Page 248 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

152 PART 2: General Management of the Patient

TABLE 22-3 Sedatives
Dexmedetomidine Midazolam Lorazepam Diazepam Propofol
Onset 5-10 minutes 3-5 minutes 15-20 minutes 2-5 minutes 1-2 minutes
Half-life up to 3 hours, duration 2-6 hours, duration 8-15 hours 20-120 hours 26-32 hours
60-120 minutes <2 hours (dose dependent)
Metabolism Hepatic, N-glucuronidation Hepatic CYP3A4 Hepatic, glucuronidation Hepatic CYP3A4 CYP2C19 Hepatic, CYP2B6
and N-methylation, CYP2A6
Active metabolite None Yes, 1-hydroxy -midazolam None Yes, desmethyldiazepam, None
3-hydroxydiazepam, 3-hydroxy-
N-diazepam
Adverse effects Bradycardia, hypotension Respiratory depression Respiratory depression, propylene Respiratory depression, phlebitis Hypotension, respiratory depres-
glycol-related acidosis, renal sion, hypertriglyceridemia, pain on
failure injection, pancreatitis, PRIS
Dose 0.2-1.5 μg/kg/h 0.5-2 mg 0.5-2 mg Not used as a continuous infu- 5-50 μg/kg/min, doses greater
sion recommended bolus dose: than 80 μg/kg/min increase risk
5 mg of HTG and PRIS
HTG, hypertriglyceridemia; PRIS, propofol infusion syndrome.

Midazolam: The onset of action of midazolam is rapid (0.5-5 minutes), Central nervous system: All benzodiazepines cause a dose-dependent
and the duration of action following a single dose is short (~2 hours). suppression of awareness along a spectrum from mild depression of
All benzodiazepines are lipid soluble with a large volume of distribu- responsiveness to obtundation. They are potent amnestic agents 72,73 ;
tion and therefore are distributed widely throughout body tissues. lorazepam appears to produce the longest duration of antegrade
For all benzodiazepines, the duration of action after a single bolus amnesia. All are potent anxiolytic agents. A paradoxical state of agitation
depends mainly on the rate of redistribution to peripheral tissues, that worsens with escalating doses may occur occasionally, especially in
especially adipose tissue. Midazolam undergoes hepatic metabolism elderly patients. All benzodiazepines have anticonvulsant properties. 74
and renal excretion. Alpha-hydroxy midazolam is an active metabo- Respiratory system: Benzodiazepines cause a dose-dependent, centrally
lite that is excreted by the kidneys. In the presence of kidney failure, it mediated respiratory depression. This ventilatory depression is less
can accumulate and lead to prolonged effects. profound than that seen with opiates; however, it may be synergistic
The kinetics of midazolam change considerably when it is given by with opiate-induced respiratory depression. In contrast to opiates
continuous infusion to critically ill patients. After continuous infusion (described earlier), the respiratory pattern of a patient receiving
for extended periods, this lipid-soluble drug accumulates in peripheral benzodiazepines is a decrease in tidal volume and an increase in
tissues rather than being metabolized. On discontinuing the drug, respiratory rate. Even low doses of benzodiazepines can obliterate the
peripheral tissue stores release midazolam back into the plasma, and the ventilatory response to hypoxia.
duration of clinical effect can be prolonged. Obese patients with larger
57
volumes of distribution and elderly patients with decreased hepatic and Cardiovascular system: Benzodiazepines have minimal effects on the
renal function may be even more prone to prolonged effects. cardiovascular system in patients who are euvolemic. They may cause a
slight decrease in blood pressure without a significant change in heart
Lorazepam: Intravenous lorazepam has a slower onset of action than rate. Clinically important hypotensive responses are usually seen only
midazolam (~5 minutes) because of its lower lipid solubility, which in patients who are hypovolemic and in those whose increased endog-
increases the time required to cross the blood-brain barrier. The enous sympathetic activity is maintaining a normal blood pressure.
duration of action following a single dose is long (6-10 hours) and
is proportional to the dose given; however, many pharmacokinetic Propofol: Propofol is an alkylphenol intravenous anesthetic. The exact
studies are done on healthy volunteers and may not apply to critically mechanism of action is unclear, although it is thought to act at the
ill patients. Lorazepam’s longer duration of action is due to lower GABA receptor. It is an oil at room temperature and is prepared as a
lipid solubility with decreased peripheral tissue redistribution. One lipid emulsion.
risk with continuous infusion of lorazepam is the risk of propylene Pharmacokinetics Propofol is highly lipid soluble and rapidly crosses the
glycol toxicity. It is due to the diluent and usually occurs in the setting blood-brain barrier. Onset of sedation is rapid (1-5 minutes) and depends
of doses >6 mg/h for more than 48 hours. Patients may present with on whether or not a loading dose is given. Duration of action depends on
metabolic acidosis (increased lactate) and renal failure. dose but is usually very short (2-8 minutes) owing to rapid redistribution
Diazepam: The onset of action of intravenous diazepam is short to peripheral tissues. 75,76 When continuous infusions are used, duration of
(~2-5 minutes). Duration of action following a single dose is also short action may be increased, but it is rare for the effect to last longer than 60
(30-60 minutes) owing to high lipid solubility and peripheral redistri- minutes after the infusion is discontinued. The drug is metabolized mainly
bution. Diazepam is rarely given by continuous infusion because it has in the liver with an elimination half-life of 4 to 7 hours. Propofol has no
a long termination half-life. Once the peripheral tissue compartment is active metabolites. Because of its high lipid solubility and large volume of
saturated, recovery can take several days. Diazepam has several active distribution, propofol can be given for prolonged periods without signifi-
metabolites that themselves have prolonged half-lives. The metabolism cant changes in its pharmacokinetic profile. The termination of its clinical
of diazepam depends on hepatic function and is prolonged in liver effect depends solely on redistribution to peripheral fat tissue stores. When
disease and in the elderly. With the availability of midazolam and the infusion is discontinued, the fat tissue stores redistribute the drug back
lorazepam, diazepam has little, if any role in ICU sedation. into the plasma, but usually not to clinically significant levels.
Pharmacodynamics The benzodiazepines have similar effects and will be Pharmacodynamics
discussed without reference to individual drugs except where important Central nervous system: Propofol is a hypnotic agent that, like the ben-
differences are present. zodiazepines, provides a dose-dependent suppression of awareness

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