Induction Flashcards
1
Q
- Name some examples of intravenous anesthetics. What are the potential clinical
uses of intravenous anesthetics?
A
- Examples of intravenous anesthetics include the barbiturates, benzodiazepines,
opioids, etomidate, propofol, ketamine, and dexmedetomidine. These drugs can
be used as induction agents or, in combination with other anesthetics, for the
maintenance of anesthesia.
2
Q
- What type of chemical structure is propofol?
A
- Propofol is a lipid-soluble isopropyl phenol formulated as an emulsion. The current
formulation consists of 1% propofol, soybean oil, glycerol, and purified egg
phosphatide.
3
Q
- What is the mechanism of action of propofol?
A
- The mechanism by which propofol exerts its effects is not fully understood, but
it appears to be in part via the gamma-aminobutyric acid (GABA) activated
chloride ion channel. Evidence suggests that propofol may interact with the GABA
receptor and maintain it in an activated state for a prolonged period, thereby
resulting in greater inhibitory effects on synaptic transmission. Propofol also
inhibits the NMDA subtype of the glutamate receptor, which may contribute
to its CNS effects
4
Q
- What degree of metabolism does propofol undergo? How should the dose of
propofol be altered when administered to patients with liver dysfunction?
A
- Propofol is cleared rapidly from the plasma through both redistribution to inactive
tissue sites and rapid metabolism by the liver.
5
Q
- What degree of metabolism does propofol undergo? How should the dose of
propofol be altered when administered to patients with liver dysfunction?
A
- Propofol is extensively metabolized by the liver to inactive, water-soluble
metabolites, which are then excreted in the urine. Less than 1% of propofol
administered is excreted unchanged in the urine. The metabolism of propofol is
extremely rapid. Patients with liver dysfunction appear to rapidly metabolize
propofol as well, lending some proof that extrahepatic sites of metabolism exist.
This has been further supported by evidence of metabolism during the anhepatic
phase of liver transplantation.
6
Q
- What is the context-sensitive half-time of propofol relative to other intravenous
anesthetics? What is the effect-site equilibration time of propofol relative to
other intravenous anesthetics?
A
- The context-sensitive half-time refers to the time required to pass for the
concentration of a particular drug to reach 50% of its peak plasma concentration
after the discontinuation of its administration as a continuous intravenous
infusion for a given duration. The context-sensitive half-time of a drug depends
mostly on the drug’s lipid solubility and clearance mechanisms. The continuous
infusion of propofol rarely results in cumulative drug effects. After the continuous
administration of propofol for several days for sedation in the intensive care
unit the discontinuation of the infusion resulted in the rapid recovery to
consciousness. The lack of cumulative effects of propofol illustrates that the
context-sensitive half-time of propofol is short. The effect-site equilibration time
refers to the interval of time required between the time that a specific plasma
concentration of the drug is achieved and a specific effect of the drug can be
measured. The effect-site equilibration time reflects the time necessary for the
circulation to deliver the drug to its site of action, such as the brain. The rapid
administration of an induction dose of propofol results in unconsciousness in less
than 30 seconds, illustrating its rapid effect-site equilibration time.
7
Q
- How does the emergence from a propofol anesthetic or propofol induction differ
from the emergence seen with the other induction agents?
A
- After the administration of propofol, patients experience a rapid return to
consciousness with minimal residual central nervous system effects. Patients who are
to undergo brief procedures or outpatient surgical patients may especially benefit from
the rapid wake-up associated with propofol anesthesia. Propofol also tends to result in
the patient awakening with a general state of well-being and mild euphoria. Patient
excitement has also been observed. Hallucinations and sexual fantasies have been
reported to have occurred in association with the administration of propofol.
8
Q
- How does propofol affect the cardiovascular system?
A
- The administration of an induction dose of propofol results in a profound decrease
in systolic blood pressure greater than any other induction agent. This effect of
propofol appears to be primarily due to vasodilation, which is dose dependent.
Unlike the barbiturates, the heart rate is usually unchanged with the administration
of propofol. Propofol may selectively decrease sympathetic nervous system activity
more than parasympathetic nervous system activity. In fact, propofol inhibits the
normal baroreceptor reflex such that profound bradycardia and asystole have
occurred in healthy adults after its administration
9
Q
- How does propofol affect ventilation?
A
- The administration of an induction dose of propofol (1.5 to 2.5 mg/kg) almost
always results in apnea through a dose-dependent depression of ventilation in a
manner similar to, but more prolonged than, that of thiopental. The apnea that
results appears to last for 30 seconds or greater and is followed by a return of
ventilation that is characterized by rapid, shallow breathing such that the minute
ventilation is significantly decreased for up to 4 minutes. Propofol causes a greater
reduction in airway reflexes than any other induction agent, making it a better
choice as the sole agent for instrumentation of the airway. (
10
Q
- How does propofol affect the central nervous system?
