Anesthetics, Barbiturate (Systemic)

This monograph includes information on the following:

1) Methohexital
2) Thiopental

BAN:
Methohexital—Methohexitone
Thiopental sodium—Thiopentone sodium

VA CLASSIFICATION
Primary: CN202

Note: Controlled substance classification—

Note: Controlled substances in the U.S. and Canada as follows:{28}{37}



Drug
U.S.
Canada
Methohexital
IV
G
Thiopental
III
G
Commonly used brand name(s): Brevital1; Brietal1; Pentothal2.

Other commonly used names are:
methohexitone {02} and thiopentone {03}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthetic (general)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anesthesia, general or
Anesthesia, general, adjunct or
Anesthesia, local, adjunct—Methohexital and thiopental are indicated primarily for the induction of general anesthesia. They are also indicated for use alone as intramuscular, intravenous, or rectal anesthesia for brief surgical procedures with minimal painful stimuli {11} {12} {13} {75}; for supplementing other anesthetic agents; and to produce hypnosis during balanced anesthesia with other agents such as analgesics or muscle relaxants {01} {04} {05} {06} {07} {08} {13} {14}.
—Barbiturate anesthetics may be administered in appropriate doses and in combination with an opioid analgesic and nitrous oxide for maintenance of anesthesia in prolonged procedures {07}.
—Thiopental rectal suspension may be indicated for preanesthetic sedation or induction of anesthesia when administration via the rectal route is necessary {37}, although absorption from the rectum is unpredictable {21} {31}. The barbiturate anesthetics are used sometimes for sedation during short surgical operations, diagnostic procedures, or regional anesthesia in adults {32} {33} {37} {75}. Rectal methohexital or thiopental often is used as the sole sedative/induction agent for diagnostic procedures (e.g., computerized axial tomography [CAT] scans or magnetic resonance imaging [MRI]) in children {11} {12} {13}.

Convulsions (treatment)—Thiopental for injection is indicated for short-term use in the control of convulsive states during or following inhalation anesthesia, local anesthesia, or other causes {04} {07}.

Hypertension, cerebral (treatment)1—Thiopental for injection may be indicated in the treatment of increased intracranial pressure if adequate ventilation is provided {04} {38}. It may be used to attenuate the increase in intracranial pressure during the use of volatile anesthetics. It also may be useful in the management of conditions associated with acutely increased intracranial pressure, such as Reye's syndrome, cerebral edema, and acute head injury {14} {15} {16} {17} {18} {19} {20} {23}.

Narcoanalysis1—Thiopental for injection is indicated for narcoanalysis in psychiatric disorders {04}.

[Hypoxia, cerebral (treatment)]1 or
[Ischemia, cerebral (treatment)]1—Thiopental for injection is indicated to protect the brain from the effects of hypoxia and ischemia following head injuries and other related conditions {32} {38}.

1 Not included in Canadian product labeling.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Methohexital sodium: 284.29 {02}
    Thiopental sodium: 264.33 {03}

pKa—
    Thiopental sodium: 7.4 {04} {32} {37}
    Oil:water partition coefficient—Thiopental sodium: 580 {04} {37}.

Note: Methohexital is also highly lipid-soluble, but its oil:water partition coefficient is lower than that of thiopental {33}.


Mechanism of action/Effect:

Ultra short-acting barbiturate anesthetics depress the central nervous system (CNS) to produce hypnosis and anesthesia without analgesia {06} {07} {13} {14} {28} {37}.

The exact mechanism by which barbiturate anesthetics produce general anesthesia is not completely understood. However, it has been proposed that they act by enhancing responses to gamma-aminobutyric acid (GABA), diminishing glutamate (GLU) responses, and directly depressing excitability by increasing membrane conductance (an effect reversed by the GABA antagonist picrotoxin), thereby producing a net decrease in neuronal excitability to provide anesthetic action.

Although the mechanism of action of barbiturates as sedative-hypnotics has not been completely established, the barbiturates appear to act at the level of the thalamus where they inhibit ascending conduction in the reticular formation, thus interfering with the transmission of impulses to the cortex. Studies have suggested that the sedative-hypnotic effects of barbiturates may be related to their ability to enhance or mimic the inhibitory synaptic action of GABA.

The mechanism of action of barbiturate anesthetics as anticonvulsants has not been completely established; however, in electrophysiological studies, barbiturate anesthetics (such as parenteral thiopental) that exert clinical anticonvulsant activity only at doses producing deep sedation or anesthesia have been shown to act by producing a GABA-like effect and enhancing postsynaptic inhibition responses to GABA {32}.

The mechanism by which thiopental reduces intracranial pressure and protects the brain from cerebral ischemia and hypoxia is not completely understood. However, it is related to thiopental's anesthetic action and results in increased cerebral vascular resistance with a decrease in cerebral blood flow and cerebral blood volume, and decreased cerebral metabolic rate for oxygen. Various mechanisms of action have been proposed, including a reduction of cerebral metabolic rate, a decrease in the functional activity of the brain, an inhibition of the brain stem neurogenic mechanism of vasoparalysis, a sealing effect on membranes, and a scavenging of free oxygen radicals {32}.


Other actions/effects:

Barbiturate anesthetics are potent respiratory depressants; respiratory depression is dose-related and is potentiated by opioid premedication {33}.

Laryngeal reflexes are depressed with deep levels of anesthesia {32}.

Barbiturate anesthetics have little, if any, analgesic activity.

There is either a fall in or no change in mean arterial blood pressure, the former being more pronounced in hypertensive or hypovolemic patients {38}; a decrease in cardiac output; an increase in total calculated peripheral resistance; an increase or no change in heart rate; a considerable decrease in renal plasma flow; a decrease in intrathoracic blood volume; an increase in blood flow and volume in the extremities; a decrease or no change in the central, right atrial, and peripheral venous pressures; and a decrease in cerebral blood flow with a marked reduction in cerebrospinal fluid (CSF) pressure. Direct depression of cardiac contractility is dose-related.

Barbiturate anesthetics have no effect on uterine muscle tone.

