PARENTERAL ANESTHETICS
Pharmacokinetic Principles
Parenteral anesthetics are small, hydrophobic, substituted aromatic or heterocyclic compounds (Figure 14–1). Hydrophobicity is the key factor
governing the pharmacokinetics of this class of drugs (Bischoff and Dedrick, 1968; Burch and Stanski, 1983; Shafer and Stanski, 1992). After a
single intravenous bolus, each of these drugs preferentially partitions into the highly perfused and lipophilic brain and spinal cord tissue where it
produces anesthesia within a single circulation time. Subsequently, blood levels fall rapidly, resulting in redistribution of anesthetic out of the
central nervous system back into the blood, where it then diffuses into less-well-perfused tissues such as muscle, viscera and, at a slower rate,
into the poorly perfused but very hydrophobic adipose tissue. Termination of anesthesia after single boluses of parenteral anesthetics is primarily
by redistribution out of the nervous system rather than by metabolism (for example, see Figure 14–2). After redistribution, anesthetic blood
levels fall according to a complex interaction between the metabolic rate and the amount and lipophilicity of the drug stored in the peripheral
compartments (Hughes et al., 1992; Shafer and Stanski, 1992). Thus, parenteral anesthetic half-lives are "context-sensitive," and the degree to
which a half-life is contextual varies greatly from drug to drug as might be predicted based on their markedly different hydrophobicities and
metabolic clearances (Table 14–2; and Figure 14–3). For example, after a single bolus of thiopental, patients usually emerge from anesthesia
within 10 minutes; however, a patient may require more than a day to awaken from a prolonged thiopental infusion. The majority of individual
variability in sensitivity to parenteral anesthetics can be accounted for by pharmacokinetic factors (Wada et al., 1997; Wulfsohn and Joshi, 1969).
For example, in patients with lower cardiac output, the relative perfusion of and fraction of anesthetic dose delivered to the brain is higher; thus,
patients in septic shock and those with cardiomyopathy usually require lower doses of anesthetic. Elderly patients typically require a smaller
anesthetic dose, primarily because of a smaller initial volume of distribution (Arden et al., 1986; Homer and Stanski, 1985). As described below,
similar principles govern the pharmacokinetics of the hydrophobic inhalational anesthetics with the added complexity of drug uptake by inhalation.
Figure 14–1. Structures of Parenteral Anesthetics.
Figure 14–2. Thiopental Serum Levels after a Single Intravenous Induction Dose.
Thiopental serum levels after a bolus can be described by two time constants, t1/2 and t1/2 . The initial fall is rapid (t1/2 < 10 min) and is due to
redistribution of drug from the plasma and the highly perfused brain and spinal cord into less well-perfused tissues such as muscle and fat. During this
redistribution phase, serum thiopental concentration falls to levels (AL—awakening level) where patients awaken (see inset—the average thiopental serum
concentration in 12 patients after a 6 mg/kg intravenous bolus of thiopental). Subsequent metabolism and elimination is much slower and is characterized
by a half-life (t1/2
of more than 10 hours. (Adapted with permission from Burch and Stanski, 1983.)
Figure 14–3. Context-Sensitive Half-Time of General Anesthetics.
The duration of action of single intravenous doses of anesthetic/hypnotic drugs is similarly short for all and is determined by redistribution of the drugs away
from their active sites. However, after prolonged infusions, drug half-lives and durations of action are dependent on a complex interaction between the rate
of redistribution of the drug, the amount of drug accumulated in fat, and the drug's metabolic rate. Thus, drug half-lives vary greatly. This phenomenon has
been termed the context-sensitive half-time (that is, the half-time of a drug can only be estimated if one knows the context—the total dose and over what
time it has been given). Note that the half-times of some drugs such as etomidate, propofol, and ketamine increase only modestly with prolonged infusions;
others (e.g., diazepam and thiopental) increase dramatically. (Reproduced with permission from Reves et al., 1994.)