A
- The administration of propofol results in decreases in intracranial pressure, cerebral
blood flow, and cerebral metabolic oxygen requirements in a dose-dependent
manner. In patients with an elevated intracranial pressure, the administration of
propofol, however, may be accompanied by undesirable decreases in the cerebral
perfusion pressure. (
11
Q
A
- The effects of propofol on the seizure threshold are controversial. The administration
of propofol has resulted in seizures and opisthotonos and has been used to facilitatethe mapping of seizure foci. Propofol has also been used to treat seizures. High
doses of propofol can result in burst suppression on the electroencephalogram.
Excitatory effects that cause muscle twitching are not uncommon, but do not
indicate seizure activity
12
Q
A
- Propofol appears to have a significant antiemetic effect, given the low incidence
of nausea and vomiting in patients who have received a propofol anesthetic.
In addition, propofol administered in subhypnotic doses of 10 to 15 mg has
successfully treated both postoperative nausea and vomiting and nausea in patients
receiving chemotherapy
13
Q
- How is propofol administered for sedation?
A
- Propofol may be administered for sedation through a continuous intravenous
infusion at a rate of 25 to 75 mg/kg/min. At these doses, propofol will provide
sedation and amnesia without hypnosis. Because of the pronounced respiratory
depressant effect, propofol, even for sedation, should only be administered by
individuals trained in airway management.
14
Q
- How is propofol administered for maintenance anesthesia?
A
- Propofol may be administered for maintenance anesthesia through a continuous
intravenous infusion at a rate of 100 to 200 mg/kg/min. The clinician may use signs
of light anesthesia such as hypertension, tachycardia, diaphoresis, or skeletal
muscle movement as indicators for the need to increase the infusion rate of
propofol. For procedures lasting more than 2 hours, the use of propofol for
maintenance anesthesia may not be cost effective. (
15
Q
- How can the pain associated with the intravenous injection of propofol be
attenuated?
A
- The injection of propofol intravenously can cause pain in awake patients. The pain
can be attenuated by using large veins for its administration, or with the prior
administration of lidocaine at the injection site. Alternatively, lidocaine may be
mixed with the propofol for simultaneous infusion.
16
Q
- Why is asepsis important when handling propofol?
A
- Asepsis is important when handling propofol because the solvent for propofol, a
lipid emulsion containing soybean oil, glycerol, and lecithin, provides for a
favorable culture medium for bacterial growth. Ethylenediaminetetraacetic acid,
metabisulfate, or benzyl alcohol is added to the propofol formulation in an attempt
to suppress bacterial growth. (
17
Q
- Which patients may be at risk for a life-threatening allergic reaction to propofol?
A
- Patients at risk for a life-threatening allergic reaction to propofol are those with a
history of atopy or allergy to other drugs that also contain a phenyl nucleus or
isopropyl group. Anaphylactoid reactions to the propofol itself and separate from
the lipid emulsion have been reported
18
Q
- What type of drug is fospropofol?
A
- Fospropofol is a water-soluble phosphate ester prodrug of propofol. It is metabolized
by alkaline phosphatase in a reaction that produces propofol and also phosphate
and formaldehyde, which is then further metabolized.
19
Q
- How are the structure, function, and physicochemical properties of fospropofol
different from propofol?
A
- Fospropofol is water-soluble and comes in an aqueous, sterile preparation. It can
be injected without the need for a lipid emulsion, thereby reducing the risk for
contamination.
20
Q
- What are the clinical uses of fospropofol?
A
- In the United States, fospropofol is currently approved for sedation during
monitored anesthesia care.
21
Q
- Name some of the barbiturates. From what chemical compound are they derived?
A
- Thiopental is the most commonly used barbiturate in the practice of anesthesia.
Other barbiturates include pentobarbital, thiamylal, and methohexital. The
barbiturate compounds are a derivative of barbituric acid. Structural alterations
of two of the carbon atoms of barbituric acid result in the barbiturates used in
clinical practice. Historically, the barbiturates had been classified as short-acting
or long-acting agents. This method of classification is no longer used because of
the erroneous implication that the duration of action is predictable for a given
agent
22
Q
- What is the mechanism of action of barbiturates?
A
- The mechanism of action of barbiturates is based on their ability to enhance and
mimic the action of the neurotransmitter gamma-aminobutyric acid (GABA) in
the central nervous system. GABA is the main inhibitory neurotransmitter in the
central nervous system. Barbiturates bind to the GABA receptor and increase
the duration of activity of the GABA receptor, such that the chloride ion influx
into the cells is prolonged. The chloride ion hyperpolarizes the cell and inhibits
postsynaptic neurons. At higher concentrations, the chloride ion channel may be
stimulated by the barbiturate alone even in the absence of GABA
23
Q
- How are barbiturates cleared from the plasma?
A
- Barbiturates are cleared from the plasma primarily through its rapid redistribution
to inactive tissue sites after its administration as a bolu
24
Q
- What degree of metabolism do barbiturates undergo?
A
- Barbiturates are eliminated from the body through hepatic metabolism. Less than
1% of the drug is excreted unchanged by the kidneys
25
Q
- What is the context-sensitive half-time of barbiturates relative to other intravenous
anesthetics? What is the effect-site equilibration time of barbiturates relative to
other intravenous anesthetics?