Renal, hepatic, and gastrointestinal functions are depressed by barbiturate anesthetics, but the effects are rarely of clinical significance {32}.

Oxybarbiturates such as methohexital can cause central excitation and can induce seizures in patients with temporal lobe epilepsy {24}.

Absorption:

Methohexital rectal solution—May be unpredictable {21} {74}.

Thiopental rectal suspension—May be unpredictable {31}.

Distribution:

Because of their high lipid solubility and low degree of ionization, barbiturate anesthetics rapidly cross the blood-brain barrier and are rapidly redistributed from the brain to other body tissues, first to highly perfused visceral organs (liver, kidneys, heart) and muscle, and later to fatty tissues {32} {37}.

When barbiturate anesthetics are administered repeatedly or by continuous infusion, accumulation in and slow release from lipoidal storage sites may result in prolonged anesthesia, somnolence, and respiratory and circulatory depression {28} {32} {33} {37}. Concentrations of thiopental in fatty tissues may be six to twelve times greater than in plasma {07}. Because of methohexital's lower lipid solubility (and, consequently, lower concentrations in fatty tissues) and shorter elimination half-life, methohexital is less likely than thiopental to accumulate with repeated or continuous administration {43}.

Barbiturate anesthetics rapidly cross the placenta and appear in cord blood {01} {06} {32}. Also, after administration of large doses, thiopental is distributed into breast milk.


Volume of distribution at steady-state (V DSS):

Methohexital: 1.9 to 2.2 L per kg of body weight (L/kg) {51} {53} {54} {56}.

Thiopental: 1.7 to 2.5 L/kg {32} {51} {52} {55} {56} {57}; may increase to 4.1 L/kg during pregnancy at term and to 7.9 L/kg in obese patients.


Protein binding:

Methohexital—High (73%) {52}.

Thiopental—High (72 to 86%) {05} {32} {37} {52} {62}.

Biotransformation:

Primarily hepatic; also, biotransformed to a small extent in other tissues, especially the kidneys and brain {37}.

Methohexital is metabolized more rapidly than thiopental. Although most of thiopental's metabolites are inactive, about 3 to 5% of a dose is desulfurated to pentobarbital, which is cleared from the body much more slowly than thiopental. The significance of this metabolic pathway is relevant only in patients receiving large doses of thiopental.

When large quantities of thiopental are administered by continuous intravenous infusion over a prolonged period of time, progressively increasing saturation of hepatic metabolizing enzymes may occur, resulting in a rapid increase in the plasma concentration {32}.

Half-life:


Distribution:

Rapid.


Methohexital—

5.6 ± 2.7 minutes {56}.



Thiopental—

4.6 to 8.5 minutes {56} {57} {59}.




Elimination:


Methohexital—

Adults—1.5 to 5 hours {32} {51} {52} {53} {54} {56} {60}; increases with increasing age {55} {58}.



Thiopental—

Adults—3 to 8 hours after a single intravenous dose {05}; the elimination half-life may be longer after prolonged administration (10 to 12 hours) {51} {52} {55} {56} {57} {59}; the elimination half-life increases with increasing age {55} {58} and is dependent on hepatic blood flow. It may be increased to 26.1 hours during pregnancy at term {63} and to 27.85 hours in obese patients.

Children—6.1 hours {52} {55}.


Note: When low doses of thiopental (e.g., 5 mg per kg of body weight) are administered for induction of anesthesia, the elimination half-life is independent of plasma concentration {32}.
Administration of high doses of thiopental (e.g., 300 to 600 mg per kg of body weight) results in an increase in the elimination half-life {32}.



Onset of action:

Rapid, due to the high lipid solubility of the barbiturate anesthetics {32}.


Anesthesia:


Methohexital—

Intramuscular—In pediatric patients, within 2 to 10 minutes {01}.

Intravenous—Within 60 seconds {01} {33}.

Rectal—Within 5 to 11 minutes {64} {65}; in pediatric patients, within 5 to 15 minutes {01}.



Thiopental—

Intravenous—30 to 40 seconds {05} {32} {33} {52}.

Rectal—Within 8 to 10 minutes {33}.



Note: Following intravenous administration of induction doses of thiopental, muscle relaxation occurs about 30 seconds after unconsciousness is attained.
After intravenous administration of induction doses of a barbiturate anesthetic, the depth of anesthesia may increase for up to 40 seconds and then decrease progressively until consciousness returns. This reflects rapid changes in the concentration of the anesthetic at its sites of action in the brain and is a consequence of its initial distribution to the brain followed by subsequent redistribution to other tissues {32}.



Hypnosis:


Thiopental (intravenous)—

Within 10 to 40 seconds {04} {07}.



Time to peak concentration:


Intravenous administration:

Brain: Methohexital or thiopental—Within 30 seconds {32} {33}.

Muscles: Thiopental—15 to 30 minutes {32}.

Fat: Thiopental—Several hours {32}.


Note: Very highly perfused tissues such as the brain, heart, liver, and kidneys achieve concentrations equal to peak plasma concentrations {32}.


Duration of action:


Intravenous administration:

Methohexital: 5 to 7 minutes {01}.

Thiopental: 10 to 30 minutes {05}.


Note: The brief duration of action is due to the rapid rate of redistribution {01} and, to some extent, metabolism {32} accompanied by a rapid fall in plasma concentration. Administration of large or repeated doses may substantially delay recovery {01}.


Elimination:
    Renal {37}; however, renal elimination is minimal because of extensive renal tubular reabsorption due to the high lipid solubility of barbiturate anesthetics.


Clearance—
        Methohexital: In adults, 9.3 to 12.1 mL per kg per minute {32} {51} {53} {54} {60}.
        Thiopental: 1.6 to 4.3 mL per kg per minute {32} {51} {52} {55} {56} {57} {61}; may be increased during pregnancy at term to 286 mL per minute.

Note: When thiopental is administered in large doses by continuous infusion over a prolonged period of time, the kinetics of elimination change from first-order to nonlinear or zero-order kinetics. In low doses (e.g., 5 mg per kg of body weight) for induction of anesthesia, thiopental shows first-order kinetics and the rate of elimination is independent of plasma concentration. In higher doses (300 to 600 mg per kg of body weight) for more prolonged periods, it shows zero-order kinetics and the rate of elimination varies with the plasma concentration {32}.




Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one barbiturate may be sensitive to other barbiturates also.

Carcinogenicity/Mutagenicity

Studies in animals have not been performed to determine the carcinogenic and mutagenic potential of methohexital or thiopental {01} {37}.

Pregnancy/Reproduction
Fertility—
Studies in animals have not been performed to determine the effect of methohexital or thiopental on fertility {37}.

Pregnancy—
Use of barbiturate anesthetics during pregnancy may cause CNS depression in the fetus. Adequate and well-controlled studies in humans have not been done to determine whether barbiturate anesthetics are teratogenic.


Methohexital

Methohexital crosses the placenta {01} {06}.

Studies in pregnant rabbits and rats given methohexital up to four and seven times the human dose, respectively, produced no evidence of teratogenicity and no fetal abnormalities {01} {06}.

FDA Pregnancy Category B {01} {06}.



Thiopental

Thiopental crosses the placenta {32}. The concentration in cord vein blood is at its maximum 2 to 3 minutes after an intravenous dose is administered to the mother {32}.

Studies in animals have not been done.

FDA Pregnancy Category C {04} {05} {37}.


Breast-feeding

Problems in humans have not been documented. However, barbiturate anesthetics are distributed into breast milk; small amounts may appear in breast milk following administration of large doses to the nursing mother {04} {05} {37}.

Pediatrics

Infants and children require slightly more methohexital and thiopental on a weight basis than adults require {25} {28} {36}.

Although there are reports in the literature of methohexital being administered intravenously in pediatric patients, methohexital has not been well-studied for this route of administration in pediatric patients {01}. Methohexital is approved by the drug regulatory agency in the U.S. (i.e., the Food and Drug Administration [FDA]) for intramuscular and rectal administration in infants and children 1 month of age and older {01}. Methohexital is not approved by the FDA for use in infants younger than 1 month of age {01}. Methohexital is not approved by the drug regulatory agency in Canada. (i.e., the Health Protection Branch [HPB]) for use in pediatric patients {06}.

Thiopental is not labeled by the FDA or the HPB for intravenous administration to pediatric patients {05}.


Geriatrics


Following administration of barbiturate anesthetics for short (outpatient) procedures, recovery of cognitive and psychomotor functions is generally slower in elderly patients than in younger adults {42}. In addition, elderly patients are more likely to have age-related hepatic function impairment, which may require reduction {42} of dosage in patients receiving barbiturate anesthetics, and age-related renal function impairment, which may prolong the effects of these medications {05}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, also may interact with this medication.

» Alcohol or
» CNS depression–producing medications, other, including those commonly used for preanesthetic medication or induction or supplementation of anesthesia (see Appendix II )    (concurrent administration may result in increasing the CNS depressant, respiratory depressant, or hypotensive effects of barbiturate anesthetics as well as decreasing anesthetic requirements and prolonging recovery from anesthesia; dosage adjustments may be required {01} {72})


» Antihypertensives, especially diazoxide or ganglionic blockers such as guanadrel, guanethidine, mecamylamine, or trimethaphan or
Diuretics or
» Hypotension-producing medications, other (see Appendix II )    (concurrent use of these medications with barbiturate anesthetics may result in an additive hypotensive effect, which could be severe; dosage adjustments may be necessary; patients should be monitored for excessive fall in blood pressure during and following concurrent use)

    (concurrent use of antihypertensives with CNS depressant effects, such as clonidine, guanabenz, methyldopa, metyrosine, pargyline, and rauwolfia alkaloids, may increase the CNS depressant effects of barbiturate anesthetics)


Hypothermia-producing medications, other (see Appendix II )    (concurrent use with barbiturate anesthetics may increase the risk of hypothermia)


Ketamine    (concurrent use of ketamine, especially in high doses or when rapidly administered, with barbiturate anesthetics may increase the risk of hypotension and/or respiratory depression; also, the hypnotic effect of thiopental may be antagonized by ketamine {71})


Magnesium sulfate, parenteral    (concurrent use may increase the CNS depressant effects of barbiturate anesthetics)


Phenobarbital or
Phenytoin    (a higher dose of methohexital may be needed {44})


Phenothiazines, especially promethazine    (in addition to possibly increasing CNS depressant effects, concurrent use may potentiate the hypotensive and CNS excitatory effects of barbiturate anesthetics {73})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Sodium iodide I 123 and
Sodium iodide I 131 and
Sodium pertechnetate Tc 99m    (thiopental may decrease thyroidal uptake of sodium iodide I 123 and I 131 and sodium pertechnetate Tc 99m)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For parenteral and rectal administration:
» Porphyria, acute intermittent or variegata or history of    (barbiturate anesthetics may aggravate symptoms by inducing enzymes responsible for porphyrin synthesis {01} {04} {05} {06} {07} {08} {13} {28} {32} {33} {37})


For rectal administration:
» Inflammatory, ulcerative, bleeding or neoplastic lesions of the lower bowel    (symptoms may be exacerbated {37}; also, rapid absorption may result in higher peak blood concentrations and increased risk of apnea)


Risk-benefit should be considered when the following medical problems exist

Note: Dosage should be reduced and the medication administered slowly if barbiturate anesthetics are used in the presence of the following medical problems.


