intraocular pressure. However, it frequently causes vomiting. Thus, in most patients with concern for an open globe, other sedatives are better choices. (See "Open globe injuries: Emergency evaluation and initial management", section on 'Initial emergency assessment and treatment'.)

Initial studies in children indicated ketamine was a potent sialogogue and recommended premedication with atropine [11,12]. However, more recent evidence suggests that excessive salivation is uncommon in doses typically used for RSI. As an example, in 947 pediatric sedations performed without atropine, significant salivation was reported in approximately 1 percent of patients and was felt to cause airway complications in only one instance [13]. Thus, the use of anticholinergic premedication for ketamine sedation during RSI is not routinely necessary.

Propofol — Propofol is a highly lipid soluble, nonbarbiturate sedative-hypnotic that binds the gamma-aminobutyric acid_A (GABA_A) receptor complex with resulting sedation (induction) and amnesia.

The initial dose of propofol used in hemodynamically stable children undergoing RSI is 1 to 1.5 mg/kg with an onset of effect in 15 to 45 seconds and duration of action of 5 to 10 minutes, depending upon dose. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Propofol'.)

Propofol is a good choice for RSI in hemodynamically stable patients with status epilepticus. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent'.)

However, the following characteristics limit its usefulness for RSI for patients who are hemodynamically unstable (see "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Propofol'):

●Vasodilatation and myocardial depression are even more pronounced with propofol than with thiopental.

●The neuroprotective effect of propofol can be offset by a decrease in cerebral perfusion pressure as a result of decreased arterial pressure.

Although the manufacturer lists egg or soybean allergies as contraindications to the use of propofol, significant allergic reactions to the newer preparation of the drug appear to be rare. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Hypnotic induction agents'.)

Midazolam — Midazolam is a rapid-acting benzodiazepine that binds the gamma-aminobutyric acid_A (GABA_A) receptor complex with potent amnestic and anticonvulsant properties, as well as a short duration of action.

The dose of midazolam used for RSI is 0.2 to 0.3 mg/kg IV with a time to effect of 2 to 3 minutes and a duration of action of that is approximately 30 to 45 minutes, depending upon dose. This dose is significantly higher than what is typically used for procedural sedation.

Midazolam is appropriate for RSI in hemodynamically stable children with status epilepticus. However, several factors make other agents preferable for most patients (see "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent' and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Benzodiazepines'):

●In children, the time to clinical effect is longer for midazolam than for any of the other sedative agents. Underdosing of midazolam may contribute to this observation [14]. However, several reports have noted that it inconsistently induces unconsciousness, even at appropriate doses [10,15].

●Midazolam also causes respiratory depression. As a result, patients may develop apnea before they have received a paralytic agent, decreasing the effectiveness of preoxygenation prior to intubation.

●Finally, midazolam has a myocardial depressant effect and produces a dose-related reduction in systemic vascular resistance. It should not be used in hemodynamically compromised patients.

Fentanyl — Fentanyl is a synthetic centrally acting opioid agonist that has a rapid onset of action, short duration of effect, and lack of histamine release.

The suggested dose of fentanyl for sedation (induction) during RSI ranges from 1 to 5 mcg/kg [16]. For children who are not in shock, the suggested dose is 3 mcg/kg (up to 5 mcg/kg). For children in shock, the physician should start at 1 mcg/kg and titrate to effect while monitoring hemodynamic status.

Fentanyl should be given slowly over 30 to 60 seconds to avoid respiratory depression that may compromise preoxygenation. Chest wall rigidity with inability to ventilate is a rare complication that is typically associated with rapid infusion and higher doses but has been reported with doses as low as 1 mcg/kg in neonates and infants [17].

Although evidence is lacking, fentanyl is favored by some experts for RSI in children with cardiogenic shock or shock with suspected catecholamine depletion (eg, patients with persistent hypotension despite receiving vasopressors).

Thiopental — Thiopental is no longer readily available nor widely used as a sedation (induction) agent for RSI. For those with access to these medications, a brief overview of its use is provided here.

The dose of thiopental used in RSI is 3 to 5 mg/kg IV with a time to effect of <30 seconds and a duration of effect of 5 to 10 minutes, depending upon dose. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Barbiturates'.)

Thiopental is a short-acting barbiturate with a rapid onset of action that has been used extensively for sedation and induction in RSI. It may provide better intubating conditions than etomidate, as was demonstrated in one large, prospective, observational series of adults and children where successful intubation on the first attempt was more likely with thiopental than with etomidate [4]. However, thiopental causes vasodilatation and myocardial depression, resulting in a decrease in systolic blood pressure. Thus, it should not be used in patients with cardiovascular instability. Furthermore, thiopental causes histamine release that may contribute to a decrease in systolic blood pressure and may exacerbate bronchospasm in patients with asthma or bronchospasm from other causes. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Barbiturates'.)