Table 14–2. Pharmacological Properties of Parenteral Anesthetics
DRUG FORMULATION IV
INDUCTION
DOSE
(mg/kg)
Thiopental
25 mg/ml in aqueous solution +
1.5 mg/ml Na2CO3; pH = 10–11
3–5
MINIMAL
HYPNOTIC
LEVEL (
g/ml)
DURATION t1/2 *
CL
PR
OF
(hours) (ml·min– BIN
1·kg–1)
INDUCTION
(%
DOSE (min)
15.6
5–8
12.1
3.4
85
Methohexital 10 mg/ml in aqueous solution +
1.5 mg/ml Na2CO3; pH = 10–11
1–2
10
4–7
3.9
10.9
85
Propofol
10 mg/ml in 10% soybean oil,
2.25% glycerol, 1.2% egg
phospholipid, 0.005% EDTA or
0.025% Na metabisulfite; pH =
4.5–7
1.5–2.5
1.1
4–8
1.8
30
98
Etomidate
2 mg/ml in 35% propylene
glycol; pH = 6.9
0.2–0.4
0.3
4–8
2.9
17.9
76
Ketamine
10, 50, or 100 mg/ml in aqueous 0.5–1.5
solution; pH = 3.5–5.5
1
10–15
3.0
19.1
27
SOURCES: Data for thiopental from Clarke et al., 1968; Burch and Stanski, 1983; Hudson et al., 1983; Hung et al., 1992; for methohexital from Brand et al., 1963; Clarke et a
1981; Hudson et al., 1983; McMurray et al., 1986; for propofol from Kirkpatrick et al., 1988; Langley and Heel, 1988; Shafer et al., 1988; for etomidate from Doenicke, 1974; Me
1976; Fragen et al., 1983; Hebron et al., 1983; for ketamine from Chang and Glazko, 1974; Clements and Nimmo, 1981; Whi te et al., 1982; Dayton et al., 1983.
*
t1/2
=
phase half-life; CL= clearance; Vss= volume of distribution at steady state; EDTA = ethylenediaminetetraacetic acid.
Barbiturates
CHEMISTRY AND FORMULATIONS
Anesthetic barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine), with either an oxygen or sulfur at the 2-position
(Figure 14–1). The three barbiturates used for clinical anesthesia are sodium thiopental (PENTOTHAL), thiamylal (SURITAL), and methohexital
(BREVITAL). Sodium thiopental is the most frequently used of the barbiturates for inducing anesthesia. All three barbiturate anesthetics are
supplied as racemic mixtures despite enantioselectivity in their anesthetic potency (Andrews and Mark, 1982; Christensen and Lee, 1973; Nguyen
et al., 1996). Barbiturates are formulated as the sodium salts with 6% sodium carbonate and reconstituted in water or isotonic saline solution to
produce 1% (methohexital), 2% (thiamylal), or 2.5% (thiopental) alkaline solutions with pHs of 10 to 11. Once reconstituted, the thiobarbiturates
are stable in solution for up to 1 week and methohexital for up to 6 weeks if refrigerated. Mixing with more acidic drugs commonly used during
anesthetic induction can result in precipitation of the barbiturate as the free acid; thus, standard practice is to delay the administration of other
drugs until the barbiturate has cleared the intravenous tubing.
PHARMACOKINETICS
Pharmacokinetic parameters for each drug are given in Table 14–2. As discussed above, the principal mechanism limiting anesthetic duration after
single doses is redistribution of these hydrophobic drugs from the brain to other tissues. However, after multiple doses or infusions, the duration
of action of the barbiturates varies considerably depending on their clearances. Methohexital differs from the other two barbiturates in its much
more rapid clearance; thus, it accumulates less during prolonged infusions (Schwilden and Stoeckel, 1990). Prolonged infusions or very large
doses of thiopental and thiamylal can produce unconsciousness lasting several days because of their slow elimination and large volume of
distributions (Stanski et al., 1980). Even single induction doses of thiopental and, to a lesser degree, methohexital can produce psychomotor
impairment lasting up to 8 hours (Beskow et al., 1995; Korttila et al., 1975). Methohexital had been used frequently for outpatient procedures
where rapid return to an alert state is particularly desirable, but this role now has been filled largely by the anesthetic propofol (see below). All
three drugs are eliminated primarily by hepatic metabolism and renal excretion of inactive metabolites (Broadie et al., 1950); a small fraction of
thiopental undergoes a desulfuration reaction to the longer-acting hypnotic pentobarbital (Chan et al., 1985). Each drug is highly protein bound
(Table 14–2). Hepatic disease or other conditions that reduce serum protein concentrations will decrease the volume of distribution and thereby
increase the initial free concentration and hypnotic effect of an induction dose (Ghoneim and Pandya, 1975).
