Nitrous oxide is typically supplied in a 50:50 mixture with oxygen (Table 37-6). Nitrous oxide can be used alone for minimal sedation or as an adjunct with IV medications for moderate sedation (Table 37-6).45,46 Technical aspects of nitrous oxide administration include the use of a demand delivery system triggered by the patient's inspiratory force and a disposal or scavenger system to prevent accumulation of nitrous oxide in the room. Nitrous oxide has a rapid onset (1 to 2 minutes) and a rapid recovery (3 to 5 minutes) when inhalation of the gas is discontinued.
TABLE 37-6Sedation Agents for Adult Procedural Sedation and Analgesia ||Download (.pdf) TABLE 37-6 Sedation Agents for Adult Procedural Sedation and Analgesia
|Medication ||Recommended Dosage ||Route of Administration ||Peak Effect ||Approximate Duration ||Use |
|Nitrous oxide ||50:50 mixture with oxygen ||Inhalational ||1–2 min ||3–5 min ||Minimal sedation |
|Midazolam || |
0.05–0.1 milligram/kg. May repeat 0.05 milligram/kg every 2 min until adequately sedated
Minimal or moderate sedation
|Fentanyl ||1–3 micrograms/kg, can be titrated up to 5 micrograms/kg ||IV ||2–3 min ||30–60 min ||Minimal sedation |
|Fentanyl and midazolam ||1–2 micrograms/kg fentanyl plus 0.1 milligram/kg midazolam ||IV ||2–3 min ||1 h ||Moderate and deep sedation |
|Methohexital ||1 milligram/kg ||IV ||1 min ||3–5 min ||Moderate or deep sedation |
|Pentobarbital ||2.5 milligrams/kg followed by 1.25 milligram/kg, as needed, up to two times ||IV rate should be <50 milligrams/min ||3–5 min ||15 min ||Minimal and moderate sedation. Frequently used for radiologic procedures. |
|Ketamine || |
|Ketamine and midazolam ||Ketamine as above plus midazolam, 0.03 to 0.05 milligram/kg ||IV ||1–3 min ||30–60 min ||Dissociative sedation |
|Etomidate ||0.15 milligram/kg, followed by 0.1 milligram/kg every 2 min, if needed ||IV ||15–30 s ||3–8 min ||Moderate and deep sedation |
|Propofol ||0.5–1.0 milligram/kg, followed by 0.5 milligram/kg every 3 min, if needed ||IV ||30–60 s ||5–6 min ||Moderate and deep sedation |
|Ketamine and propofol "ketofol" ||Ketamine 0.125–0.5 milligram/kg and Propofol 0.5 milligram/kg ||IV ||30–60 s ||15 min ||Moderate and deep sedation |
Nitrous oxide has few adverse side effects.47 Nitrous oxide is a mild cardiac depressant and pulmonary vasoconstrictor so it is relatively contraindicated in patients with pulmonary hypertension. Nitrous oxide is an inhibitor of folate metabolism and is therefore contraindicated in pregnant women. Nitrous oxide may promote expansion of internal gas-filled structures and should be avoided in patients with pneumothorax, pneumocephalus, and vascular air embolism.
Midazolam is a short-acting benzodiazepine commonly used as a sole agent for minimal sedation.48 After IV administration, peak effect is seen within 2 to 3 minutes, and duration of retrograde amnesia is 20 to 30 minutes (Table 37-6). Midazolam can be combined with an opioid for moderate or deep procedural sedation, but when given with an opioid, there is an increased risk of respiratory depression.
Midazolam causes mild cardiovascular depression, and hypotension can result when this agent is given to hypovolemic patients. Paradoxical agitation has been reported with the use of midazolam in 1% to 15% of patients, and flumazenil can be given for reversal.48
Midazolam can be administered IV, PO, IM, PR, or intranasally. The IV route has the most predictable onset and duration of action. The PO route can result in unreliable levels of sedation as a result of first-pass hepatic metabolism. Because the agent has a low pH and benzyl alcohol is added as a preservative, intranasal midazolam irritates the nasal mucosa, which can be painful and provoke anxiety. Buffering the solution does not decrease the irritation. Both the PR and IM routes have unreliable onset and depth of sedation, but can be easier to administer in some patients.
