Pharmacology for Rapid Sequence Intubation (RSI) Airway Management in Trauma Patients

Abstract

The primary survey of every trauma patient begins with ABC: airway, breathing, circulation. If the patient is deemed to require airway management, endotracheal intubation may be performed utilizing rapid sequence intubation (RSI). In RSI, an induction agent and a rapid-acting neuromuscular blocking agent (NMBA or paralytic) are administered and intubation is performed as soon as unconsciousness and paralysis are achieved.¹ Trauma patients may require intubation for a number of reasons (Table 1) including, but not limited to, hypoxia, hypoventilation, potential for deterioration in clinical status, or failure to maintain or protect the airway due to altered mental status or injury to the head or neck.²  Historically RSI was described as a series of “seven p’s”: (1) preparation, (2) preoxygenation, (3) pretreatment, (4) paralysis with induction, (5) protection and positioning, (6) placement of the tube in the trachea, and (7) postintubation management.³ For this review, we will focus on the pharmacology, dosing, and other considerations for use of common medications for pretreatment, paralysis with induction, and post-intubation management in trauma patients.

Pretreatment

During endotracheal intubation there may be stimulation of both sympathetic and parasympathetic nerves in the airway. Sympathetic stimulation may result in an increase in heart rate of up to 30 beats per minute and an increase in mean arterial pressure (MAP) of approximately 25–50 mmHg, which may contribute to increases in intracranial pressure (ICP).⁴ Conversely, pediatric patients may develop bradycardia from parasympathetic stimulation due to hypoxia or direct vagal stimulation from manipulation of the laryngopharynx during intubation.⁵ Additionally, the physical act of placing the endotracheal tube also stimulates upper-airway reflexes, resulting in cough, laryngospasm, and lower-airway bronchospasm, which may also contribute to increases in ICP.³ The goal of pretreatment is to mitigate these physiologic responses. 

Fentanyl may be used to blunt the sympathetic response to intubation. Consider pretreatment with fentanyl for patients who are at greatest risk of harm from elevated heart rate, blood pressure, or ICP. These patients may include those with increased ICP (with or without intracranial hemorrhage), known or suspected cerebral or aortic aneurysm, or major vessel dissection.³ Avoid fentanyl pretreatment in patients who are dependent on sympathetic drive to maintain their cardiac output, such as those who are in decompensated shock or are hemodynamically unstable. The onset of action of fentanyl is nearly instantaneous and the duration of action is approximately 30–60 minutes.⁶ Fentanyl should be administered approximately three minutes prior to the induction agent at a dose of 1–3 mcg/kg IV. The pretreatment dose should be given over 30–60 seconds to avoid precipitous respiratory depression. Higher doses (5–10 mcg/kg) of fentanyl have been implicated in causing excessive hypotension, apnea, and chest wall rigidity.⁴

The term “hemodynamic instability" is used in the literature without full general consensus. Different authors employ varying criteria to define hemodynamic instability. These criteria most often include disturbances in heart rate, systolic blood pressure, and respiratory rate. The cutoff points also vary, with average numbers being >103 bpm, <96 mmHg, and <34 breaths per minute.⁴⁷

Atropine may be used as a premedication for patients who are bradycardic prior to intubation or are at risk of becoming bradycardic during intubation due to vagal stimulation or succinylcholine use. Succinylcholine has the potential to cause or worsen bradycardia due to its action on muscarinic receptors. The incidence and severity of this bradycardia is more common in children than adults.⁷  The 2020 PALS guidelines state that it “may be reasonable” to use atropine as a premedication for intubation to prevent bradycardia in high risk patients, such as those younger than one year of age or those receiving succinylcholine.⁸ Consider atropine administration for adult and adolescent patients receiving a second dose of succinylcholine. The dose of atropine to prevent bradycardia is 0.02 mg/kg (maximum dose 0.5 mg).^8, 9 The effects of atropine on heart rate are nearly immediate when given intravenously, and persist for up to four minutes.¹⁰ 

Lidocaine has been used to blunt the cough response to intubation and its effect on hemodynamics and ICP.^3, 4 The significance of the effect is unknown—no studies have been published assessing the effects of lidocaine and intubation on ICP or patient-centered outcomes.¹¹ One study found no difference in  hemodynamics for patients with severe traumatic brain injury (TBI) whether they received intravenous lidocaine or not before intubation.¹² Currently lidocaine pretreatment is not recommended.^11, 13 If lidocaine is used for pretreatment, the typical dose is 1.5 mg/kg given three minutes prior to induction.³ At this dose the onset of action of lidocaine is less than a minute and the duration of action is 10–20 minutes.  Lidocaine is metabolized by the liver and the duration may be doubled in patients with significant hepatic dysfunction. 