CLINICAL USE
Recommended intravenous doses for all three drugs in a healthy young adult are given in Table 14–2. The typical induction dose of thiopental (3
to 5 mg/kg) produces unconsciousness in 10 to 30 seconds with a peak effect in one minute and duration of anesthesia of 5 to 8 minutes (Dundee
et al., 1982). Neonates and infants usually require a higher induction dose (5 to 8 mg/kg), whereas elderly and pregnant patients require less (1
to 3 mg/kg) (Gin et al., 1997; Homer and Stanski, 1985; Jonmarker et al., 1987). Dosage calculation based on lean body mass reduces individual
variation in dosage requirements. Doses can be reduced 10% to 50% after premedication with benzodiazepines, opioids, and/or
2
-adrenergic
receptor agonists because of their additive hypnotic effect (Nishina et al., 1994; Short et al., 1991; Wang et al., 1996). Thiamylal is
approximately equipotent with and in all aspects very similar to thiopental (Tovell et al., 1955). Methohexital is three times as potent as but
otherwise similar to thiopental in onset and duration of action (Thornton, 1970; Tovell et al., 1955). Thiopental and thiamylal produce little or no
pain on injection; methohexital elicits mild pain. Venoirritation can be reduced by injection into larger non-hand veins and by prior intravenous
injection of lidocaine (0.5 to 1 mg/kg). Intraarterial injection of thiobarbiturates can induce a severe inflammatory and potentially necrotic
reaction and should be avoided (Dohi and Naito, 1983; Waters, 1966). Thiopental often evokes the taste of garlic just prior to inducing anesthesia
(Nor et al., 1996). Methohexital and, to a lesser degree, the other barbiturates can produce excitement phenomena such as muscle tremor,
hypertonus, and hiccoughs (Clarke, 1981; Thornton, 1970). For induction of pediatric patients without intravenous access, all three drugs can be
given by rectum at approximately 10 times the intravenous dose.
SIDE EFFECTS
Nervous System
Besides producing general anesthesia, barbiturates dose-dependently reduce cerebral metabolic rate as measured by cerebral oxygen utilization
(cerebral metabolic rate for oxygen; CMR O2). Induction doses of thiopental reduce CMRO2 about 25% to 30% with a maximal decrease of 55%
occurring at about 2 to 5 times the induction dose (Pierce et al., 1962; Stullken et al., 1977). As a consequence of the decrease in CMRO2,
cerebral blood flow and intracranial pressure are similarly reduced Nussmeier et al., 1986). Thiopental also reduces intraocular pressure (Joshi
and Bruce, 1975). Presumably because of their CNS-depressant activity, barbiturates are effective anticonvulsants (see Chapter 21: Drugs
Effective in the Therapy of the Epilepsies). Thiopental in particular is of proven value in the treatment of status epilepticus (Modica et al., 1990).
Cardiovascular System
The anesthetic barbiturates produce dose-dependent decreases in blood pressure. The effect primarily is caused by vasodilation, particular
venodilation, and to a lesser degree by a mild direct decrease in myocardial contractility (Elder et al., 1955; Etsten and Li, 1955; Fieldman et al.,
1955). Typically, heart rate increases as a compensatory response to a lower blood pressure, although barbiturates do blunt the baroreceptor
reflex (Bristow et al., 1969). Drops in blood pressure can be severe in patients with impaired ability to compensate for venodilation, such as those
with hypovolemia, cardiomyopathy, valvular heart disease, coronary artery disease, cardiac tamponade, or
-adrenergic-receptor blockade.
Thiopental is not necessarily contraindicated in patients with coronary artery disease, because the ratio of myocardial oxygen supply to demand
appears to be adequately maintained within a patient's normal blood pressure range (Reiz et al., 1981). None of the barbiturates has been shown
to be arrythmogenic.
Respiratory System
Barbiturates are respiratory depressants. Induction doses of thiopental decrease minute ventilation and tidal volume with a smaller and
inconsistent reduction in respiratory rate (Grounds et al., 1987). Reflex responses to hypercarbia and hypoxia are diminished by anesthetic
barbiturates (Gross et al., 1983; Hirshman et al., 1975), and apnea can result at higher doses or in the presence of other respiratory depressants
such as opioids. With the exception of uncommon anaphylactoid reactions, these drugs have little effect on bronchomotor tone and can be used
safely in asthmatic patients (Kingston and Hirshman, 1984).