For parenteral and rectal administration:
Addison's disease or{08}{28}{33}
Anemia, severe or{07}{33}
Hepatic function impairment{01}{04}{05}{06}{07}{08}{13}{14}{28}{33}{37} or
Myxedema{06}{07}{13}{33} or
Renal function impairment    (hypnotic effect may be prolonged or potentiated {33})


» Cardiovascular disease, severe{01}{04}{05}{07}{08}{32}{33}{37} or
» Congestive heart failure or
» Hypotension or shock{01}{07}{32}{37}    (barbiturate anesthetics produce cardiovascular depressant effects; condition may be exacerbated {04} {05})


Myasthenia gravis{07}{33}{37} or
Neuromuscular disorders, other, such as muscular dystrophies and myotonias{33}{48}    (respiratory depression may be prolonged; dosage should be carefully titrated {04} {48} {49})


» Respiratory disease involving dyspnea or obstruction, particularly status asthmaticus{01}{06}{07}{13}{28}{32}{33}{37}    (barbiturate anesthetics produce respiratory depressant effects {01} {04} {05} {08} {13} {14})


» Sensitivity to barbiturates
Caution should be used also in debilitated patients because respiratory depression, apnea, or hypotension may be more likely to occur in these patients{05}{06}{08}{13}{14}{28} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Note: Various organizations, including the American Society of Anesthesiologists and the American Academy of Pediatrics, have established guidelines for pre-, intra-, and post-procedural care, evaluation, and monitoring of patients receiving sedation for diagnostic and therapeutic procedures {68} {69} {70}. The level of monitoring should be appropriate to the level of sedation and the procedure being performed. When an anesthetic agent is used for light sedation (i.e., the patient is able to tolerate unpleasant procedures without cardiorespiratory compromise and is able to respond purposefully to verbal commands) by non-anesthesiologists, the American Society of Anesthesiologists recommends that a designated individual, other than the person performing the procedure, be present to monitor the patient {70}. That designated person would be permitted to assist with other minor, interruptible tasks {70}. However, when an anesthetic agent is used to produce deep sedation, the patient should be monitored continuously by someone not involved in conducting the surgical or diagnostic procedure {70}. For deeply sedated patients, the person monitoring the patient should not assist with other tasks, even if the tasks are minor and interruptible {70}.

» Blood pressure and
» Body temperature and
» Cardiac/pulse rate and
» Electrocardiographic evaluation and
» Oxygenation and
» Respiratory and ventilatory status    (it is recommended that the patient's blood and tissue oxygenation, ventilation, circulation, and body temperature be monitored continuously during anesthetic administration and as required during the recovery period {69})


For thiopental only
Plasma thiopental concentrations    (monitoring of plasma thiopental concentration is recommended if thiopental is administered by intravenous infusion over an extended period of time, such as in the treatment of increased intracranial pressure {50})




Side/Adverse Effects

Note: Because barbiturate anesthetics are potent respiratory depressants, apnea may occur immediately after intravenous injection, especially in the presence of hypovolemia, cranial trauma, or opioid premedication. Apnea can occur with any route of administration of barbiturate anesthetic {44}. The duration of apnea may be longer with methohexital than with other barbiturate anesthetics {01}.
During induction of anesthesia or in lightly anesthetized patients, laryngospasm may be induced by a variety of stimuli such as surgical stimulation, the premature insertion of the laryngoscope blade or airway, and pharyngeal secretions {01} {07} {32} {33}. Laryngospasm and airway obstruction can occur with any route of administration of barbiturate anesthetic {44}.
Excitatory phenomena such as involuntary muscle movements, coughing, and hiccups occur more frequently with methohexital than with thiopental {08} {32} {33}. Seizures have occurred rarely in patients with a history of seizure disorders, especially partial seizure disorders {01} {24}.
True anaphylaxis has been reported to occur with barbiturate anesthetics, but is rare.
Overdosage may occur from too rapid or repeated injections {37}. Too rapid injection may cause a severe drop in blood pressure, possibly to shock levels, especially in patients who are hypovolemic {37}. Excessive or too rapid injections may result in respiratory difficulties such as laryngospasm and apnea {04} {37}. Repeated administration also may lead to accumulation of the barbiturate, resulting in substantial prolongation of the medication's effects {01}.
Impairment of psychomotor skills may occur following barbiturate anesthesia and may persist for varying lengths of time (usually about 24 hours), depending upon the anesthetic and/or combination of medications used and the total dosages administered. Possible adverse effects on the patient's ability to drive or perform other tasks requiring alertness and coordination should be kept in mind when a barbiturate anesthetic is administered for outpatient surgery {33}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
    
Abdominal pain
    
anxiety or restlessness
    
bronchospasm
    
cardiac arrhythmias{04}{32}{37}
    
circulatory depression{01}{05}{06}{08}{07}{13}{14}
    
coughing
    
hiccups
    
hypotension
    
laryngospasm
    
muscle twitching or jerking —occurring during induction of anesthesia or in light anesthesia{01}{05}{07}{08}{14}
    
respiratory depression{01}{04}{05}{06}{07}{08}{13}{37}
    
seizures
    
skin rash, hives, itching, or redness
    
swelling of eyelids, face, or lips
    
tachycardia
    
thrombophlebitis{01}{05}{06}{07}{08}{13}{14}{28}
    
wheezing
With rectal administration only
    
Burning{37}
    
cramping{37}
    
diarrhea{37}
    
rectal irritation{37}



Those occurring postsurgically and indicating need for medical attention
Incidence rare
    
Emergence delirium {01}{05}{06}{08}{14}{28}(anxiety; confusion; excitement; hallucinations; nervousness; restlessness)
    
immune hemolytic anemia with renal failure (back, leg, or stomach pain; nausea, vomiting, or loss of appetite; unusual tiredness or weakness; fever; pale skin)
    
radial nerve palsy (weakness of wrist and fingers)

Note: Immune hemolytic anemia with renal failure and radial nerve palsy have occurred rarely with the use of thiopental.




Those occurring postsurgically and indicating need for medical attention only if they continue
Incidence more frequent
    
Increased sensitivity to cold, during recovery (shivering or trembling{04}{07}{08}{37})

Incidence less frequent or rare
    
Drowsiness, prolonged{04}{06}{07}{37}
    
headache{01}{06}{08}{14}{28}
    
nausea or vomiting{01}{06}{08}{13}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Acute effects

CNS depression, severe

hypotension, severe

loss of peripheral vascular resistance

respiratory depression, severe, including apnea{33}{37}

Note: Overdose can result from too rapid or repeated injections of barbiturate anesthetics {05}. Circulatory and respiratory depression may result in pulmonary edema and/or cardiorespiratory arrest.


Treatment of overdose
Discontinuation of the anesthetic.