As long as cerebral perfusion pressure is maintained, thiopental provides neuroprotection through reduction in cerebral oxygen consumption and blood flow. It also has anticonvulsant properties, making it a preferred sedative for patients with neurologic injury who are hemodynamically stable. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Barbiturates'.)

Production of thiopental was discontinued by the sole United States manufacturer in 2011, and it is not available in the United States, Canada, and many other countries [18].

PARALYTIC AGENTS — Paralytic agents provide complete muscle relaxation, which facilitates rapid tracheal intubation. They do not provide sedation, analgesia, or amnesia. As a result, a sedative agent must also be used both for RSI and when paralysis is maintained after intubation. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent'.)

Each of the major paralytic agents in common use for pediatric RSI is provided in the rapid overview (table 1) and discussed below. Further information about each of these drugs including pathophysiology and use in adults is provided separately. (See "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)

Succinylcholine — Succinylcholine is the classic depolarizing agent, which acts as an analogue of acetylcholine (ACh) with stimulation of all cholinergic receptors throughout the parasympathetic and sympathetic nervous systems. Succinylcholine binds directly to the postsynaptic ACh receptors of the motor endplate, causing continuous stimulation of these receptors. This effect leads to transient fasciculations followed by muscular paralysis. Evidence regarding the relative efficacy of succinylcholine versus other paralytic agents is presented in the next section. (See 'Rocuronium' below.)

The dose of succinylcholine for infants and children younger than two years of age is 2 mg/kg intravenous (IV), which is higher than that recommended for older children and adolescents. This is because succinylcholine is rapidly distributed in extracellular water, and infants and young children have a larger relative volume of extracellular fluid [19,20]. For older children and adolescents, the dose of succinylcholine is 1 to 1.5 mg/kg. Succinylcholine has a rapid onset of effect (30 to 60 seconds, IV) and short duration of action (4 to 6 minutes, IV). (See "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Succinylcholine'.)

Bradycardia following the administration of succinylcholine occurs more commonly in infants and children younger than five years of age. The risks of bradycardia and, sometimes, asystole are also more significant when repeated doses of succinylcholine are administered [21,22]. To avoid these complications, many experts suggest pretreating with atropine for children younger than five years of age and for all patients when a second dose is required. Repeated doses of succinylcholine should be avoided whenever possible. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Pretreatment'.)

Due to adverse effects, the use of succinylcholine is absolutely contraindicated under the following circumstances (see "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Contraindications and side effects'):

●Chronic skeletal muscle disease (eg, Becker or Duchenne muscular dystrophy)

●Denervating neuromuscular disease (eg, cerebral palsy with paralysis)

●>48 hours after burns, multiple traumas, or an acute denervating event (eg, stroke or spinal cord injury)

●Extensive crush injury with rhabdomyolysis

●History of malignant hyperthermia in patient or relatives

●Significant hyperkalemia (eg, suggested by characteristic changes on electrocardiogram)

Relative contraindications to the use of succinylcholine include:

●Increased intracranial pressure – Although evidence supports elevated ICP related to fasciculations in adults [23], many experts do not regard the potential for increased ICP as a contraindication to use of succinylcholine in children with traumatic brain injury. (See "Severe traumatic brain injury (TBI) in children: Initial evaluation and management", section on 'Rapid sequence intubation'.)

●Increased intraocular pressure [10].

●Known pseudocholinesterase deficiency (risk for prolonged duration of action) [20].

Elevated intracranial pressure (ICP) with the use of succinylcholine has been reported in animal studies and in humans with brain tumors. Although a systematic review found no definitive evidence that succinylcholine causes a rise in ICP in humans with brain injury, the available studies are small and of poor quality [24]. Thus, most experts do not regard the potential for increased ICP as a contraindication to use of succinylcholine for RSI.

Rocuronium — Rocuronium is a nondepolarizing paralytic agent that induces muscle paralysis by competitive antagonism at the nicotinic cholinergic receptor. At a dose of 1 mg/kg, it has a rapid onset of effect (30 to 60 seconds, IV), but a duration of action that is considerably longer than succinylcholine (30 to 40 minutes) [6]. For this reason, succinylcholine is favored over rocuronium for RSI when rapid reversal with sugammadex is not available, especially if a difficult airway is anticipated. (See "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Succinylcholine'.)

We suggest using rocuronium, at a dose of 1 mg/kg, as the paralytic agent for RSI when succinylcholine may be contraindicated. Superior intubating conditions are a more important consideration than prolonged duration of action under these circumstances.

When sugammadex is readily available, rocuronium, in a dose of 1 mg/kg, followed by sugammadex reversal may be equivalent to succinylcholine with respect to intubating conditions and avoids the problem of prolonged paralysis, although evidence is limited. (See 'Sugammadex' below.)