Other Side Effects
Short-term administration of barbiturates has no clinically significant effects on the hepatic, renal, or endocrine systems. A single induction dose
of thiopental does not alter gravid uterine tone but produces mild, transient depression of activity of the newborn (Kosaka et al., 1969). True
allergies to barbiturates are rare (Baldo et al., 1991); however, drug-induced histamine release occasionally is seen (Hirshman et al., 1982;
Sprung et al., 1997). Barbiturates can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria and are
contraindicated in such patients (Dundee et al., 1962). Unlike inhalational anesthetics and succinylcholine, barbiturates and all other parenteral
anesthetics do not appear to trigger malignant hyperthermia (Rosenberg et al., 1997).
Propofol
CHEMISTRY AND FORMULATIONS
Along with thiopental, propofol (DIPRIVAN) is the most commonly used parenteral anesthetic. Propofol, 2,6-diisopropylphenol, is essentially
insoluble in aqueous solutions and is formulated only for intravenous administration as a 1% (10 mg/ml) emulsion in 10% soybean oil, 2.25%
glycerol, and 1.2% purified egg phospholipid. In the United States, disodium EDTA (0.05 mg/ml) or sodium metabisulfite (0.25 mg/ml) is added
to inhibit bacterial growth. Nevertheless, significant bacterial contamination of open containers still has been reported and associated with serious
infection (Bennett et al., 1995); propofol should be administered shortly after removal from sterile packaging or discarded.
PHARMACOKINETICS
The pharmacokinetics of propofol are governed by the same principles that apply to barbiturates. Onset and duration of anesthesia after a single
bolus are similar to those of thiopental (Langley and Heel, 1988). However, recovery after multiple doses or infusion has been shown to be much
faster after propofol than after thiopental or even methohexital (Doze et al., 1986; Langley and Heel, 1988). The rapid rate of recovery after
infusion of propofol can be explained by its very high clearance coupled with the slow diffusion of drug from the peripheral to the central
compartment (Figure 14–3). The rapid clearance of propofol explains its less severe hangover compared to barbiturates and may allow for a more
rapid discharge from the recovery room (Bryson et al., 1995). Propofol is metabolized primarily in the liver to less-active metabolites that are
renally excreted (Simons et al., 1988); however, its clearance exceeds hepatic blood flow, and extrahepatic metabolism has been demonstrated
(Veroli et al., 1992). Propofol is highly protein bound, and its pharmacokinetics, like that of the barbiturates, may be affected by conditions that
alter serum protein levels (Kirkpatrick et al., 1988).
CLINICAL USE
The induction dose of propofol in a healthy adult is 1.5 to 2.5 mg/kg. Propofol has an onset and duration of anesthesia similar to those of
thiopental (Table 14–2). As with barbiturates, dosages should be reduced in elderly patients and in the presence of other sedatives and increased
in young children (Aun et al., 1992; Dundee et al., 1986). Propofol often is used for maintenance of anesthesia as well as induction. For short
procedures, small boluses (10% to 50% of the induction dose) every 5 minutes or as needed are effective. Because they produce more stable
drug levels, propofol infusions (100 to 300
g/kg per minute) are better suited for longer-term anesthetic maintenance. Infusion rates should be
tailored to patient response and the levels of other hypnotics. Sedating doses of propofol are 20% to 50% of those required for general
anesthesia. However, even at these lower doses, caregivers should be vigilant and prepared for all of the side effects of propofol discussed below,
particularly airway obstruction and apnea. Propofol elicits pain on injection, which can be reduced with lidocaine and the use of larger arm and
antecubital veins (McCulloch and Lees, 1985; Picard and Tramer, 2000). Excitatory phenomena during induction with propofol occur at about the
same frequency as with thiopental but much less frequently than with methohexital (Langley and Heel, 1988).
SIDE EFFECTS
Nervous System
The central nervous system effects of propofol are similar to those of barbiturates. Propofol decreases CMR O2, cerebral blood flow, and intracranial
and intraocular pressures by about the same amount as does thiopental (Langley and Heel, 1988; Ravussin et al., 1988; Vandesteene et al.,
1988). Like thiopental, propofol has been used in patients at risk for cerebral ischemia (Ravussin and de Tribolet, 1993); however, no human
outcome studies have been performed to determine propofol's efficacy as a neuroprotectant. Results from studies on the anticonvulsant effects of
propofol have been mixed, with some data even suggesting that it has proconvulsant activity when combined with other drugs (Modica et al.,
1990). Thus, unlike thiopental, propofol is not a proven acute intervention for seizures.