A
- Barbiturates are most often used for the intravenous induction of general
anesthesia. Maximal brain uptake and onset of effect takes place within 30 seconds
after the rapid intravenous injection of a barbiturate. Rapid awakening follows the
administration of an induction dose of a barbiturate secondary to the rapid
redistribution of these drugs. This accounts for the short effect-site equilibration
time for these agents. The duration of action of a barbiturate after its intravenous
injection is dictated by its redistribution from the plasma to inactive sites. Large or
repeated doses of the lipid-soluble barbiturates can result in saturation of the
inactive sites. This may lead to the accumulation of a drug and to prolonged effects
of the usually short-acting drugs. The context-sensitive half-time of barbiturates
is thus prolonged
26
Q
A
- The induction dose of methohexital is 1 to 1.5 mg/kg intravenously, whereas the
induction dose of thiopental is 3 to 5 mg/kg IV. Methohexital undergoes greater
hepatic metabolism than thiopental, resulting in a shorter duration of action and
more rapid awakening. Based on the shorter duration of action of methohexital, it is
sometimes chosen over thiopental for the induction of anesthesia for patients
undergoing outpatient procedures when rapid awakening is desired. An example of
a procedure in which methohexital is frequently chosen for the induction of
anesthesia is electroconvulsive shock therapy. This is not only due to the short
duration of action of methohexital, but also to its epileptogenic property.
27
Q
- How do barbiturates affect the arterial blood pressure?
A
- The administration of barbiturates typically results in a decrease in arterial
blood pressure by 10 to 20 mm Hg. This decrease in blood pressure primarily
results from peripheral vasodilation. The vasodilation that accompanies the
administration of barbiturates is due to a combination of depression of the
vasomotor center in the medulla and a decrease in sympathetic nervous system
outflow from the central nervous system. Exaggerated blood pressure decreases
may be seen in patients who are hypertensive, whether or not they are being
treated by antihypertensives. The administration of barbiturates should also be
undertaken with caution in patients who are dependent on the preload to the heart
to maintain cardiac output, as in patients with ischemic heart disease, pericardial
tamponade, congestive heart failure, heart block, or hypovolemia. (
28
Q
- How do barbiturates affect the heart rate?
A
- The administration of barbiturates results in an increase in heart rate. This increase
in heart rate is thought to be due to a baroreceptor-mediated reflex response to the
decrease in blood pressure caused by the administration of the barbiturate. The increase
in heart rate may increase myocardial oxygen requirements during a time when
significant decreasesin blood pressure may decrease coronary artery blood flow as well.
Given this, the administration of a barbiturate to patients with ischemic heart disease
must be done with extreme caution. Although the administration of barbiturates
typically results in an increase in heart rate, the cardiac output may be decreased.
This is in part due to the direct myocardial contractile depression that results from the
administration of barbiturates. The effect of a decrease in cardiac output by barbiturates
is not of such significance that it is frequently seen clinically, however.
29
Q
- How do barbiturates affect ventilation?
A
- Barbiturates depress ventilation centrally by depressing the medullary ventilatory
centers. This is manifest clinically as a decreased responsiveness to the ventilatory
stimulatory effects of carbon dioxide. Depending on the dose administered, the
patient will have a slow breathing rate and small tidal volumes to the extent that
apnea follows. Typically, after an induction dose of barbiturate transient apnea will
result and require controlled ventilation of the lungs. When spontaneous ventilation
is resumed, it is again characterized by a slow breathing rate and small tidal
volumes.
30
Q
- How do barbiturates affect laryngeal and cough reflexes?
A
- Induction doses of thiopental alone do not reliably depress laryngeal and
cough reflexes. Stimulation of the upper airway, as with the placement of an oral
airway or an endotracheal tube, can result in laryngospasm or bronchospasm.
It is therefore recommended that adequate suppression of these reflexes be
obtained before instrumenting the airway. This can be accomplished with
increased doses of a barbiturate, by the administration of a neuromuscular
blocking drug, or by the addition of another preoperative medicine, such as
opioids, to augment the anesthetic effects of thiopental during stimulation of
the upper airway
31
Q
- How do barbiturates affect the central nervous system? How do barbiturates affect
an electroencephalogram?
A
- Barbiturates are potent cerebral vasoconstrictors. This results in a decrease in
cerebral blood flow, a decrease in cerebral blood volume, a decrease in intracranial
pressure, and a decrease in cerebral metabolic oxygen requirements. Barbiturates
are also thought to depress the reticular activating system, which is believed to be
important in maintaining wakefulness. Thiopental produces a dose-dependent
depression of the electroencephalogram. A flat electroencephalogram may be
maintained with a continuous infusion of thiopental. Methohexital is the only
barbiturate that does not decrease electrical activity on an electroencephalogram.