Specific treatment—If overdosage occurs with a rectal barbiturate anesthetic preparation, the contents of the rectum should be promptly evacuated; further dosing should be delayed until the effects of absorption of the initial dose can be determined {37}.

Monitoring—Vital signs, blood gases, and serum electrolytes should be monitored.

Supportive care—Supportive measures such as establishing and maintaining a patent airway (by endotracheal intubation if necessary), administering 100% oxygen with assisted ventilation if necessary {04} {07} {37}. For hypotension—Intravenous fluids should be administered and the patient's legs raised. If a desirable increase in blood pressure is not obtained, vasopressor and/or inotropic drugs may be used as required.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anesthetics, General (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Sensitivity to barbiturates

Pregnancy—Crosses the placenta and may cause CNS depression in the fetus





Use in the elderly—Recovery from the effects of anesthesia may be prolonged
Other medications, especially other CNS depressants
Other medical problems, especially acute intermittent or variegata porphyria (or history of); cardiovascular disease, severe; congestive heart failure; hypotension or shock; respiratory disease involving dyspnea or obstruction (particularly status asthmaticus); and, for rectal administration only, inflammatory, ulcerative, bleeding, or neoplastic lesions of lower bowel

Proper use of this medication

Proper dosing

Precautions after receiving this medication
» Possibility of psychomotor impairment following use of anesthetics; for about 24 hours following anesthesia, using caution in driving or performing other tasks requiring alertness and coordination

» Avoiding use of alcohol or other CNS depressants within 24 hours following anesthesia except as directed by physician or dentist


General Dosing Information
Barbiturate anesthetics should be administered only by individuals familiar with their use and skilled in airway management {01}. Age- and size-appropriate resuscitative and endotracheal intubation equipment, oxygen, and medications for prevention and treatment of anesthetic emergencies must be immediately available. Airway patency must be maintained at all times {01} {04} {05} {06} {07} {08} {13} {14} {37} {42}.

Dosage of the barbiturate anesthetics must be individualized according to the desired depth of anesthesia, concomitant use of other medications and/or nitrous oxide, and the patient's physical condition, age, sex, and weight {04}.

Young patients may require relatively larger doses than middle-aged or elderly patients. Prepuberty dose requirements are the same for both sexes, but adult females require doses smaller than those required by adult males {04}.

Care should be taken to avoid extravasation or intra-arterial injection of barbiturate anesthetics. Extravascular injection may cause pain, swelling, ulceration, and necrosis {01} {28}. Intra-arterial injection may produce arteritis, followed by vasospasm, edema, thrombosis, and gangrene of an extremity {01} {04} {05} {07} {08} {13} {28}.

Repeated doses or continuous infusion of barbiturate anesthetics may have cumulative effects, resulting in prolonged somnolence and respiratory and circulatory depression {01} {05} {06} {08} {13} {14}.

Caution is required if the patient requires a second anesthetic on the same day; a reduction in the dose of the intravenous barbiturate anesthetic may be required {32} {37}.

Although barbiturate anesthetics may be given in sufficient doses to produce deep surgical anesthesia in the presence of external stimulation such as surgical incision, these doses also may produce dangerous cardiovascular and respiratory depression {32}.

Because the rapid distribution of barbiturate anesthetics out of the brain can result in light anesthesia characterized by reflex hyperactivity of the airway to stimulation (e.g., intubation, instrumentation, secretions), an adequate depth of anesthesia should be induced in patients predisposed to bronchospasm or with upper airway obstruction, when coughing and hiccupping are undesirable, and to avoid laryngospasm that may occur from direct or indirect stimulation.

To minimize mucous secretions, anticholinergics, such as atropine or glycopyrrolate, may be administered as premedication. In addition, an opiate may be administered to enhance the otherwise poor analgesic effects of the barbiturate anesthetic {05} {33}. The peak effects of the premedication should be attained shortly before induction of anesthesia. Also, muscle relaxants may be required and should be administered separately {04}.

Tolerance has been reported following multiple use, as in burn patients. In pediatric patients this tolerance may continue for 1 year or longer following burn injury {29}.

Individuals tolerant to alcohol or barbiturates may require higher doses of barbiturate anesthetics.

Barbiturate anesthetics have little analgesic effect. Use of barbiturate anesthetics in the presence of pain may cause excitation {01}.

Treatment of adverse effects
Recommended treatment for adverse effects of barbiturate anesthetics includes:

   • For laryngospasm—Positive pressure oxygen 100% should be administered; then, if necessary, a skeletal muscle relaxant may be administered {37}; cricothyrotomy may be required in difficult cases {04}.
   • For extravasation—Procaine 1% may be administered locally to relieve pain and enhance vasodilation. Local application of heat also may help to increase local circulation and remove the infiltrate {04}.
   • For inadvertent {39} intra-arterial injection—There is no established treatment for intra-arterial injection. Injury (i.e., thrombosis and resulting gangrene) is more likely with injection of higher concentrations of barbiturate solutions {01}. Treatment can be attempted with one or more of the following strategies; however, the support in the literature for all of these strategies is weak {01}. The injected barbiturate anesthetic can be diluted by removing the tourniquet and any restrictive garment. The needle should be left in place, if possible. A dilute solution of 1% procaine, 10 mL, may be injected into the artery to inhibit smooth muscle spasm {40}. Sympathetic block of the brachial plexus or stellate ganglion can be performed to relieve pain and assist in opening collateral circulation. To prevent thrombus formation, heparinization may be instituted immediately (i.e., arterial injection of heparin at the site of the injury followed by systemic anticoagulation) {01}, unless otherwise contraindicated. Local infiltration of an alpha-adrenergic blocking agent into the vasospastic area may be considered {40}. Intra-arterial injection of a glucocorticoid at the site of injury, followed by administration of systemic corticosteroids, may be considered. Also, it has been reported that intra-arterial administration of urokinase may promote fibrinolysis even if administration is late in treatment {01}. Postinjury arterial injection of vasodilators and/or arterial infusion of parenteral fluids generally are not useful in reducing the area of necrosis {01}.
   • For shivering—Treatment includes warming the patient with blankets, maintaining room temperature at 22 °C (72 °F), and administering chlorpromazine or methylphenidate {04}.
   • For thrombophlebitis—Treatment is symptomatic and may require rest and application of heat {33}.