Cardiovascular System
Propofol produces a dose-dependent decrease in blood pressure that is significantly greater than that produced by thiopental (Grounds et al.,
1985; Langley and Heel, 1988). The fall in blood pressure can be explained by both vasodilation and mild depression of myocardial contractility
(Claeys et al., 1988; Grounds et al., 1985). Propofol appears to blunt the baroreceptor reflex and/or is directly vagotonic, because smaller
increases in heart rate are seen for any given drop in blood pressure after doses of propofol (Claeys et al., 1988; Langley and Heel, 1988). As
with thiopental, propofol should be used with caution in patients at risk for or intolerant of decreases in blood pressure.
Respiratory and Other Side Effects
At equianesthetic doses, propofol produces a slightly greater degree of respiratory depression than does thiopental (Blouin et al., 1991; Taylor et
al., 1986). Patients given propofol should be monitored to ensure adequate oxygenation and ventilation. Propofol appears to be less likely than
barbiturates to provoke bronchospasm (Eames et al., 1996; Pizov et al., 1995). It has no clinically significant effects on hepatic, renal, or
endocrine organ systems. Unlike thiopental, propofol appears to have significant antiemetic action and is a good choice for sedation or anesthesia
in patients at high risk for nausea and vomiting (Gan et al., 1996; McCollum et al., 1988). Propofol provokes anaphylactoid reactions and
histamine release at about the same low frequency as does thiopental (Bryson et al., 1995; Laxenaire et al., 1992). Although propofol does cross
placental membranes, it is considered safe for use in pregnant patients and transiently depresses activity of the newborn similarly to thiopental
(Abboud et al., 1995).
Etomidate
CHEMISTRY AND FORMULATION
Etomidate (AMIDATE) is a substituted imidazole that is supplied as the active D-isomer (Figure 14–1). Etomidate is poorly soluble in water and
is formulated as a 2-mg/ml solution in 35% propylene glycol. Unlike thiopental, etomidate does not induce precipitation of neuromuscular
blocking agents or other drugs frequently given during anesthetic induction (Hadzija and Lubarsky, 1995).
PHARMACOKINETICS
An induction dose of etomidate has a rapid onset and redistribution-limited duration of action (Table 14–2). Metabolism of etomidate occurs in the
liver, where it is primarily hydrolyzed to inactive compounds (Gooding and Corssen, 1976; Heykants et al., 1975). Elimination is both renal (78%)
and biliary (22%). Compared to thiopental, the duration of action of etomidate increases less with repeated doses (Figure 14–3). The plasmaprotein binding of etomidate is high but less than that of barbiturates and propofol (Table 14–2).
CLINICAL USE
Etomidate primarily is used for anesthetic induction of patients at risk for hypotension. Induction doses of etomidate (0.2 to 0.4 mg/kg) have a
rapid onset and a short duration of action (Table 14–2); they are accompanied by a high incidence of pain on injection and myoclonic movements
(Giese and Stanley, 1983). As with propofol, lidocaine effectively reduces the pain of injection (Galloway et al., 1982). The myoclonic movements
can be reduced by premedication with either benzodiazepines or opioids (Zacharias et al., 1979). Etomidate is pharmacokinetically suitable for
infusion for anesthetic maintenance (10
g/kg per minute) or sedation (5
g/kg per minute) (Fragen et al., 1983); however, long-term infusions
are not recommended for reasons discussed below. Etomidate also may be given by rectum (6.5 mg/kg) with an onset of about 5 minutes (Linton
and Thornington, 1983).
SIDE EFFECTS
Nervous System
The effects of etomidate on cerebral blood flow, metabolism, and intracranial and intraocular pressures are similar to those of thiopental (Modica
and Tempelhoff, 1992; Renou et al., 1978; Thomson et al., 1982). Etomidate has been tried as a protective agent against cerebral ischemia
(Batjer, 1993). However, animal studies have failed to show a consistent beneficial effect (Drummond et al., 1995; Guo et al., 1995), and no
controlled human trials have been performed. Etomidate has been shown in some studies to be a proconvulsant and is not a proven treatment for
seizures (Modica et al., 1990).