Fentanyl is a potent, relatively short-acting opioid. A single IV dose has rapid onset of <1 minute, peak effect in 2 to 3 minutes, and duration of 30 to 60 minutes. It is easily titratable when used alone for minimal sedation and can be used in combination with midazolam for moderate and deep procedural sedation and analgesia.
Rigid chest syndrome, a rare complication characterized by spasm of the respiratory muscles leading to respiratory depression or apnea, is seen when high doses (>5 micrograms/kg) of fentanyl are given by rapid IV bolus. In small children, this syndrome may be precipitated by rapidly flushing the IV line. Rigid chest syndrome is not reversible with opioid receptor antagonists. Intubation with rapid-sequence induction and pharmacologic paralysis is usually required to ventilate the patient in this situation. Slow administration of fentanyl (1 to 3 micrograms/kg over 5 minutes) followed by slow and careful flushing of the IV line can prevent rigid chest syndrome.
Alfentanil is an effective agent but is associated with a 30% to 40% rate of airway and respiratory adverse effects,49,50 a rate typically higher than that seen with fentanyl or propofol alone.
Methohexital is an ultra-short-acting barbiturate that produces sedation within 1 minute of IV administration and has an effective duration of 3 to 5 minutes. Methohexital is best used for brief moderate and deep sedation, such as that needed for joint dislocation reduction. The major adverse effect of methohexital is respiratory depression; the risk increases if additional boluses are given after the initial dose.12
Pentobarbital is a short-acting barbiturate that is useful when the procedure itself is painless, but the associated circumstances may cause anxiety (e.g., radiologic procedures). Pentobarbital produces sedation within 3 to 5 minutes of IV administration and lasts approximately 15 minutes, and complete recovery occurs in 30 to 40 minutes.
Ketamine produces a state of dissociation characterized by profound analgesia, sedation, and amnesia. Unlike other agents used for procedural sedation, ketamine possesses both analgesic and anxiolytic properties.13 Ketamine is an effective agent for ED procedural sedation13,51,52,53,54,55 and for prehospital analgesia and sedation when used by physicians.55
Ketamine does not have a typical dose-response continuum with progressive titration. At doses lower than a threshold, analgesia and sedation occur. Once a critical dosing threshold is exceeded (about 1.0 to 1.5 milligrams/kg IV or 3 to 4 milligrams/kg IM), the characteristic dissociative state abruptly appears. This dissociation has no observable levels of depth. The only value of additional ketamine is to prolong the dissociative state for extended procedures.
Ketamine can be given either IV or IM. The IM route allows for approximately 40 minutes of sedation, compared with 10 minutes by the IV route. Ketamine is the only sedative agent that typically preserves a patient's ventilatory effort and has minimal effect on blood pressure. Ketamine can induce hypersalivation. Anticholinergics, such as atropine 10 micrograms/kg IV or glycopyrrolate 4 micrograms/kg IV, are often administered to counter this effect. However, studies evaluating this practice of coadministering anticholinergics fail to demonstrate tangible benefit or harm. Thus anticholinergics can be reserved for the treatment of clinically significant hypersalivation or for patients with an impaired ability to mobilize secretions.13 Other adverse effects also include laryngospasm, vomiting (most often in the late recovery phase), and emergence reactions. Laryngospasm has been reported primarily in children, with reported rates of occurrence of <1.0% to 2.5%. It is typically transient and responds to positive pressure ventilation with a bag-valve mask. Children with significant upper respiratory tract infectious symptoms and patients who will undergo major stimulation of the oropharynx (e.g., endoscopy) should not receive ketamine due to a possible increased risk of laryngospasm.13
Emergence reactions are common with ketamine and range from mild agitation to recurrent nightmares and hallucinations.53,54 Midazolam can be given along with ketamine to blunt the occurrence of emergence reactions.56,57 However, the overall clinical benefit of such prophylaxis has not been demonstrated.13 It is sufficient to give ketamine without midazolam and then treat patients who develop emergence reactions with midazolam as they occur. Because of these emergence reactions, ketamine should not be used in patients with schizophrenia and psychosis.13
It is commonly stated that ketamine increases intracranial pressure, which potentially limits its use in many emergent situations.58 The experimental data from animal studies and human observations are conflicting, depending on the specific circumstances.58,59 Thus there is no clear evidence that ketamine is harmful as an induction or sedation agent in patients with potential head injury. Ketamine does increase intraocular pressure and should be avoided in patients with eye injuries or glaucoma.60
Etomidate is a nonbarbiturate sedative-hypnotic with a rapid onset (15 to 30 seconds) and a short duration of effect (3 to 8 minutes). Compared with the other sedative agents, etomidate causes less cardiovascular depression but a similar degree of respiratory depression. Etomidate is an effective agent for ED procedural sedation, with a reported complication rate of 10% to 15%, most complications being minor.61,62,63,64
Myoclonic jerking occurs in up to 20% of patients and can interfere with the procedure for which the patient was sedated.64 Etomidate causes suppression of the adrenal-cortical axis, and when used for rapid sequence induction in critically ill patients, it is associated with adrenal insufficiency and increased mortality.65,66,67,68 However, no clinically significant adverse event related to adrenal suppression has been detected from etomidate used during ED procedural sedation in stable patients.