METHOHEXITAL

Summary of Differences


Pharmacology/pharmacokinetics:
Physicochemical characteristics—Oil:water partition coefficient is lower than that of thiopental.

Distribution—Does not concentrate in lipids to the same extent as thiopental; less likely than thiopental to accumulate with repeated or prolonged administration.

Biotransformation—More rapid than thiopental.

Half-life—Distribution and elimination half-lives are shorter than those of thiopental.

Duration of action—Shorter than thiopental.



Side/adverse effects:
Excitatory phenomena occur more frequently than with thiopental.

The duration of apnea may be longer with methohexital than with other barbiturate anesthetics {01}.



Additional Dosing Information
See also General Dosing Information .

Methohexital is about two to three times more potent than thiopental {01} {10}.

Preanesthetic medication may be advisable with methohexital. Any preanesthetic medication may be used; however, the combination of an opioid and a belladonna derivative is preferable to the phenothiazines, which have been reported to potentiate the hypotensive and CNS excitatory effects of methohexital {01}.

A 1% solution of methohexital is recommended for induction of anesthesia and for maintenance by intermittent injection {01} {33}. Higher concentrations greatly increase the incidence of muscular movements and irregularities in respiration and blood pressure {33}.


Parenteral Dosage Forms

METHOHEXITAL SODIUM FOR INJECTION USP

Usual adult dose
Anesthesia, general


Induction:
Dosage must be individualized by physician; however, as a general guideline—Intravenous, 1 to 1.5 mg per kg of body weight as required, administered as a 1% solution, at a rate of 1 mL per five seconds {01}.



Maintenance:
Dosage must be individualized by physician; however, as a general guideline—Intravenous (intermittent), 20 to 40 mg (2 to 4 mL of a 1% solution) as required, usually every four to seven minutes {01}.

Note: Some anesthesiologists prefer the continuous drip method of maintenance with a 0.2% solution, the rate of flow being individualized for each patient {01} {06}. The average requirement is 3 mL of a 0.2% solution per minute (1 drop per second) {01}.




Usual pediatric dose
Anesthesia, general

Induction
Dosage must be individualized by physician; however, as a general guideline—

Intramuscular, 6.6 to 10 mg per kg of body weight as required {01}.

Intravenous, 1 to 2 mg per kg of body weight as required. Although there are reports in the literature of intravenously administered methohexital being used in pediatric patients, methohexital has not been well-studied for intravenous administration in pediatric patients {01}. Methohexital is approved by the drug regulatory agency in the U.S. (i.e., the Food and Drug Administration [FDA]) for intramuscular and rectal administration in infants and children 1 month of age and older {01}.


Size(s) usually available:
U.S.—


500 mg (Rx) [Brevital (lyophilized) (anhydrous sodium carbonate 30 mg)]


2.5 grams (Rx) [Brevital (lyophilized) (anhydrous sodium carbonate 150 mg)]


5 grams (Rx) [Brevital (lyophilized) (anhydrous sodium carbonate 300 mg)]

Canada—


500 mg (Rx) [Brietal (lyophilized) (anhydrous sodium carbonate 30 mg)]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection may be used as diluents. Bacteriostatic diluents and lactated Ringer's injection should not be used as diluents because they tend to cause precipitation {01} {06}.

For direct intravenous injection, sterile water for injection should be used as the diluent for preparation of a 1% methohexital sodium injection.

To prepare a 1% methohexital injection, 50 mL diluent is added to a vial of 500 mg methohexital sodium for injection {01}. The 2.5-gram vial of methohexital sodium should be diluted with 15 mL diluent, then further diluted to a total volume of 250 mL {01}. The 5-gram vial of methohexital sodium should be diluted with 30 mL diluent, then further diluted to a total volume of 500 mL {01}.

To prepare a 5% solution of methohexital injection for intramuscular injection, the 500-mg vial should be diluted with 10 mL diluent for a resulting concentration of 50 mg per mL (mg/mL) {01}. The 2.5-gram vial of methohexital sodium should be diluted with 50 mL diluent for a resulting concentration of 50 mg/mL {01}.

For administration via intravenous infusion, a 0.2% injection is prepared by adding 500 mg of methohexital sodium to 250 mL of 5% dextrose injection or 0.9% sodium chloride injection; however, dextrose injections are sometimes sufficiently acid to cause precipitation. Sterile water for injection should not be used because of the resultant extreme hypotonicity, which will cause hemolysis {01} {06}.

Stability:
Methohexital is stable in sterile water for injection at room temperature (25 °C [77 °F] or lower) for at least 6 weeks; solutions prepared with 5% dextrose injection or 0.9% sodium chloride injection are not stable for more than 24 hours {01} {06}.

Only clear injections should be used; if an injection becomes cloudy or a precipitate forms, the medication should be discarded {01} {06}.

Incompatibilities:
Methohexital injections should not be mixed with acidic substances, such as atropine sulfate, metocurine iodide, or succinylcholine chloride, because precipitation will occur {06}.

For additional information on the chemical compatibility of methohexital sodium with medications having a low (acid) pH, see the manufacturer's package insert {06}.

Methohexital injections are incompatible with silicone and should not be allowed to come in contact with rubber stoppers or parts of disposable syringes that have been treated with silicone {01} {06}.

Methohexital sodium is incompatible with bacteriostatic diluents and with lactated Ringer's injection; precipitation will occur {06}.

Note: Controlled substance in the U.S. and Canada.




Rectal Dosage Forms

METHOHEXITAL SODIUM FOR RECTAL SOLUTION

Usual pediatric dose

Anesthesia, local, adjunct
Rectal, 25 mg per kg of body weight as a 1% solution {01}.

Note: Some USP experts recommend that 20 to 30 mg per kg of body weight of 10% methohexital sodium solution be administered rectally to pediatric patients {76}.
For inactive or debilitated patients—Lower dosage is advisable.