Cardiovascular System
Cardiovascular stability after induction is a major advantage of etomidate over either barbiturates or propofol. Induction doses of etomidate
typically produce a small increase in heart rate and little to no decrease in blood pressure or cardiac output (Criado et al., 1980; Gooding and
Corssen, 1977; Gooding et al., 1979). Etomidate has little effect on coronary perfusion pressure and reduces myocardial oxygen consumption
(Kettler et al., 1974). Thus, of all induction agents, etomidate is best suited to maintain cardiovascular stability in patients with coronary artery
disease, cardiomyopathy, cerebral vascular disease, and/or hypovolemia.
Respiratory and Other Side Effects
The degree of respiratory depression by etomidate appears to be less than that by thiopental (Colvin et al., 1979; Morgan et al., 1977). Like
methohexital, it sometimes induces hiccups but does not significantly stimulate histamine release (Doenicke et al., 1973; Zacharias et al., 1979).
Despite minimal cardiac and respiratory effects, etomidate does have two major drawbacks. First, etomidate has been associated with a
significant increase in nausea and vomiting (Fragen and Caldwell, 1979). A second problem was discovered when an increase in the mortality of
intensive-care-unit patients sedated with etomidate infusions was observed (Ledingham and Watt, 1983). The increased mortality was linked to
suppression of the adrenocortical stress response (Ledingham et al., 1983). Indeed, etomidate inhibits certain adrenal biosynthetic enzymes
required for the production of cortisol and some other steroids. Even single induction doses of etomidate may mildly and transiently reduce
cortisol levels (Allolio et al., 1985; Fragen et al., 1984; Wagner et al., 1984), but no significant differences in outcome after short-term
administration have been found even for variables specifically known to be associated with adrenocortical suppression (Wagner et al., 1984).
Thus, while etomidate is not recommended for long-term infusion, it appears to be safe for anesthetic induction and has some unique advantages
in patients prone to hemodynamic instability.
Ketamine
CHEMISTRY AND FORMULATION
Ketamine (KETALAR) is an arylcyclohexylamine, a congener of phencyclidine (Figure 14–1). It is supplied as a racemic mixture, despite the (S)isomer being more potent and having less side effects than the (R)-isomer (White et al., 1982). Although more lipophilic than thiopental,
ketamine is water-soluble and available as 10, 50, and 100 mg/ml in sodium chloride solution plus the preservative benzethonium chloride.
PHARMACOKINETICS
The onset and duration of an induction dose of ketamine is determined by the same distribution/ redistribution mechanism operant for all the
other parenteral anesthetics. Ketamine is hepatically metabolized to norketamine, which has reduced CNS activity; norketamine is further
metabolized and excreted in the urine and bile (Chang and Glazko, 1974). Ketamine has a large volume of distribution and rapid clearance that
makes it suitable for continuous infusion without the drastic lengthening in duration of action seen with thiopental (Table 14–2 and Figure 14–3).
Protein binding is much lower with ketamine than with the other parenteral anesthetics (Table 14–2).
CLINICAL USE
Ketamine has unique properties that make it useful for certain pediatric procedures and for anesthetizing patients at risk for hypotension or
bronchospasm. However, it has significant side effects that limit its routine use. Ketamine rapidly produces a hypnotic state distinct from that of
other anesthetics. Patients have profound analgesia, unresponsiveness to commands, and amnesia but may have their eyes open, move their
limbs involuntarily, and usually have spontaneous respiration. This cataleptic state has been termed dissociative anesthesia. Ketamine is typically
administered intravenously but also is effective by intramuscular, oral, and rectal routes. The induction doses are 0.5 to 1.5 mg/kg intravenously,
4 to 6 mg/kg intramuscularly, and 8 to 10 mg/kg rectally (White et al., 1982). The onset of action after an intravenous dose is similar to that of
the other parenteral anesthetics, but the duration of anesthesia of a single dose is longer (Table 14–2). For anesthetic maintenance, ketamine
occasionally is continued as an infusion (25 to 100
g/kg per minute) (White et al., 1982). Ketamine does not elicit pain on injection or true
excitatory behavior as described for methohexital, although involuntary movements produced by ketamine can be mistaken for anesthetic
excitement.
SIDE EFFECTS
Nervous System
As mentioned, ketamine has behavioral effects distinct from those of other anesthetics. The ketamine-induced cataleptic state is accompanied by
nystagmus with pupillary dilation, salivation and/or lacrimation, and spontaneous limb movements with increased overall muscle tone. Although
ketamine does not produce the classic anesthetic state, patients are anesthetized in that they are amnestic and unresponsive to painful stimuli.