In fact, methohexital activates epileptic foci and is often used intraoperatively
to identify epileptic foci during the surgical ablation of these foci. The effects of
barbiturates on the central nervous system indicate that barbiturates are useful
for patients in whom elevated intracranial pressures are a concern. Examples of
patients who may benefit from the administration of a barbiturate as an induction
agent or as maintenance anesthesia include patients with intracranial space-
occupying lesions or patients who have suffered head trauma
32
Q
- How should thiopental be administered and dosed for cerebral protection in patients
with persistently elevated intracranial pressures?
A
- In patients with persistently elevated intracranial pressures, barbiturates may be
administered intravenously in high doses to decrease the intracranial pressure.
Care must be taken to avoid decreases in mean arterial pressure that would
compromise the cerebral perfusion pressure under these conditions. To ascertain
the optimal dose of barbiturate administered for these patients, an
electroencephalogram can be obtained. The dose of barbiturate can be titrated to a
flat-line electroencephalogram. When the electroencephalogram is isoelectric
there is no further depression of cerebral metabolism or of cerebral metabolic
oxygen requirements with increasing doses of barbiturate. This allows the clinician
to administer the dose of barbiturate that provides the maximal benefit with
minimal adverse effects. Barbiturates may offer some cerebral protection for
patients with regional cerebral ischemia. Patients with global cerebral ischemia,
such as from cardiac arrest, are not thought to derive any protection from
the administration of barbiturates.
33
Q
- What are the various routes and methods for the administration of barbiturates
in clinical anesthesia practice?
A
- There are various routes and methods for the administration of barbiturates in
clinical anesthesia practice. For instance, the rapid intravenous administration of a
bolus of barbiturate is indicated for a rapid sequence induction of anesthesia. The
bolus of barbiturate should be immediately followed by the administration of
succinylcholine or a nondepolarizing neuromuscular blocking drug to produce
skeletal muscle paralysis and facilitate tracheal intubation under these conditions.
Alternatively, small doses of intravenous thiopental, in the range of 0.5 to 1 mg/kg,
may be administered to adult patients who have difficulty accepting the application
of an anesthesia mask and/or the inhalation of a volatile anesthetic. The rectal
34
Q
- What are some potential adverse complications of the injection of thiopental?
A
- Potential adverse complications of the injection of thiopental may result from
accidental intraarterial, subcutaneous, and even appropriate venous administration
of thiopental. The accidental intraarterial injection of barbiturates results in
excruciating pain and intense vasoconstriction that can last for hours. It is believed
that barbiturate crystal formation in the blood causes the occlusion of distant small
diameter arteries and arterioles. There are several treatment modalities for this
potential problem, including the intraarterial injection of papaverine and/or
lidocaine, sympathetic nervous system blockade by stellate ganglion block of the
involved upper extremity, and the administration of heparin to prevent thrombosis.
Despite aggressive therapy, gangrene of the extremity often results. The accidental
subcutaneous injection of barbiturates results in local tissue irritation. The irritation
may proceed to pain, edema, erythema, or even tissue necrosis, depending on the
volume and concentration injected. It has been recommended that 5 to 10 ml of 0.5%
lidocaine be injected locally when the subcutaneous injection of thiopental occurs in
an attempt to dilute the barbiturate. Venous thrombosis has been seen after the
intravenous administration of thiopental. It is presumed that the thrombosis results
from the deposition of barbiturate crystals in the vein. The crystallization of
barbiturates is more likely to occur when the pH of the blood is too low to keep
the alkaline barbiturate in solution.
35
Q
- What is the risk of a life-threatening allergic reaction to barbiturates?
A
- Life-threatening allergic reactions to barbiturates are rare. The risk has been
estimated to be 1 in 30,000.
36
Q
- Name some of the commonly used benzodiazepines. What are some of the clinical
effects and properties of benzodiazepines that make them useful in anesthesia
practice?
A
- Benzodiazepines that are commonly used in the perioperative period include
midazolam, diazepam, and lorazepam. The most common effects of benzodiazepines
are their anxiolytic and sedative effects. When administered at higher doses,
benzodiazepines may also produce unconsciousness. Other properties of
benzodiazepines include anterograde amnesia, a lack of retrograde amnesia, minimal
cardiopulmonary depression, anticonvulsant activity, and relative safety when taken
in overdose. Clinical uses of benzodiazepines include their use for preoperative
medication, for intravenous sedation, for the intravenous induction of anesthesia,
and for the suppression of seizure activity. In addition to the intravenous route of
administration, benzodiazepines can be administered via intramuscular,
intranasal, and sublingual routes.
37
Q
- What is the mechanism of action of benzodiazepines?
A
- Benzodiazepines exert their effects through their actions on the gamma-
aminobutyric acid (GABA) receptor. When GABA receptors are stimulated by the
inhibitory neurotransmitter GABA, a chloride ion channel opens, allowing chloride
ions to flow into the cell. This results in hyperpolarization of the neuron and a
resistance of the neuron to subsequent depolarization. Benzodiazepines enhance the
effect of GABA by binding to subunits of the GABA receptor and maintaining the
chloride channel open for a longer period of time.
38
Q
- Where are benzodiazepine receptors located?