Induction

The goal of induction is to rapidly sedate the patient to a state of general anesthesia, allowing for the administration of paralytics and facilitating conditions for ideal intubation. The optimal induction agent has a smooth and rapid onset of sedation while providing amnesia and analgesia. This ideal agent would be hemodynamically neutral, immediately reversible, and have minimal adverse effects.¹ While no single agent encompasses all of these qualities, patient-specific factors drive the selection of the most appropriate induction agent for the clinical scenario. A 2016 registry of U.S. academic emergency department intubations found etomidate to be the the most common induction agent used for RSI, followed by ketamine and then propofol.¹⁴ 

Etomidate is a non-barbiturate hypnotic agent that provides rapid sedation without analgesia by enhancing the effects of GABA. The popularity of etomidate can be attributed to its stable hemodynamic profile and potential to lower ICP as well as its reliable pharmacokinetic and pharmacodynamic effects.^3, 4 However, single-doses of etomidate are associated with adrenal suppression. 

The clinical significance of this beyond sepsis has been debated, but a study comparing etomidate to ketamine for induction in trauma patients did not find a difference in rates of mortality, intensive care unit (ICU)-free-days, or ventilator-free-days.¹⁵ Clinicians must weigh the benefits of rapid induction and hemodynamic stability provided by etomidate against the potential risks of adrenal suppression. Alternative agents like ketamine or propofol may be considered, especially in patients at higher risk of adrenal insufficiency (e.g., those with sepsis or chronic illness). While etomidate remains a valuable agent, its use requires thoughtful consideration. A balanced approach, informed by the patient’s condition is crucial.⁴⁶

One distinct advantage of etomidate over other induction agents is that it is not a controlled substance and therefore does not require additional documentation during storage or wastage of unused medication. The dose of etomidate for RSI is 0.3 mg/kg. The onset of action is less than one minute and duration of action is three to five minutes.¹⁶

The use of ketamine for induction has increased in popularity due to its favorable hemodynamic profile and in response to the concern for adrenal suppression with etomidate. Ketamine is an NMDA-receptor antagonist that provides rapid sedation, analgesia, and amnesia. Interestingly, ketamine has indirect sympathomimetic effects by inhibiting reuptake of endogenous catecholamines, resulting in increased heart rate and blood pressure.¹⁵ However, ketamine also has direct myocardial depressant effects which may be more pronounced in catecholamine-depleted patients.¹⁵ While there are concerns that the myocardial depression could outweigh sympathomimetic effects in critically ill septic patients, this finding has not persisted when looking specifically at use of ketamine for RSI in trauma patients.^15, 17 Historically, ketamine was avoided in patients with elevated intraocular pressure (IOP) or ICP. However, current evidence suggests that ketamine does not increase ICP in patients with a severe TBI who are sedated and ventilated (Oxford level 2b, GRADE C). In fact, it may even lower ICP in certain cases.⁴⁶  The induction dose of ketamine is 1–2 mg/kg with an onset of approximately 30 seconds and a dose-dependent sedation duration of five to ten minutes.¹⁸ Of note, rapid administration of ketamine over less than 60 seconds can result in apnea, so timing is imperative while facilitating intubation.

