Uses
Intravenous Sedation
Benzodiazepines are used for sedation as preoperative premedication,
intraoperatively during regional or local anesthesia, and postoperatively. The anxiolysis,
amnesia, and elevation of the local anesthetic seizure threshold are desirable benzodiazepine
actions. The dose of drugs should be titrated for this use; end points of titration
are adequate sedation or dysarthria ( Table
10-9
). The onset of action is more rapid with midazolam, with a peak effect
usually reached within 2 to 3 minutes of administration; the time to peak effect
is slightly longer with diazepam and is still longer with lorazepam. The duration
of action of these drugs depends primarily on the dose used. Although the onset
is more rapid with midazolam than with diazepam after bolus administration, recovery
is similar,[397]
probably because both drugs have
similar early plasma decay (redistribution) patterns (see Fig.
10-11
and Fig. 10-12
).
With lorazepam, sedation and particularly amnesia are slower in onset[398]
and are longer lasting than with the other two benzodiazepines.[370]
[399]
[400]
A disparity
in the level of sedation versus the presence of amnesia (patients seem conscious
and reasonably coherent, yet they are amnesic for events and instructions) is often
seen with all three benzodiazepines. Lorazepam is particularly unpredictable with
regard to the duration of amnesia, and such unpredictability is undesirable in patients
who wish or need to have recall in the immediate post-operative period.[398]
The degree of sedation and reliable amnesia, as well as preservation of respiratory
and hemodynamic function, are better overall with benzodiazepines than with other
sedative-hypnotic drugs used for conscious sedation. When midazolam is compared
with propofol for sedation, the two are generally similar except that emergence or
wake-up is more rapid with propofol. Propofol requires closer medical supervision
because of its respiratory depression.[401]
[402]
Despite the wide safety margin with benzodiazepines, respiratory function must be
monitored when these drugs are used for sedation to prevent undesirable degrees of
respiratory depression. There may be a slight synergistic action between midazolam
and spinal anesthesia with respect to ventilation.[403]
Thus, the use of midazolam for sedation during regional and epidural anesthesia
requires vigilance with regard to respiratory function, just as when these drugs
are given with opioids. Sedation for longer periods, for example, in the ICU, is
accomplished with benzodiazepines. Prolonged infusion will result in accumulation
of drug and, in the case of midazolam, significant concentration of the active metabolite.
Reviews have pointed out concerns as well as advantages of benzodiazepine sedation.
[370]
[404]
[405]
[406]
[407]
The
chief advantages are amnesia and hemodynamic stability, and the disadvantage with
respect to propofol is the sometimes longer dissipation of effects when infusions
are terminated. Superiority of one drug over the other has not been established;
both agents should always be titrated downward to maintain sedation as required.
Dosing should not be fixed; instead, it should be reduced over time to avoid the
accumulation of parent or metabolites during prolonged infusion.
Oral Sedation
For many years diazepam was given orally for preoperative sedation.
It is still used in 5- to 15-mg doses in adults for this purpose. More recently,
an oral formulation of midazolam has been used primarily for oral premedication in
pediatric patients. The dose is 0.5 mg/kg, and one preparation is from the Roche
parenteral formulation of 0.5 mg/mL (Roche Laboratories, Inc., Nutley, NJ) mixed
with 10 mg/kg oral acetaminophen (McNeil-PPC, Inc., Fort Washington, PA).[408]
Other preparations have been developed, such as strawberry-flavored glucose (pH
4.5) prepared by the pharmacy that is stable for 8 weeks.[409]
The 0.5-mg/kg oral dose is rapid acting; it provides reliable amnesia within 10
minutes and effectively sedates children for induction of anesthesia.[408]
Induction and Maintenance of Anesthesia
Midazolam is the benzodiazepine of choice for induction of anesthesia.
Although both diazepam and lorazepam have been used for induction of general anesthesia,
the faster onset and lack of venous complications make midazolam better suited for
this use. With midazolam, induction of anesthesia is defined as unresponsiveness
to command and loss of the eyelash reflex. When midazolam is used in appropriate
doses (see Table 10-9
), induction
occurs less rapidly than with thiopental,[359]
but
the amnesia is more reliable. Numerous factors influence the rapidity
Figure 10-17
Simulated quantal concentration-response curves generated
by the parameterized pharmacodynamic model for midazolam. (Redrawn from
Jacobs JR, Reves JG, Marty J, et al: Aging increases pharmacodynamic sensitivity
to the hypnotic effects of midazolam. Anesth Analg 80:143–148, 1995.)
of action of midazolam and the other benzodiazepines when used for induction of general
anesthesia, including the dose, speed of injection, degree of premedication, age,
American Society of Anesthesiologists (ASA) physical status, and concurrent anesthetic
drugs.[359]
[410]
In a well-premedicated, healthy patient, midazolam (0.2 mg/kg given in 5 to 15 seconds)
will induce anesthesia in 28 seconds, whereas with diazepam (0.5 mg/kg given in 5
to 15 seconds), induction occurs in 39 seconds.[169]
Elderly patients require lower doses of midazolam than younger patients do ( Fig.
