Induction of Intubation and Sedation of the Mechanically Ventilated Patient

Jin H. Han and Pratik Pandharipande

BACKGROUND

Sedation is the pharmacologic reduction of agitation and anxiety, and it is an indispensable tool for the clinician treating critically ill emergency department (ED) patients. Sedation is used in the induction of intubation, as well as for maximizing comfort and reducing anxiety in the already intubated patient. Choice of sedative agents in the ED may have ramifications in the intensive care unit (ICU) and hospital course and may affect patient outcomes. This chapter reviews the pharmacologic agents used for the induction for intubation and for the sedation of mechanically ventilated patients.

INDUCTION AGENTS

The ED is frequently tasked with the initial management of a critically ill patient’s airway. Induction for endotracheal intubation employs sedatives—called, in this context, induction agents—at doses that typically suppress ventilation. Etomidate, ketamine, barbiturates (methohexital), benzodiazepines (midazolam), and propofol have all been used in this capacity (Table 58.1).

TABLE 58.1 Induction Agents for Intubation in the Emergency Department

ICP, intracranial pressure. Consider using the lowest dose of induction agent possible to minimize precipitating or exacerbating hemodynamic instability.

Etomidate

Etomidate is a carboxylated imidazole derivative that is a potent hypnotic and activates the γ-aminobutyric acid type A (GABA) receptors in the brain; it has no analgesic effects.¹ For induction of intubation, the etomidate dose is 0.3 mg/kg given intravenously (IV).² Etomidate is an ideal induction agent in the ED because it has rapid and predictable onset of action (5 to 15 seconds), a short duration of action (5 to 14 minutes), negligible effect on spontaneous respiration at lower doses, and no direct effects on cardiac output or vascular resistance.¹^,³^,⁴ Etomidate may be particularly useful in patients with suspected traumatic brain injury or intraocular injuries; by reducing cerebral blood flow and oxygen consumption, it can decrease intracranial and intraocular pressure.³

It should be noted that etomidate use can lead to adrenal suppression, and as such its safety has come into question. Etomidate inhibits the 11β-hydroxylase enzyme, which is involved in the production of cortisol. A single dose of etomidate can cause adrenal suppression for up to 72 hours, but whether this has a clinically relevant effect on outcomes has been a source of significant controversy.⁵

A recent meta-analysis that included five studies reported that critically ill patients who were septic and received etomidate were more likely to die (relative risk = 1.20).⁶ However, only two of the five studies included in this meta-analysis were primary analyses of randomized controlled trials.⁷^,⁸ A recent retrospective cohort study enrolled 2,014 septic patients and reported that one-time etomidate use was not associated with ICU mortality, hospital mortality, vasopressor use, duration of mechanical ventilation, or ICU length of stay (LOS) in the unadjusted and adjusted models.⁹ However, the limitations of retrospective studies are well documented, and larger randomized controlled trials comparing etomidate with other induction agents are needed.

Data regarding the safety of etomidate in nonseptic patients are even more uncertain, as there are few rigorously performed randomized controlled trials comparing etomidate to other induction agents. An association between single-dose etomidate and adverse outcomes (mortality, hospital LOS, ventilator days) has been noted in several retrospective cohort studies of critically ill patients.¹⁰^,¹¹ One randomized controlled trial enrolled 469 critically patients with and without sepsis and compared etomidate with ketamine.⁸ Though the etomidate group was more likely to have adrenal sufficiency, no significant difference in 28-day mortality was observed in the septic and nonseptic groups. There was, however, a trend toward increased vasopressor use in the etomidate group compared with the ketamine group (59% vs. 51%).⁸

Some clinicians have advocated the use of supplemental hydrocortisone and/or fludrocortisone when etomidate is administered for intubation.¹² In a secondary analysis of a major randomized controlled trial comparing the role of corticosteroids in septic shock, it was found that patients who received hydrocortisone and fludrocortisone for 7 days had lower 28-day mortality rates compared with patients who received placebo (55% vs. 76%).¹³^,¹⁴ However, two additional studies compared hydrocortisone with placebo in patients who received etomidate and observed no improvement in mortality in patients with and without septic shock.¹⁵^,¹⁶

Based upon these limited data, etomidate should be used judiciously in patients with sepsis; however, given its favorable hemodynamic profile, etomidate is still preferable to propofol or barbiturates in unstable patients. In nonseptic patients, despite the reports of adrenal insufficiency, the effect of etomidate on patient outcomes remains uncertain.