Less common agents for RSI induction include propofol and midazolam. Propofol is a highly lipid-soluble GABA agonist with a rapid onset of sedation.¹ However, bolus doses of propofol decrease MAP via reductions in preload, afterload, and decreased contractility.³ These characteristics contribute to propofol’s ability to decrease ICP, so propofol may be a reasonable option in hemodynamically stable or hypertensive patients with elevated ICP. When compared to non-propofol induction (etomidate or midazolam), one study found that after adjusting for age, injury severity score, and pre-RSI hypotension, propofol was nearly four times as likely to cause postintubation hypotension in traumatically injured patients.¹⁹  While propofol is formulated in an emulsion with soybean oil and egg lecithin, the American Academy of Allergy Asthma & Immunology states that patients with soy or egg allergies can receive propofol without any special precautions.²⁰ The dose of propofol for induction is 1.5–2.5 mg/kg, with dose reductions for hemodynamically unstable patients.^1, 3Midazolam is uncommonly used as the sole induction agent for RSI due to its slower onset of action (up to five minutes) and unreliable level of sedation.¹ The onset time can be improved to 90 seconds with the coadministration of fentanyl. The induction dose of midazolam is 0.2-0.3 mg/kg.^1, 3 Providers may be unfamiliar and uncomfortable with the administration of large doses of midazolam and may need assurance that these doses are indicated to provide the level of sedation necessary to provide amnesia and optimize intubating conditions. Midazolam exhibits dose-dependent decreases in systemic vascular resistance and myocardial depression and should be used with caution in patients with hemodynamic instability.¹ Midazolam use for induction should be reserved for patients with specific indications (seizures) or when other agents are unavailable due to medication shortages.

Paralysis

Succinylcholine

Succinylcholine, a depolarizing neuromuscular blocking agent, has a fast onset and short duration of action. These properties make it ideal for use in RSI for trauma patients. It allows for accurate assessment of post-intubation sedation levels and is especially ideal if there is concern for a difficult airway or need for an accurate neurological assessment shortly after intubation. At a dose of 1.5 mg/kg, it provides an onset within 45 seconds and a duration of 6–10 minutes.²¹

However, several considerations exist which may limit use in specific patients. First, succinylcholine is contraindicated in patients with a personal or family history of malignant hyperthermia.⁷  Second, succinylcholine can cause a profound hyperkalemia in some patients, leading to ventricular arrhythmias and cardiac arrest. In most patients, succinylcholine will cause an average increase of 0.3–1 mEq/L in serum potassium.^1, 22 However, in patients with a predisposition to hyperkalemia, this increase can be 5–10 mEq/L, which can cause ventricular arrhythmias and cardiac arrest.^21, 23 Thus, succinylcholine should also be avoided in patients with symptomatic hyperkalemia, end-stage renal disease, rhabdomyolysis, or any diseases causing extensive denervation of skeletal muscle (e.g., multiple sclerosis, muscular dystrophy).¹ The risk of succinylcholine-induced profound hyperkalemia in crush injury, denervation injury, or burns develops after the acute phase (approximately 3–5 days after injury, or 7–10 days post-burn), so it is safe to use succinylcholine in an otherwise healthy patient during the initial 24–48 hours of acute crush or burn injuries. There is also a black box warning for acute rhabdomyolysis and cardiac arrest developing when succinylcholine is used in pediatric patients who are subsequently found to have skeletal muscle myopathy (i.e. Duchenne’s muscular dystrophy).⁷ Some centers avoid succinylcholine altogether in pediatric patients to avoid this risk, though most would still consider its use for emergent intubations in otherwise healthy patients. Finally, a retrospective study at one trauma center found an association between succinylcholine use and increased mortality in severe TBI patients,²⁴ though others still recommended succinylcholine use in TBI when no contraindications exist.¹³

Rocuronium

In the context of a modified RSI, rocuronium emerges as the only alternative. It is noteworthy that the required dosage for this application is approximately double the standard induction dose of rocuronium.

Rocuronium, an aminosteroid nondepolarizing neuromuscular blocking agent, has an onset of about 1–2 minutes at doses of 1 mg/kg.^25, 26 Higher doses of ≥1.4 mg/kg were associated with improved first-attempt success with direct laryngoscopy in hypotensive patients ages ≥14 years in a study of the National Emergency Airway Registry.²⁷ Rocuronium duration is dependent on dose and hepatic function. At usual intubating doses, the duration is about 40–90 minutes, but can last up to 120 minutes or more in some patients.²⁵ In contrast to succinylcholine, rocuronium has only one contraindication—history of anaphylaxis to rocuronium or other NMBAs. Thus, it is often chosen in the trauma patient where medical history is unknown or lab values have not yet resulted. 