10-17
).[411]
[412]
Patients older than 55 years and those with ASA physical status higher than class
III require a 20% or greater reduction in the induction dose of midazolam.[359]
The usual induction dose of midazolam in premedicated patients is between 0.05 and
0.15 mg/kg. When midazolam is used with other anesthetic drugs (coinduction), a
synergistic interaction occurs,[382]
[413]
[414]
and the induction dose is less than 0.1 mg/kg
( Fig. 10-18
). Synergy is
seen when midazolam is used with opioids or other hypnotics such as thiopental and
propofol.
Awakening after benzodiazepine anesthesia is a result of redistribution
of drug from the brain to other less well perfused tissues. Emergence (defined as
orientation to time and place) of young, healthy volunteers who have received 10
mg of intravenous midazolam occurs in about 15 minutes,[382]
and after an induction dose of 0.15 mg/kg, it occurs in about 17 minutes.[29]
Emergence time is related to the dose of midazolam, as well as the dose of adjuvant
anesthetic drugs.[359]
Emergence from midazolam
(0.32 mg/kg)/fentanyl anesthesia is about 10 minutes longer than that from thiopental
(4.75 mg/kg)/fentanyl anesthesia[330]
and is more
prolonged than with propofol.[30]
This difference
accounts for some anesthesiologists' preference for propofol induction for short
operations.
Benzodiazepines lack analgesic properties and must be used with
other anesthetic drugs to provide sufficient analgesia; however, as maintenance anesthetic
drugs during general anesthesia, benzodiazepines provide hypnosis and amnesia. Double-blind
studies comparing midazolam and thiopental as the hypnotic component of balanced
Figure 10-18
Vertical axes all represent drug dose in milligrams per
kilogram. On the right, median effective dose (ED50
)
isobolograms for the hypnotic interactions among midazolam, alfentanil, and propofol
are shown. The dotted lines are additive effect
lines; note that all combinations fall within the line representing synergism or
supra-additive effect. On the left, a triple interaction
is depicted. The shaded area represents an additive
plane passing through three single-drug ED50
points (small
open circles). The largest closed circle
(with arrows) is the ED50
point for the
triple combination. The smaller closed circles are
ED50
points for the binary combinations. R ratios on all graphs represent
the interaction (1.0 indicates an additive effect) of the various drug combinations.
Note that the combination of midazolam and alfentanil produces the greatest synergism,
but the combination of all three is also synergistic. P
values denote the significance of the additive effects. (Redrawn with modification
from Vinik HR, Bradley EL Jr, Kissin I: Triple anesthetic combination: Propofol-midazolam-alfentanil.
Anesth Analg 76:S450, 1993.)
anesthesia[330]
[415]
have shown that midazolam is superior for this use because of better amnesia and
a smoother hemodynamic course. Opioid requirements are less with midazolam. Midazolam
(0.6 mg/kg) lowers the MAC of halothane by 30%[416]
and presumably has a similar effect on other inhaled anesthetics. The question of
an optimal redosing scheme after induction when midazolam is used as a maintenance
hypnotic component of general anesthesia has not been answered. The amnesic period
after an anesthetic dose is about 1 to 2 hours. Infusions of midazolam have been
used to ensure a constant and appropriate depth of anesthesia.[416]
Experience indicates that a plasma level of more than 50 ng/mL when used with adjuvant
opioids (e.g., fentanyl) or inhaled anesthetics (e.g., nitrous oxide, volatile anesthetics),
or with both, is achieved with a bolus loading dose of 0.05 to 0.15 mg/kg and a continuous
infusion of 0.25 to 1 µg/kg/min.[413]
This
dose is sufficient to keep the patient asleep and amnesic but arousable at the end
of surgery. Lower infusion doses may be required in some patients and with certain
opioids. Midazolam, as well as diazepam and lorazepam, will accumulate in the blood
with repeated bolus administration or with continuous infusion, just as most intravenous
anesthetics do on repeated injection. If the benzodiazepines do accumulate with
repeated administration, prolonged arousal time can be anticipated. This concern
is less of a problem with midazolam than with diazepam and lorazepam because of the
shorter context-sensitive half-time and greater clearance of midazolam.