Size(s) usually available:
U.S.—
Dosage form not commercially available. Compounding required for prescriptions.

Canada—
Dosage form not commercially available. Compounding required for prescriptions.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container. Protect from freezing.

Preparation of dosage form:
To prepare a 1% methohexital rectal solution, dissolve an appropriate amount of methohexital sodium for injection in sterile water.

Stability:
If the solution becomes cloudy or a precipitate forms, the solution should be discarded.

Incompatibilities:
Methohexital should not be mixed with acidic substances, such as atropine sulfate, metocurine iodide, or succinylcholine chloride, because precipitation will occur {06}.

For additional information on the chemical compatibility of methohexital sodium with medications having a low (acid) pH, see the manufacturer's package insert for methohexital sodium for injection {06}.

Methohexital solutions are incompatible with silicone and should not be allowed to come in contact with rubber stoppers or parts of disposable syringes that have been treated with silicone {01} {06}.

Methohexital sodium is incompatible with bacteriostatic diluents and with lactated Ringer's injection; precipitation will occur {06}.


THIOPENTAL

Summary of Differences


Indications:
Parenteral thiopental also indicated in the treatment of cerebral hypertension, for narcoanalysis in the treatment of psychiatric disorders, in the treatment of cerebral ischemia and hypoxia, and to control convulsive states during or following inhalation anesthesia, local anesthesia, or other causes {05}.



Pharmacology/pharmacokinetics:


Physicochemical characteristics—
Oil:water partition coefficient is greater than that of methohexital.



Distribution—
Concentrates in fatty tissues to a greater extent than methohexital; risk of accumulation with repeated or prolonged administration is higher than with methohexital.

Appears in breast milk following administration of large doses {05}.



Biotransformation—
Less rapid than methohexital.



Half-life—
Distribution and elimination half-lives longer than those of methohexital {05}.



Duration of action—
Greater than that of methohexital {01} {05}.




Laboratory value alterations:
May decrease thyroidal uptake of sodium iodide I 123, sodium iodide I 131, and sodium pertechnetate Tc 99m



Patient monitoring:
Monitoring of plasma concentrations is recommended if thiopental is administered by intravenous infusion over a prolonged period of time.



Additional Dosing Information
See also General Dosing Information .
For parenteral dosage form only

   • A test dose of 25 to 75 mg (1 to 3 mL of a 2.5% solution) may be administered to determine tolerance or unusual sensitivity to thiopental; patient reaction should be observed for at least 60 seconds {04} {05}. In pediatric patients, a test dose of 0.5 mg per kg of body weight may be used {74}.
   • A 2 or 2.5% concentration of thiopental solution is used for intermittent intravenous administration {04} {05}.
   • A 3.4% concentration of thiopental in sterile water for injection is isotonic; concentrations less than 2% in sterile water for injection should not be used because they cause hemolysis {04}.
For rectal suspension dosage form only

   • To assure easy extrusion of thiopental rectal suspension, instructions should be followed for filling the applicator and extruding a small amount before setting the stop device at the desired dose for rectal administration. Care should be taken not to use excessive pressure on the syringe plunger since this can cause the stop device to break or slip, which may result in an overdose {37}.


Parenteral Dosage Forms

THIOPENTAL SODIUM FOR INJECTION USP

Usual adult dose
Anesthesia, general


Induction:
Dosage must be individualized by physician; however, as a general guideline—Intravenous, 50 to 75 mg (2 to 3 mL of a 2.5% solution) as required; or 3 to 4 mg per kg of body weight as a single dose {07}.



Maintenance:
Dosage must be individualized by physician; however, as a general guideline—Intravenous (intermittent), 50 to 100 mg (2 to 4 mL of a 2.5% solution) as required {04} {07}.

Note: When thiopental is used as the sole anesthetic agent, the desired level of anesthesia can be maintained by injection of small repeated doses as needed. Also, 0.2 to 0.4% solutions have been administered by continuous intravenous drip for maintenance {05} {07}.



Hypertension, cerebral1
Intravenous (intermittent), 1.5 to 3.5 mg per kg of body weight, repeated as required to reduce elevations of intracranial pressure {04}.

Note: Adequate ventilation must be provided {04}.


Convulsions
Intravenous, 75 to 125 mg (3 to 5 mL of a 2.5% solution), administered as soon as possible after the convulsion begins {04} {05}.

Narcoanalysis1
Intravenous, as a 2.5% solution, administered at a rate of 100 mg per minute with the patient counting backwards from one hundred. Injection should be discontinued after counting becomes confused but before actual sleep is produced {04} {05}.

Note: As alternative dosing, thiopental may be administered by rapid intravenous drip using a 0.2% concentration in 5% dextrose injection; however, the rate of administration should not exceed 50 mL per minute {04} {05}.



Usual pediatric dose
[Anesthesia, general]1


Children up to 15 years of age:
Induction—Dosage must be individualized by physician; however, as a general guideline: Intravenous, 4 to 6 mg per kg of body weight {29}.

Maintenance—Dosage must be individualized by physician; however, as a general guideline: Intravenous (intermittent), about 1 mg per kg of body weight as required.

Note: Thiopental is not labeled by drug regulatory agencies in the U.S. (i.e., the Food and Drug Administration [FDA]) or Canada (i.e., the Health Protection Branch [HPB]) for use in pediatric patients.




Size(s) usually available:
U.S.—


250 mg (Rx) [Pentothal][Generic]


400 mg (Rx) [Pentothal][Generic]


500 mg (Rx) [Pentothal][Generic]


1 gram (Rx) [Pentothal]


2.5 grams (Rx) [Pentothal][Generic]


5 grams (Rx) [Pentothal][Generic]


10 grams (Rx)[Generic]

Canada—


1 gram (Rx) [Pentothal{07}]


2.5 grams (Rx) [Pentothal{07}]


5 grams (Rx) [Pentothal{07}]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection should be used as the diluent {04} {07}. Because of the acidity of 5% dextrose injection, thiopental sodium diluted with 5% dextrose injection is not as stable as when thiopental sodium is prepared with sterile water for injection or 0.9% sodium chloride injection.