Two main drawbacks of rocuronium exist for trauma patients—both as a consequence of its significantly longer duration of action. As will be discussed in post-intubation sedation, inadequate doses, or delayed initiation of analgosedation are more likely to occur.^28, 29 Prolonged paralysis also inhibits the ability to obtain a neurological exam. Reversal agents for rocuronium exist, but these also carry risks. Neostigmine, a cholinesterase inhibitor, can be given once the patient has recovered some neuromuscular function (i.e., train-of-four of at least 2 out of 4).³⁰ An anticholinergic agent, such as atropine or glycopyrrolate, is given concurrently to reduce the risk of bradycardia due to muscarinic receptor activation.²¹ Sugammadex is a novel cyclodextrin that binds to rocuronium or vecuronium in plasma, reducing the effective amount of NMBA available to bind acetylcholine receptors at the neuromuscular junction. Sugammadex has the advantage of being able to reverse any degree of neuromuscular blockade, including a deep block. The sugammadex-rocuronium complex is renally cleared, and is not recommended for use in patients with creatinine clearance of < 30 mL/min due to prolonged elimination and potential risk for rebound paralysis.³¹ Sugammadex has also been associated with anaphylaxis, bradycardia, and cardiac arrest, so caution is warranted. Sugammadex also binds and reduces the effectiveness of oral or non-oral hormonal contraception for 7 days after use, requiring a backup contraception method.³¹

Other Nondepolarizing NMBAs

Two other nondepolarizing agents are not commonly used for RSI due to their pharmacokinetic properties. Vecuronium, an aminosteroid, has an onset of 2–3 minutes and duration of 60–80 min at a standard dose of 0.08–0.1 mg/kg.³² In addition, vecuronium is supplied as a powder requiring reconstitution, adding another step to the process of preparing medications in an urgent intubation. Cisatracurium is a benzylisoquinolinium nondepolarizing NMBA with an onset of 2–3 minutes and duration of 55–80 minutes at an intubating dose of 0.15 mg/kg, and cannot be reversed using sugammadex.³³ It has organ-independent metabolism via Hofmann elimination. Both agents could be considered as alternatives in the case of drug shortage of rocuronium, keeping in mind the slower onset.

Post-intubation Analgosedation

Once the patient has been intubated, it is imperative that we provide adequate analgesia and sedation for our patients’ safety and comfort. Due to the shorter duration of action of succinylcholine, we can accurately assess a patient’s level of pain and sedation relatively quickly after intubation. However, if using rocuronium for RSI, the mismatch in duration of induction agent compared with paralytic has been associated with delayed or inadequate sedation which puts the patient at risk of awareness with paralysis.^26, 27 In a recent study, 2.6% of patients intubated in the Emergency Department were determined to have suffered awareness with paralysis, and this risk was found to be significantly higher with rocuronium compared to succinylcholine.³⁴

The 2018 PADIS guidelines recommend protocol-driven analgosedation for management of pain and agitation, where an analgesic agent (usually an opioid) is used either before a sedative, or instead of a sedative.³⁵ Considering that patients In the trauma bay are likely to have painful injuries, this approach is prudent. In addition, the patient may benefit from the amnestic effects of a sedative agent. 

There are multiple strategies for analgosedation, but opiates remain the mainstay of therapy. Fentanyl is often chosen due to its fast onset of action, neutral hemodynamic effects, and short duration when given as a single bolus. With repeated doses or a continuous infusion, fentanyl will display two-compartment model pharmacokinetics, leading to a prolonged duration of action, especially in patients with heart failure, liver disease, or larger weight.³⁶ Providing an initial bolus dose followed by a continuous infusion allows faster titrations and gives the ability to deliver further bolus doses via the infusion pump. This is ideal both for safety and to reduce the need for a nurse or pharmacist to return to the automated dispensing cabinet repeatedly during the remainder of the trauma assessment and imaging studies. Fentanyl infusions are commonly available as premixed continuous infusions, thus may be more quickly accessible in the emergency department compared to other opiate infusions.

If succinylcholine is used for RSI, follow-up assessments of the level of pain and sedation using standard scales can drive the decision to increase the dose of fentanyl or add on a sedative agent.^37, 38 However, if rocuronium is used and not reversed, these scales are not valid assessments of pain and sedation. Thus, it is important to use the information from the patient’s initial presentation to determine if a sedative agent should be started empirically in addition to fentanyl. For example, in a patient initially agitated and intoxicated with methamphetamine or ethanol, propofol or a benzodiazepine will provide a desired pharmacological effect to combat the intoxication.