A
- Benzodiazepine receptors are located primarily on postsynaptic nerve endings in
the central nervous system. The greatest density of benzodiazepine receptors is in
the cerebral cortex. The distribution of benzodiazepine receptors is consistent
with the minimal cardiopulmonary effects of these drugs.
39
Q
- How does midazolam compare with diazepam with regard to its affinity for the
benzodiazepine receptor?
A
- Midazolam has almost two times the affinity for benzodiazepine receptors than does
diazepam, which is consistent with its greater potency
40
Q
- How does water-soluble midazolam cross the blood-brain barrier to gain access to
the central nervous system?
A
- Midazolam is a hydrophilic drug. When midazolam is exposed to the pH of the
blood it undergoes a change in its structure and becomes highly lipid soluble.
This change in structure allows it to cross the blood-brain barrier and gain access
to the central nervous system.
41
Q
- What is the effect-site equilibration time of benzodiazepines relative to other
intravenous anesthetics? How do the context-sensitive half-times of the
benzodiazepines compare?
A
- Benzodiazepines are highly lipid-soluble drugs. This allows them to gain rapid
entrance into the central nervous system by crossing the blood-brain barrier,
where they are able to exert their effects. Thus the effect-site equilibration time of
benzodiazepines is short, although it is slower than propofol or thiopental. The
duration of action of benzodiazepines is dependent on the redistribution of the
drug from the brain to inactive tissue sites. A continuous infusion or repeated
boluses can result in saturation of the inactive tissue sites and a prolongation of
the drug effect, particularly for the benzodiazepines that have active metabolites.
For instance, diazepam undergoes hepatic metabolism to active metabolites,
whereas midazolam has no active metabolites. The context-sensitive half-times
for diazepam and lorazepam are prolonged when compared with that of
midazolam
42
Q
- How do benzodiazepines affect the cardiovascular system?
A
- Induction doses of midazolam may lead to decreases in systemic blood pressure that
are greater than those seen with the induction dose of diazepam. This effect of
midazolam may be particularly pronounced in patients who are hypovolemic.
The decrease in systemic blood pressure is believed to be due to decreases in
systemic vascular resistance.
43
Q
- How do benzodiazepines affect ventilation?
A
- In general, benzodiazepines alone produce dose-dependent ventilatory depressant
effects. Transient apnea may occur with the rapid administration of induction
doses of midazolam, particularly if an opioid has been used for premedication
44
Q
- How do benzodiazepines affect the central nervous system?
A
- Benzodiazepines decrease cerebral blood flow and cerebral metabolic oxygen
requirements in a dose-dependent manner, but there is a ceiling to this effect.
This makes benzodiazepines safe for use in patients with intracranial space-
occupying lesions, although the administration of benzodiazepines to patients with
intracerebral pathologic processes may make subsequent neurologic evaluation
of the patient difficult secondary to the potentially prolonged effects of these drugs.
Benzodiazepines also have anticonvulsant effects that are thought to occur
through the enhancement of the inhibitory effects of the neurotransmitter
GABA acid in the central nervous system. Benzodiazepines have been shown to
increase the seizure threshold or treat seizures due to local anesthetic toxicity,
alcohol withdrawal, and epilepsy. The dose of diazepam used to treat seizures is
0.1 mg/kg intravenously. An isoelectric electroencephalogram is not able to be
achieved with the administration of benzodiazepines.
45
Q
- What are some clinical uses of benzodiazepines in anesthesia practice?
A
- Clinical uses of benzodiazepines in anesthesia practice include preoperative
medication, intravenous sedation, the intravenous induction of anesthesia, and
the suppression of seizure activity.
46
Q
- How do midazolam and diazepam compare with regard to time of onset and degree
of amnesia when administered for sedation?
A
- When administered for sedation, midazolam has a more rapid onset and produces
a greater degree of amnesia than diazepam. The slow onset and greater duration
of action of lorazepam limits its usefulness as a preoperative medication. All
benzodiazepines may have prolonged and more pronounced sedative effects in the
elderly
47
Q
- What are some advantages and disadvantages of benzodiazepines for use as
induction agents?
A
- The intravenous induction doses of midazolam and diazepam are 0.1 to 0.2 mg/kg
and 0.2 to 0.3 mg/kg, respectively. The time of onset of midazolam is anywhere
between 30 and 80 seconds, depending on the dose and premedication. The time
of onset of midazolam is more rapid than the time of onset of diazepam, making it
the benzodiazepine of choice for the induction of anesthesia. The speed of onset
of both these agents can be facilitated by the prior administration of opioids.
Benzodiazepines are advantageous over barbiturates for the induction of anesthesia
only because of their potentially lesser circulatory effects and greater reliability for
the production of amnesia. A disadvantage of benzodiazepines for the induction
of anesthesia is their lack of analgesic properties. Additional medicines would need
to be administered to blunt the cardiovascular and laryngeal responses to direct
laryngoscopy. The major disadvantage of benzodiazepines for the induction of
anesthesia is delayed awakening, which limits the usefulness of benzodiazepines forthis purpose. Midazolam is the shortest-acting of the benzodiazepines and therefore
the most appropriate choice of benzodiazepine for the induction of anesthesia. Even
so, awakening after a single induction dose of midazolam in healthy volunteers
takes more than 15 minutes. Diazepam and lorazepam require even greater periods
of time before awakening after an induction dose, precluding their use as anesthesia
induction agents.