Indeed, ketamine produces profound analgesia, a distinct advantage over other parenteral anesthetics (White et al., 1982). Unlike other
parenteral anesthetics, ketamine increases cerebral blood flow and intracranial pressure with minimal alteration of cerebral metabolism (Gardner
et al., 1971; Takeshita et al., 1972; Wyte et al., 1972). These effects can be attenuated by concurrent administration of thiopental and/or
benzodiazepines along with hyperventilation (Belopavlovic and Buchthal, 1982; Mayberg et al., 1995). However, given that other anesthetics
actually reduce intracranial pressure and cerebral metabolism, ketamine is relatively contraindicated for patients with increased intracranial
pressure or those at risk for cerebral ischemia. In some studies, ketamine has been shown to increase intraocular pressure, and its use for
induction of patients with open eye injuries is controversial (Whitacre and Ellis, 1984). The effects of ketamine on seizure activity appear to be
mixed, with neither strong pronor anticonvulsant activity (Modica et al., 1990). Emergence delirium characterized by hallucinations, vivid dreams,
and illusions is a frequent complication of ketamine that can result in serious patient dissatisfaction and can complicate postoperative
management (White et al., 1982). Delirium symptoms are most frequent in the first hour after emergence and occur less frequently in children
(Sussman, 1974). Benzodiazepines reduce the incidence of emergence delirium (Dundee and Lilburn, 1978).
Cardiovascular System
Unlike other anesthetics, induction doses of ketamine typically increase blood pressure, heart rate, and cardiac output (Stanley et al., 1968). The
cardiovascular effects are indirect and are most likely mediated by inhibition of both central and peripheral catecholamine reuptake (White et al.,
1982). Ketamine has direct negative inotropic and vasodilating activity, but these effects usually are overwhelmed by the indirect
sympathomimetic action (Pagel et al., 1992). Thus, ketamine is a useful drug in patients at risk for hypotension during anesthesia. While not
arrythmogenic, ketamine increases myocardial oxygen consumption and is not an ideal drug for patients at risk for myocardial ischemia (Reves et
al., 1978).
Respiratory System
The respiratory effects of ketamine are perhaps the best indication for its use. Induction doses of ketamine produce small and transient decreases
in minute ventilation, but respiratory depression is less severe than with other general anesthetics (White et al., 1982). Ketamine is a potent
bronchodilator due to its indirect sympathomimetic activity and perhaps some direct bronchodilating activity (Hirshman et al., 1979; Wanna and
Gergis, 1978). Thus, ketamine is particularly well suited for anesthetizing patients at high risk for bronchospasm.
Summary of Parenteral Anesthetics
Parenteral anesthetics are the most commonly used drugs for anesthetic induction of adults. Their lipophilicity coupled with the relatively high
perfusion of the brain and spinal cord results in a rapid onset and short duration after a single bolus dose. However, these drugs ultimately
accumulate in fatty tissue, prolonging the patient's recovery if multiple doses are given, particularly for drugs with lower rates of clearance. Each
anesthetic has its own unique set of properties and side effects (summarized in Table 14–3). Thiopental and propofol are the two most commonly
used parenteral agents. Thiopental has a long-established track record of safety. Propofol is advantageous for procedures where rapid return to a
preoperative mental status is desirable. Etomidate usually is reserved for patients at risk for hypotension and/or myocardial ischemia. Ketamine is
best suited for patients with asthma and/or for children undergoing short, painful procedures.
Table 14–3. Some Pharmacological Effects of Parenteral Anesthetics*
DRUG
CBF
CMRO2
ICP
MAP
HR
CO
RR
E
Thiopental
–––
–––
–––
–
+
–
–
––
Etomidate
–––
–––
–––
+/–
+/–
+/–
–
–
Ketamine
++
+/–
++
+
++
+
+/–
+/–
Propofol
–––
–––
–––
––
+
–
––
–––
KEY: CBF, cerebral
blood flow; CMRO2, cerebral metabolic rate for oxygen; ICP, intracranial pressure; MAP, mean arterial pressure; HR, heart rate; CO,
cardiac output; RR, respiratory rate;
*
E,
minute ventilation.
Typical effects of a single induction dose in human beings; see text for references.
Qualitative scale from ––– to +++= slight, moderate, or large decrease or increase, respectively; +/– indicates no significant change.