The 2018 PADIS guidelines suggest the use of continuous infusion propofol or dexmedetomidine over benzodiazepines for the sedation of mechanically ventilated patients due to decreased ICU length of stay, duration of mechanical ventilation, and delirium.³⁵ When given as a continuous infusion propofol has a rapid onset and short duration of sedation which is ideal when interruptions are necessary to evaluate a patient’s mental status. Propofol may be neuroprotective in sedated patients with TBI due to its inherent antioxidant properties as well as its potential to reduce cerebral oxygen consumption and ICP.^39, 40 While hypotension is a known side effect of propofol, it can be profound. One study found that a SBP decrease of approximately 30 mmHg was more likely in trauma patients older than 55 years, obese, and those with lower baseline SBP.⁴¹  Consider a lower initial propofol infusion dose and utilizing ideal body weight for these patients. Hypotension can be mitigated using either push-dose or continuous infusion vasopressors, in addition to ATLS-driven resuscitation with fluids and blood products.

Dexmedetomidine is another common sedative agent, an alpha-2 agonist with opiate-sparing properties, and is a preferred agent for ICU sedation.³⁵ However, dexmedetomidine is less ideal in the immediate post-intubation period in a trauma patient, as it has a longer onset of action and does not provide a deep enough level of sedation for a patient who remains under the effects of a long-acting NMBA. 

Both propofol and dexmedetomidine have been implicated in causing hypotension and bradycardia. One study comparing propofol to standard-dose (≤0.7 mcg/kg/hr) and high-dose (>0.7 mcg/kg/hr) dexmedetomidine in the trauma ICU found that high-dose dexmedetomidine infusions were associated with increased ICU LOS, higher rates of hypotension, and increased use of analgesics, sedatives, and antipsychotics.^42, 43 Specifically in TBI patients, Pajoumand and colleagues showed that patients receiving dexmedetomidine monotherapy had higher mean maximum ICP during the first two days of admission compared to dexmedetomidine-propofol or propofol monotherapy, despite greater time at goal level of sedation.⁴² However, a more recent study found that with prolonged use in the ICU patients receiving dexmedetomidine spent a significantly greater time at their target level of sedation compared to propofol, although both groups were at target >90% of the time.⁴³ Propofol, in addition to adequate analgesia, may be a more desirable sedative early in the course of treatment of the trauma patient, especially those requiring ICP management.

An alternative for immediate sedation in the hypotensive trauma patient is midazolam. Midazolam is a short-acting benzodiazepine with IV onset within 3–5 minutes and peak effect at 30–60 minutes in adults, 15–30 minutes in pediatrics.⁴⁴ It has relatively neutral hemodynamic effects. One common strategy is to dose midazolam as intermittent boluses during the trauma survey and imaging studies, and transition to a preferred continuous infusion sedative agent after transfer to the ICU.⁴⁵

Conclusion

There are many medication options for RSI pretreatment, induction, paralysis, and post-intubation sedation. Selection of agents for the trauma patient will depend on the presenting injuries, available medical history, hemodynamic profile, and desired strategy. If a long-acting NMBA is chosen for RSI and not reversed, it is important to begin empiric analgosedation to avoid awareness with paralysis.

Figures and Tables

Table 1. Indications for Emergency Tracheal Intubation²

Level 1

1. 1. Indicated in trauma patients with the following traits:
      1. Airway obstruction
      2. Hypoventilation
      3. Persistent hypoxemia (SaO2 </ 90%) despite supplement O₂
      4. Severe cognitive impairment (GCS </8)
      5. Severe hemorrhagic shock
      6. Cardiac arrest
   2. Indicated for patients with smoke inhalation and any of the following traits:
      1. Airway obstruction
      2. Severe cognitive impairment (GCS </8)
      3. Major cutaneous burn (>/ 40%)
      4. Major burns and/or smoke inhalation with an anticipated prolonged transport time to definitive care, and
      5. Impending airway obstruction as follows:
         1. Moderate-to-severe facial burn
         2. Moderate-to-severe oropharyngeal burn, and
         3. Moderate-to-severe airway injury seen on endoscopy.

Level 2—No recommendations

Level 3

1. 1. Intubation may be indicated in trauma patients with any of the following traits:
      1. Facial or neck injury with the potential for airway obstruction.
      2. Moderate cognitive impairment (GCS score >9–12).
      3. Persistent combativeness refractory to pharmacologic agents.
      4. Respiratory distress (without hypoxia or hypoventilation).

Table 2. Properties of Medications used for Pretreatment, Induction, Paralysis, and Post-intubation Sedation

Figure 1. Onset and duration of induction and paralytic agents.