48
Q
- How can the effects of benzodiazepines be reversed?
A
- The effects of benzodiazepines can be reversed by a specific antagonist drug,
flumazenil. Flumazenil is a competitive antagonist that binds to the benzodiazepine
receptor but has little intrinsic activity. Flumazenil should be titrated to effect
by administering 0.2 mg intravenously every 60 seconds up to a total dose of 1
to 3 mg. Flumazenil binds tightly to the benzodiazepine receptor but is cleared
rapidly from the plasma. This results in a short duration of action of only about
20 minutes. The short duration of action of flumazenil requires that the patient be
closely monitored for resedation after a dose of flumazenil is administered to
reverse the effects of a benzodiazepine. Alternatively, an infusion of flumazenil may
be started and titrated to the desired effect to maintain a constant plasma
level of this reversal agent.
49
Q
- What organic solvent is used to dissolve diazepam into solution? What are some
of the effects of this solvent?
A
- Propylene glycol is an organic solvent used to dissolve lipid soluble diazepam into
solution. Propylene glycol is likely responsible for the unpredictable absorption
of diazepam when administered intramuscularly. It is also responsible for the
pain and possible subsequent thrombophlebitis experienced by patients on
the intravenous injection of diazepam.
50
Q
- How common are allergic reactions to benzodiazepines?
A
- Allergic reactions to benzodiazepines are extremely rare.
51
Q
- What chemical compound is ketamine a derivative of? What is its mechanism of
action?
A
- Ketamine is a derivative of phencyclidine. The administration of ketamine
produces unconsciousness and analgesia that is dose related. The exact mechanism
by which ketamine exerts its effects is unknown. Ketamine occupies some m-opioid
receptors in the brain and spinal cord, which may partially explain its analgesic
effects. Ketamine also binds to the NMDA receptor, which is believed to mediate
the general anesthetic actions of ketamine. Other receptors that ketamine interacts
with include monoaminergic receptors, muscarinic receptors, and calcium ion
channels. Functionally, ketamine is believed to cause selective depression of the
projections from the thalamus to the limbic system and cortex. The anesthesia
derived from the administration of ketamine has thus been termed a dissociative
anesthesia. There have not been any drugs isolated that are able to antagonize
the effects of ketamine.
52
Q
- How do patients appear clinically after an induction dose of ketamine?
A
- After an induction dose of ketamine the patient appears to be in a cataleptic state.
The appearance of the patient may be characterized as eyes remaining open with a
slow nystagmic gaze; the maintenance of cough, swallow, and corneal reflexes;
moderate dilation of the pupils; lacrimation; salivation; and an increase in skeletal
muscle tone, with apparently coordinated but purposeless movements of the
extremities. Induction doses of ketamine provide an intense analgesia and amnesia
in patients despite the patient appearing as if he or she may be awake.
53
Q
- What is the mechanism by which the effects of ketamine are terminated
A
- The redistribution of highly lipid-soluble ketamine to inactive tissue sites allows
for rapid awakening after the administration of a bolus of ketamine. Ketamine
undergoes extensive hepatic metabolism to norketamine for its elimination.
Norketamine has between 20% and 30% of the potency of ketamine and may
contribute to some of the delayed effects of ketamine when administered as
a continuous infusion.
54
Q
- What are the induction doses for intravenous and intramuscular routes of
administration of ketamine? What is the time of onset for the effect of ketamine
subsequent to its administration?
A
- For the induction of anesthesia, the intravenous dose of ketamine is 1 to 2 mg/kg,
whereas the intramuscular dose is 5 to 10 mg/kg. The induction of anesthesia after
intravenous administration is achieved within 60 seconds. The induction of
anesthesia after intramuscular administration is achieved within 2 to 4 minutes.
55
Q
- How does ketamine affect the cardiovascular system?
A
- The administration of ketamine results in an increase in systemic blood pressure,
pulmonary artery blood pressure, heart rate, and cardiac output. The systemic
blood pressure may increase by 20 to 40 mm Hg over the first 5 minutes after
induction doses of ketamine are administered. The rise in blood pressure is often
sustained for over 10 minutes. The degree of hemodynamic change elicited by the
administration of ketamine is not influenced by the dose of ketamine that is
administered, but it can be blunted by the prior administration of barbiturates,
benzodiazepines, or opioids. These cardiovascular effects of ketamine are most
likely mediated centrally through the activation of the sympathetic nervous system
and the direct stimulation of sympathetic nervous system outflow. Endogenous
norepinephrine release has been found to accompany the administration of
ketamine. This property of ketamine may make it useful as an induction agent in
hypovolemic patients in whom hemodynamic support is beneficial. Conversely,
patients with a history of myocardial ischemia may be adversely affected by the
increases in myocardial oxygen demand induced by the administration of ketamine,
making ketamine a poor choice for an induction agent in this patient population.