Rocuronium has none of the adverse effects of succinylcholine, such as bradycardia, hyperkalemia, or malignant hyperthermia, making it a safe and efficacious alternative. As a result, some experts prefer the disadvantage of a longer duration of paralysis with rocuronium to the small risk of using succinylcholine for a child with an undiagnosed contraindication, such as a congenital myopathy or malignant hyperthermia [10]. In addition, in a meta-analysis of 26 trials (3 in children), rocuronium at a dose of 1 mg/kg was equivalent to succinylcholine for producing clinically acceptable intubating conditions [25,26]. However, the duration of action of rocuronium is longer at the higher dose and succinylcholine is more likely to provide excellent intubating conditions.

Vecuronium and pancuronium — Vecuronium is the nondepolarizing agent from which rocuronium was developed. Like rocuronium, it has a favorable safety profile. However, to achieve as rapid an onset of action as rocuronium, higher doses of vecuronium (eg, 0.15 to 0.2 mg/kg) must be used, which also prolongs paralysis in an unpredictable fashion unless reversed by sugammadex.

Vecuronium should be avoided in patients for whom endotracheal intubation is predicted to be difficult. In two trials that compared vecuronium with rocuronium for RSI, intubating conditions were less optimal in patients who received vecuronium compared with those who received rocuronium [27,28]. For these reasons, its usefulness for RSI is limited.

Pancuronium is a longer acting nondepolarizing neuromuscular blocking agent that should not be used for RSI outside of the operating room because of its slower onset of action and prolonged duration. Pancuronium also causes histamine release and has a pronounced vagolytic effect that increases heart rate, blood pressure, and cardiac output.

SUGAMMADEX — Sugammadex is a novel agent that encapsulates and binds with molecules of rocuronium and other steroidal neuromuscular blocking agents (NMBAs; eg, vecuronium and pancuronium), thereby rapidly reversing their neuromuscular blocking effects. Limited evidence suggests that sugammadex has a similar safety profile in children 2 to 17 years of age as in adults [29]. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Sugammadex'.)

Although variations in individual patient response have been noted, a dose of 16 mg/kg can reverse profound rocuronium-induced blockade within three minutes. Cardiac arrhythmias, including marked bradycardia, may occur after administration of sugammadex. Patients with cardiac disease appear to be at increased risk. Although rare, anaphylaxis within minutes after sugammadex administration has occurred, and the incidence is proportional to the administered dose. Thus, full electrocardiography (ECG) monitoring should be continued during and after administration of sugammadex, and resuscitation drugs, including atropine and epinephrine, should be immediately available.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Airway management in children".)

SUMMARY AND RECOMMENDATIONS

●Definition – Rapid sequence intubation (RSI) describes a sequential process of preparation, sedation, and paralysis to facilitate safe, emergency tracheal intubation. Pharmacologic sedation and paralysis are induced in rapid succession to perform laryngoscopy and tracheal intubation. (See 'Rapid sequence intubation' above.)

●Rapid overview and checklist – A rapid overview with drug doses and a checklist provide a simple systematic approach to preparation and performance of RSI in children (table 1 and figure 1). This approach is discussed in detail separately. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Approach'.)

●Sedation (induction) – Sedation (induction) agents are integral to the performance of RSI. They provide amnesia, unconsciousness, blunt sympathetic responses, and can improve intubating conditions:

•Etomidate – Etomidate is an effective induction agent for most children undergoing RSI and is especially useful for patients with hypovolemic shock (eg, pediatric trauma patients), hypotensive patients with status epilepticus, and those with increased intracranial pressure (ICP). (See 'Etomidate' above and "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of sedation (induction) agent'.)

•Ketamine – Ketamine is generally considered the preferred agent in children with septic shock because, unlike etomidate, it does not cause adrenocortical suppression and, compared with other options (eg, midazolam, propofol, or thiopental), it does not cause hypotension. (See 'Ketamine' above.)

•Propofol and midazolam – Propofol and midazolam are appropriate for RSI in hemodynamically stable children with status epilepticus. Otherwise, other agents are preferable because both agents can cause hypotension or myocardial depression. (See 'Propofol' above and 'Midazolam' above.)

•Fentanyl – Fentanyl is favored by some experts for RSI in selected children with cardiogenic shock or shock with suspected catecholamine depletion (eg, patients with persistent hypotension despite receiving vasopressors). (See 'Fentanyl' above.)

●Paralytic agents – Paralytic agents provide complete muscle relaxation, which facilitates rapid tracheal intubation. They do not provide sedation (induction), analgesia, or amnesia. Thus, a sedation (induction) agent must also be used both for RSI and when paralysis is maintained after intubation. Succinylcholine, if not contraindicated, or rocuronium with sugammadex immediately available are suggested paralytic agents for children undergoing RSI. (See 'Paralytic agents' above and "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Selection of paralytic agent'.)

●Sugammadex – Sugammadex is a novel agent that encapsulates and binds with molecules of rocuronium and other steroidal neuromuscular blocking agents (NMBAs; eg, vecuronium and pancuronium) thereby rapidly reversing their neuromuscular blocking effects. (See 'Sugammadex' above.)