Myoclonus is another, albeit less serious, side effect of etomidate and has been reported to occur in 10% to 80% of patients when a paralytic is not used.³ For intubations without neuromuscular blockade, premedication with fentanyl or diazepam prior to etomidate administration may help reduce the incidence of myoclonus.³

Ketamine

Ketamine is a promising alternative to etomidate since it does not, in most cases, affect blood pressure or cardiac output and can be used safely in patients who are hemodynamically unstable. Ketamine is a dissociative agent that has anesthetic, amnestic, and anxiolytic properties. Unlike most other induction agents, it also provides analgesia. Ketamine noncompetitively inhibits glutamate at the N-methyl-d-aspartate receptors and causes dissociation between the thalamoneocortical and limbic regions of the central nervous system (CNS).² Ketamine may also have theoretical benefit in patients with asthma exacerbations; it causes an increase in serum catecholamine levels and may cause bronchodilation.² Lastly, patients who receive ketamine are typically able to maintain their respiratory effort and have preserved airway reflexes. For intubation, the dose is 1 to 2 mg/kg IV with an onset of action of approximately 30 seconds.²

Ketamine stimulates catecholamine release, but it can also cause slight myocardial depression.¹⁷ Typically, the sympathomimetic stimulation overcomes the myocardial depression and causes an increase in heart rate, blood pressure, and cardiac output.¹⁸ Theoretically, patients who have been physiologically stressed for a prolonged period of time may be depleted of endogenous catecholamines, allowing for the myocardial depression to dominate and cause hypotension. Because of this theoretical risk, ketamine should be used cautiously in patients in whom catecholamine depletion is suspected. Because ketamine increases myocardial oxygen demand, it should also be used cautiously in patients with coronary artery disease and avoided in patients who have evidence of myocardial ischemia.¹⁸ Ketamine can also cause an increase in heart rate and blood pressure and should be used cautiously in patients who are hypertensive or tachycardic.

Traditionally, ketamine has also been used with caution in patients with traumatic brain injury because early small observational trials observed an increase in intracranial pressure (ICP).¹⁹ More recent studies have failed to record a statistically significant increase in ICP, but these studies were similarly limited by their small sample sizes.¹⁹ Until more definitive evidence is available, caution should be exercised with ketamine in this population.

Barbiturates

Barbiturates, such as methohexital, are CNS depressants that exert effects on the GABA receptors and have anxiolytic and sedative properties. Because barbiturates decreases cerebral blood flow and the brains’ metabolic demands, they may have a protective effect in head injury patients. Barbiturates also have anticonvulsant properties and may be advantageous to patients who are actively seizing or who have a history of seizure disorder. However, since barbiturates can cause myocardial depression and peripheral vasodilatation, they are seldom used for intubation in the ED, where patients needing intubation are frequently hemodynamically unstable.² Barbiturates can also induce aminolevulinic acid synthetase and can precipitate acute porphyric crisis and should be avoided in patients with a history of porphyric disorders.²⁰ Standard induction dose for methohexital is 1 to 1.5mg/kg/IV.²

Benzodiazepines

Benzodiazepines also act on the GABA receptor and have sedative, hypnotic, amnestic, anxiolytic, and anticonvulsant properties, but provide no analgesia.² Midazolam (0.3 to 0.35 mg/kg) is the most commonly used benzodiazepine for intubation because it has a rapid onset and short duration of action. Although benzodiazepines have minimal cardiovascular effects, they can cause hypotension in patients who are hypovolemic.² Benzodiazepines have anticonvulsant activities and may be useful in patients who are actively seizing.

Propofol

Propofol binds to multiple receptors in the CNS including GABA, glycine, nicotinic, and muscarinic receptors. Propofol has sedative, hypnotic, anxiolytic, amnestic, and anticonvulsant properties, but provides no analgesia.²¹ The dose for induction is 1 to 2.5 mg/kg IV. Propofol has several appealing characteristics for an induction agent. First, it is highly lipophilic and easily crosses the blood–brain barrier, resulting in rapid onset of sedation (1 to 2 minutes). Second, it is rapidly redistributed into the peripheral tissues, resulting in a short duration of action (2 to 8 minutes) even in the setting of renal or hepatic dysfunction. The primary disadvantage of propofol is its negative inotropic effect, which can lead to decreased systemic vascular resistance and cause pronounced hemodynamic depression.²² For this reason, propofol should be used with caution in patients who are volume depleted and should be avoided in patients who are hypotensive.² Because propofol is dissolved in a 10% lipid emulsion containing egg, soybean oil, and egg lecithin, allergic reactions can be seen in patients with soybean and egg allergies.²¹

CHOICE OF INDUCTION AGENT

The choice of induction should be guided by the patient’s underlying illness and comorbid conditions. Etomidate and ketamine are ideal for use in the ED because of their favorable hemodynamic profiles. Etomidate should probably be avoided in septic patients, although the medical community has not uniformly embraced this recommendation; additional trials are needed to clarify etomidate’s safety. Ketamine may be a safer alternative, including in head injury patients. Propofol, barbiturates, and to a lesser extent, benzodiazepines can cause potentially fatal decreases in blood pressure, especially in patients who are volume depleted.