Of note, the cardiovascular stimulatory effects of ketamine may not be as
pronounced and may even be absent in patients who are catecholamine depleted.
In catecholamine-depleted patients, such as the trauma patient, the administration
of ketamine may actually lead to myocardial depression and a decrease in
systemic blood pressure.
56
Q
A
- The administration of ketamine can result in a transient depression of ventilation,
even apnea with large doses, but the resting PaCO2 is typically unaltered in these
patients. Ketamine relaxes bronchial smooth muscle, resulting in bronchodilation.
This effect of ketamine is most likely mediated by its sympathomimetic effects and
may make it useful as an induction agent in patients with bronchial asthma. The
administration of ketamine also induces an increase in airway secretions. When
ketamine is used as an induction agent, the administration of an antisialagogue
preoperatively may be useful in decreasing the amount of airway secretions.
57
Q
- How does ketamine affect skeletal muscle tone? How does this affect the upper
airway?
A
- Ketamine preserves and may even increase skeletal muscle tone. Patients have
varying degrees of purposeful skeletal muscle movement and hypertonus after an
induction dose of ketamine. The preservation of skeletal muscle tone results in
maintenance of a patent upper airway and the preservation of cough and swallow
reflexes. Despite this, airway protection by these reflexes against regurgitation or
vomiting cannot be assumed
58
Q
- How does ketamine affect the central nervous system?
A
- Ketamine has excitatory effects on the central nervous system such that there are
increases in cerebral metabolism, cerebral blood flow, intracranial pressure, and
cerebral metabolic oxygen requirements associated with its administration. These
excitatory effects of ketamine are reflected by the development of theta wave
activity on the electroencephalogram when ketamine is administered. Because of
the central nervous system excitatory effects of ketamine,itis not recommended as an
induction agent in patients with space-occupying intracranial lesions or after head
trauma in whom increases in the intracranial pressure can be detrimental
59
Q
- What does the emergence delirium associated with ketamine refer to? What is the
incidence? How can it be prevented?
A
- The emergence after the administration of ketamine has been associated with a
delirium, often referred to as an emergence delirium. The severity of the emergence
delirium varies. The emergence of delirium manifests as vivid dreaming, visual and
auditory illusions, and a sense of floating outside the body. These sensations are
often associated with confusion, excitement, and fear, and are unpleasant to the
patient. The emergence of delirium typically occurs in the first hour after
emergence and persists for 1 to 3 hours. The incidence of emergence delirium with
ketamine administration has been estimated to be up to 30%, and it is more likelyto occur when ketamine is used as the sole anesthetic agent. The risk of emergence
delirium can be decreased with the preoperative or postinduction administration of
benzodiazepines. (
60
Q
- What are some common clinical uses of ketamine?
A
- Some common clinical uses of ketamine include its administration for the
induction of anesthesia in hypovolemic patients, its intramuscular injection
for the induction of anesthesia in children or in developmentally disabled patients
who are difficult to manage, and for dressing changes and debridement procedures
in burn patients. Small doses of ketamine may be titrated for its analgesic
effects. (1
61
Q
- What can the repeated administration of ketamine lead to? How is it manifest
clinically?
A
- The repeated administration of ketamine may result in the development of a
tolerance to the analgesic effects of ketamine. Clinically, this would manifest as an
increase in the dose of ketamine required with each subsequent anesthetic to
provide sufficient analgesic effects. An example in which this situation may arise is
in burn patients who are being administered ketamine while undergoing recurrent
dressing changes.
62
Q
- How common are allergic reactions to ketamine?
A
- Allergic reactions to ketamine are uncommon
63
Q
- What type of structure is etomidate? What is its mechanism of action?
A
- Etomidate is an imidazole derivative. The mechanism by which etomidate exerts its
effects is not completely understood. It appears that etomidate acts in part through
agonist effects at the GABA receptor.
64
Q
- How is etomidate cleared from the plasma?
A
- The induction dose of etomidate is 0.3 mg/kg. The administration of etomidate
in induction doses results in unconsciousness in less than 30 seconds. The duration
of action of etomidate after an induction dose is very short, owing to its rapid
clearance from the plasma through redistribution to inactive tissue sites. (
65
Q
- What degree of metabolism does etomidate undergo?
A
- Etomidate rapidly undergoes nearly complete ester hydrolysis to pharmacologically
inactive metabolites by the liver, with less than 3% of the drug being excreted
in the urine unchanged.
66
Q
- What is the context-sensitive half-time of etomidate relative to other intravenous
anesthetics? What is the effect-site equilibration time of etomidate relative to other
intravenous anesthetics?
A
- Like thiopental and propofol, etomidate is highly lipid soluble, which allows it
to quickly cross the blood-brain barrier to exert its effects. This accounts for the
short effect-site equilibration time for these agents. The context-sensitive half-time
of etomidate may be prolonged if repeated or continuous doses of the drug result in
saturation of the inactive sites. It is less likely than thiopental to accumulate and
have prolonged effects, however.