Propofol is frequently used for moderate and deep procedural sedation in the ED.18,69, 70, 71, 72, 73, 74, 75, 76, 77 Propofol is associated with fewer complications than etomidate or methohexital in patients who received multiple doses and is much easier to titrate.12,64 Because of the short duration of action, propofol results in a shorter recovery time and ED length of stay.76,77,78,79
The most serious adverse effect of propofol is sudden respiratory depression and apnea,24,41 so ventilatory support equipment should be at the bedside when using propofol. Propofol can produce hypotension as a result of both negative inotropy and vasodilatation. Hypotension is more common in hypovolemic patients and those with American Society of Anesthesiologists physical status scores of III or IV.70 Hypovolemia should be corrected before propofol administration.
Sedation from propofol occurs within 30 to 60 seconds after injection and lasts for about 5 to 6 minutes. Propofol is rapidly distributed into tissues, and once tissues are saturated, subsequent doses will have a greater effect than the initial bolus. The recommended dose for ED procedural sedation in healthy nonelderly adults is 0.5 to 1.0 milligram/kg IV, followed by 0.5 milligram/kg IV every 3 minutes if needed. Higher doses are associated with more respiratory depression.
Propofol is formulated in a soybean oil, glycerol, and egg lecithin emulsion and is contraindicated in patients who are allergic to eggs or soy protein. Propofol causes local pain at the IV site during administration. Methods to reduce the pain of propofol administration include placing a tourniquet proximal to the IV and injecting 0.05 milligram/kg of lidocaine through the IV approximately 60 seconds before injecting the propofol, mixing the propofol with lidocaine, or coadministering the short-acting opioid alfentanil at 10 micrograms/kg.80,81
The combination of ketamine and propofol for ED procedural sedation has a well-documented safety and efficacy profile.82,83–92 Propofol is an excellent sedative, but respiratory depression and hypotension are its principal adverse events. The sympathomimetic properties of ketamine may mitigate these, in addition to adding analgesia. Ketamine causes emergence reactions and vomiting as adverse events, whereas propofol has antiemetic and hypnotic properties. This combination is safe and effective for ED procedural sedation and analgesia.83–92 Published "ketofol" ED procedural sedation studies have used a variety of combinations, from equal mixtures of propofol and ketamine to normal doses of propofol with sub-dissociative doses of ketamine for its analgesic properties. Adding ketamine to propofol promotes hemodynamic stability, which is reassuring in patients with known or potentially reduced cardiac function.88 There is also evidence of synergism between the two drugs, and data indicate that ketofol provides less erratic sedation depth than propofol alone.87 The analgesic properties of ketamine preclude the need for and risks of opioids administered with propofol.84,88 When the total dose of ketamine administered during ketofol use is less than the reliable dissociative dose (<1.5 milligram/kg), clinical observation suggests that recovery time is longer than that for full doses of propofol (1.6 to 1.8 milligrams/kg) alone82,86 but shorter than that of full dissociative doses of ketamine (1.0 to 1.5 milligrams/kg) alone.82 However, despite the theoretical benefit for decreasing complications, studies to date have failed to demonstrate a consistent difference in complications between ketofol (mixtures of ketamine and propofol from 1:1 to 1:4) compared with propofol alone.89,90 The advantage of ketofol is that it may be able to achieve adequate sedation with lower total doses compared with when either drug alone is used, and ketofol prolongs the duration of sedation more than propofol alone, which is useful for procedures anticipated to take more time, and without the need for additional doses of propofol.