Surprisingly little data exist regarding the effect of induction agent on ease of intubation. One trial randomized 469 septic and nonseptic patients to receive either etomidate or ketamine for the induction of intubation and did not observe any difference in intubation conditions (number of attempts, number of operators, number of alternative techniques, glottis visualization, lifting force, use of external laryngeal pressure, and vocal cord position).⁸ In a registry study (NEAR II) of 2,380 ED patients who underwent rapid sequence intubation, etomidate, ketamine, and benzodiazepine were associated with a lower likelihood of successful first-attempt intubation compared with barbiturates.²³ The authors concluded that using methohexital and propofol facilitated rapid sequence intubation, but that the benefits of these medications should be weighed against their capacity to produce hemodynamic instability.

ANALGESIA AND SEDATION IN THE MECHANICALLY VENTILATED PATIENT

Once a patient is intubated in the ED, a primary goal is to ensure comfort in as safe a manner possible. Endotracheal intubation (as well as other critical care procedures) can result in significant anxiety and agitation, which can lead a patient to self-remove lifesaving medical devices. Unrelieved pain and anxiety may also have long-term psychological consequences, including posttraumatic stress disorder.²¹

Analgesia and sedation are an integral part to providing comfort to the mechanically ventilated patient (Fig. 58.1). However, special care must be taken to avoid oversedation, which is associated with increased duration of mechanical ventilation, prolonged ICU stays, and delirium.²⁴ Delirium has gained increased attention in the critical care literature over the past decade; it has been shown to be a predictor of death and leads to increased duration of mechanical ventilation, longer ICU stays, and long-term cognitive impairment.²⁵^,²⁶

Figure 58.1 Empiric Sedation Protocol. *Midazolam 1 to 3 mg/hour gtt may be used if more than three midazolam boluses are given per hour, for propofol intolerance, or if the patient has been on propofol for >96 hours. #Propofol intolerance may be secondary to propofol infusion syndrome. **Delirium monitoring in critically ill patients is reviewed in Chapter 56. RASS, Richmond agitation and sedation scale; gtt, infusion; prn, as needed; ETOH, ethanol; SAT, Spontaneous awakening trial; SBT, Spontaneous breathing trial. Courtesy of icudelirium.org. Used with permission.

In 2013, the American College of Critical Care Medicine, Society of Critical Care Medicine, and American Society of Health-System Pharmacists released a clinical practice guideline for the management of pain, agitation, and delirium in critically ill patients (PAD guidelines).²¹ These guidelines were developed by a 20-person multidisciplinary task force that reviewed the latest critical care literature and provided consensus recommendations for sedation and analgesia. The subsequent paragraphs provide a summary of these guidelines.

Analgesia

Adequate analgesia is essential to minimizing discomfort, agitation, and delirium in the mechanically ventilated patient (Fig. 58.1).²⁷ Because vital sign abnormalities alone are inaccurate markers for pain, a validated pain assessment should be used for all intubated patients.²¹ The Behavioral Pain Scale and Critical-Care Pain Observation Tool are two examples of pain scales validated for this patient population.²⁸^,²⁹ These scales are based upon the health care providers’ observations of the patient’s facial expression, upper body movements, and compliance with ventilator.

While it is beyond the scope of this chapter to provide a comprehensive review of analgesia for the mechanically ventilated patient, it is important to note that the PAD guidelines recommend IV administration of opioid medications as first-line treatment of pain related to intubation.²¹ Longer-acting opioids (such as morphine and hydromorphone) and shorter-acting opioids (such as fentanyl and remifentanil) can be used.²⁴ Of the opioid medications listed above, fentanyl is the most commonly used because of its rapid onset of action, short duration of action, and minimal histaminic release.²⁴ Meperidine is generally avoided because it may be deliriogenic and because it is metabolized into normeperidine, which is neurotoxic and can cause tremors, myoclonus, and generalized tonic–clonic seizures.³⁰^,³¹ Morphine has a less clear role in the development of delirium, with studies producing conflicting results. It is possible that opioid medications may be delirium protective when used for pain control, but deliriogenic in higher doses.³²^,³³ Nonopioid analgesia—such as regional anesthesia, IV acetaminophen, oral, IV or rectal cyclooxygenase inhibitors, or IV ketorolac—can be also used as adjunctive therapy for pain control.²¹

Sedation

After adequate pain control has been achieved, the next step (Fig. 58.1) is to provide sedation, if needed, to further minimize anxiety and agitation. Dosing must be guided by ongoing, accurate assessment of a patient’s agitation and depth of sedation. Traditionally, descriptors such as lethargic, drowsy, somnolent, restless, agitated, or combative have been used, but these terms may have different meanings for different health providers; instead, arousal scales with standardized definitions should be utilized. The commonly used Richmond Agitation Sedation Scale (RASS, Table 58.2) ranges from −5 (unresponsive to pain and voice) to +4 (extreme combativeness).³⁴ Alternatively, the Riker Sedation–Agitation Scale can be used and ranges from 1 (unarousable) to 4 (calm) to 7 (dangerous agitation).³⁵

TABLE 58.2 Richmond Agitation Sedation Scale