67
Q
- How does etomidate affect the cardiovascular system?
A
- The administration of etomidate provides cardiovascular stability in that
induction doses of etomidate result in minimal changes in heart rate, mean arterial
pressure, central venous pressure, stroke volume, or cardiac index. Minimal
decreases in blood pressure may result from the administration of etomidate to
hypovolemic patients. The cardiovascular stability associated with etomidate sets it
apart from the other induction agents and is the basis for its usefulness as
an induction agent in patients with limited cardiac reserve. When etomidate is
administered to these patients, it is important to realize that it does not have any
analgesic effects. Supplemental agents need to be administered in conjunction with
etomidate to blunt the stimulatory effects of direct laryngoscopy
68
Q
- How does etomidate affect ventilation?
A
- The administration of etomidate alone appears to result in less depressant effects on
ventilation than propofol or thiopental. The effects of etomidate on ventilation
may be augmented when administered in combination with other anesthetics or
opioids. (
69
Q
- How does etomidate affect the central nervous system?
A
- The administration of etomidate results in decreases in cerebral blood flow,
intracranial pressure, and cerebral metabolic oxygen requirements. Etomidate has
similar effects as barbiturates on the electroencephalogram as well, such that
etomidate may be titrated to an isoelectric electroencephalogram to maximally
decrease cerebral metabolic oxygen requirements.
70
Q
- How does etomidate affect the seizure threshold?
A
- The administration of etomidate has been shown to increase the activity of seizure
foci on an electroencephalogram. Etomidate is similar to methohexital in this
regard. Its effects can be used intraoperatively to facilitate intraoperative mapping
of seizure foci for surgical ablation. (
71
Q
- What are the endocrine effects of etomidate?
A
- The administration of etomidate is associated with the suppression of adrenocortical
function. The suppression of adrenocortical function may last for up to 4 to
8 hours after the induction dose of etomidate has been administered. The concern
regarding this suppression of adrenocortical function is the potential for the
adrenal cortex to be unresponsive to adrenocorticotropic hormone. Should the
adrenal cortex be unresponsive to adrenocorticotropic hormone, desirable
protective responses against the stresses that accompany the perioperative period
may be prevented. No adverse outcomes have been shown to have occurred
secondary to short-term adrenocortical suppression associated with the
administration of etomidate, however.
72
Q
- What are some potential negative effects associated with the administration of
etomidate?
A
- Potential negative effects associated with the administration of etomidate include
pain during intravenous injection, superficial thrombophlebitis, involuntary
myoclonic movements, and an increased incidence of postoperative nausea and
vomiting. (1
73
Q
- What type of structure is dexmedetomidine?
A
- Dexmedetomidine, the active S-enantiomer of medetomidine, is an imidazole. It is
also a selective a2-adrenergic agonist.
74
Q
- What is the mechanism of action for dexmedetomidine?
A
- Dexmedetomidine is a highly selective a2-adrenergic agonist and exerts its effects
through activation of a2 receptors in the central nervous system. The analgesic
effects originate at the level of the spinal cord, and its hypnotic effects likely
originate through receptor sites in the locus ceruleus.
75
Q
- What are some common clinical uses for dexmedetomidine?
A
- Some common clinical uses for dexmedetomidine include infusion as an adjunct
during general anesthesia in the operating room, sedation for procedures, sedation
for airway management (i.e., fiber-optic intubation), and sedation of intubated
patients in the intensive care unit. (
76
Q
- What are the typical doses for dexmedetomidine when used as infusion in the
operating room?
A
- When administered during general anesthesia, dexmedetomidine (0.5- to 1-mg/kg
loading dose over a period of 10 to 15 minutes, followed by an infusion of 0.2 to
0.7 mg/kg/hr) decreases the dose requirements for inhaled and injected
anesthetics. (
77
Q
- How does dexmedetomidine affect the cardiovascular system?
A
- Dexmedetomidine infusion decreases systemic blood pressure by moderate
decreases in heart rate and systemic vascular resistance. Bradycardia associated
with dexmedetomidine infusion may sometimes require treatment. Severe
bradycardia, heart block, and asystole have been described. A bolus injection may
produce transient increases in systemic blood pressure and pronounced decreases in
heart rate, an effect that is probably mediated through activation of peripheral
a2-adrenergic receptors.
78
Q
- How does dexmedetomidine affect the respiratory system?
A
- Dexmedetomidine has only minor effects on the respiratory system when compared
with other intravenous anesthetics. These effects include small decreases in tidal
volume without much change in the respiratory rate. The ventilatory response
to carbon dioxide is unchanged. Upper airway obstruction as a result of sedation is
possible and may be augmented when dexmedetomidine is combined with
other sedative-hypnotics. (
79
Q
- What are the effects of dexmedetomidine on cerebral blood flow?
A
- Dexmedetomidine likely leads to a decrease in cerebral blood flow without
significant changes in intracranial pressure and cerebral metabolic oxygen
requirements.