Sterile water for injection should not be used to prepare a 0.2 or 0.4% thiopental sodium injection for intravenous infusion because of the resultant extreme hypotonicity, which will cause hemolysis {05}.

To prepare a solution containing 0.2% (2 mg per mL) of thiopental sodium, 1 gram of thiopental sodium should be diluted with 500 mL diluent {05}. To prepare a solution containing 0.4% (4 mg per mL) of thiopental sodium, 1 gram of thiopental sodium should be diluted with 250 mL diluent, or 2 grams of thiopental sodium should be diluted with 500 mL diluent {05}. To prepare a solution containing 2.5% (25 mg per mL) of thiopental sodium, 1 gram of thiopental sodium should be diluted with 40 mL diluent, or 5 grams of thiopental sodium should be diluted with 200 mL diluent {05}.

Since Thiopental for Injection USP contains no added bacteriostatic agent, aseptic technique should be used in the preparation and handling of this product to prevent the introduction of microbial contaminants {04} {05}.

Stability:
Injections should be freshly prepared and used within 24 hours after reconstitution; discard unused portions after 24 hours {04} {05} {07}.



Any factor or condition that tends to lower the pH of thiopental injections, such as diluents that are too acid or the absorption of carbon dioxide, which combines with water to form carbonic acid, will increase the possibility of precipitation of thiopental acid.

Sterilization by heating causes precipitation {04}.

Injections containing a precipitate should not be administered {04}.

Incompatibilities:
Thiopental injections should not be mixed with succinylcholine, tubocurarine, or other medications that have an acid pH, because precipitation will occur {04}.

Note: Controlled substance in the U.S. and Canada.




Rectal Dosage Forms

THIOPENTAL SODIUM FOR RECTAL SOLUTION

Usual adult and adolescent dose
Anesthesia, general, adjunct or
Anesthesia, local, adjunct
Rectal, 30 mg per kg of body weight {37}.

Anesthesia, general
Normally active patients: Rectal, up to 44 mg per kg of body weight {37}.


Note: For inactive or debilitated patients—Lower dosage is advisable {37}.


Usual adult prescribing limits
Adults weighing 90 kg or more
A total of 3 to 4 grams {37}.


Usual pediatric dose
See Usual adult and adolescent dose .

Note: Some USP experts recommend that 20 to 30 mg per kg of body weight of 10% thiopental sodium solution be administered rectally to pediatric patients {76}.


Usual pediatric prescribing limits
1 to 1.5 grams {37}.

Strength(s) usually available
U.S.—
Dosage form not commercially available. Compounding required for prescriptions.

Canada—
Dosage form not commercially available. Compounding required for prescriptions.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container. Protect from freezing.

Preparation of dosage form:
To prepare a thiopental rectal solution, dissolve an appropriate amount of thiopental sodium for injection in sterile water.

Stability:
Solutions should be freshly prepared and used within 24 hours after reconstitution; unused portions should be discarded after 24 hours {04} {07}.

Solutions are most stable when prepared with water or isotonic saline and kept refrigerated {04}.

Any factor or condition that tends to lower the pH of thiopental solutions, such as diluents that are too acid or the absorption of carbon dioxide, which combines with water to form carbonic acid, will increase the possibility of precipitation of thiopental acid.

Sterilization by heating causes precipitation {04}.

Solutions containing a precipitate should not be administered {04}.

Incompatibilities:
Thiopental solutions should not be mixed with succinylcholine, tubocurarine, or other medications that have an acid pH, because precipitation will occur {04}.


THIOPENTAL SODIUM RECTAL SUSPENSION

Usual adult and adolescent dose
Anesthesia, general, adjunct or
Anesthesia, local, adjunct
Rectal, 30 mg per kg of body weight {37}.

Anesthesia, general
Normally active patients: Rectal, up to 44 mg per kg of body weight {37}.


Note: For inactive or debilitated patients—Lower dosage is advisable {37}.


Usual adult prescribing limits
Adults weighing 90 kg or more
A total of 3 to 4 grams {37}.


Usual pediatric dose
See Usual adult and adolescent dose .

Note: Some USP experts recommend that 20 to 30 mg per kg of body weight of 10% thiopental sodium suspension be administered rectally to pediatric patients {76}.
For inactive or debilitated patients—Lower dosage is advisable {37}.


Usual pediatric prescribing limits
A total of 1 to 1.5 grams {37}.

Strength(s) usually available
U.S.—


400 mg per gram (Rx) [Pentothal (mineral oil) ( dimethyldioctadecylammonium bentonite) ( anhydrous sodium carbonate 24 mg per gram)]{37}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Contains no bacteriostatic or antimicrobial agent. Intended only for one-time use {37}.

Auxiliary labeling:
   • Shake well.

Note: Controlled substance in the U.S.




Revised: 06/01/99



References
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  1. American Society of Anesthesiologists. Position on Monitored Anesthesia (approved October 1986); Guidelines for Patient Care in Anesthesiology (approved October 1967, amended October 1985, October 1996); Standards for Basic Intra-Operative Monitoring (approved October 1986, amended October 1990, October 1992); Standards for Postanesthesia Care (approved October 1988, amended October 1990, October 1994). Park Ridge, IL: American Society of Anesthesiologists.
  1. Manani G, Valenti S, Vincenti E, et al. Interaction between thiopentone and subhypnotic doses of ketamine. Eur J Anaesthesiol 1992; 9: 43-7.
  1. Dundee JW, Halliday NJ, McMurray TJ, et al. Pretreatment with opioids: the effect on thiopentone induction requirements and on the onset of action of midazolam. Anaesthesia 1986; 41: 159-61.
  1. Moore J, Dundee JW. Promethazine: its influence on the course of thiopentone and methohexital anaesthesia. Anaesthesia 1961; 16: 61-73.
  1. Panel comment, 1994.
  1. Sa Rego MM, Inagaki Y, White PF. The cost-effectiveness of methohexital versus propofol for sedation during monitored anesthesia care. Anesth Analg 1999; 88: 723-8.
  1. Panel comment, 4/99.
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