AHFS Class:

• Barbiturates 28:04.04

Generic Name(s):

• Methohexital Sodium

Methohexital sodium is a barbiturate anesthetic.

Methohexital sodium is used IV in adults for induction of general anesthesia (prior to administration of other anesthetic agents).100 The drug also is used for inducing anesthesia and supplementing subpotent anesthetic agents (e.g., nitrous oxide and oxygen) either alone for short-term procedures or with other parenteral drugs (e.g., opiate analgesics) for longer procedures.100 In addition, methohexital is used for IV anesthesia during short surgical, diagnostic, or therapeutic procedures, associated with minimum painful stimuli, and for induction of a hypnotic state. Preanesthetic agents usually are recommended when methohexital sodium is used;100 the drug is not inhibited by the usual preanesthetic medications.

In pediatric patients older than 1 month of age, methohexital sodium may be used IM or rectally for induction of anesthesia, prior to administration of other anesthetic agents, for supplementing subpotent inhalation anesthetic agents during short surgical procedures, and for anesthesia during short surgical, diagnostic, or therapeutic procedures, associated with minimum painful stimuli.100

Reconstitution and Administration

Methohexital sodium is administered by direct IV injection or IV infusion in adults and by IM injection or rectally in pediatric patients older than 1 month of age.100 Methohexital sodium solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.100

IV Administration

Methohexital sodium is administered by IV injection or continuous IV infusion in a concentration not exceeding 1%. Higher concentrations markedly increase the incidences of respiratory and blood pressure irregularities and muscular movements. The minimum infusion rate of an IV anesthetic is the dose of the drug necessary to prevent movement in response to a painful stimulus.102 However, such an end point is not considered appropriate for drugs that have no analgesic effects (e.g., methohexital sodium) and therefore, to evaluate depth of anesthesia some experts use clinical signs (e.g., hemodynamic changes, autonomic signs [lacrimation or diaphoresis], movement).102

Methohexital sodium preferably is reconstituted with sterile water for injection; 5% dextrose injection or 0.9% sodium chloride injection also may be used. Diluents containing bacteriostatic agents should not be used.

For intermittent IV administration, the manufacturer suggests that a 1% (10 mg/mL) solution of the drug be prepared by reconstituting a vial labeled as containing 500 mg of methohexital sodium with 50 mL of an appropriate diluent.100 Alternatively, a 1% (10 mg/mL) solution of the drug may be prepared by reconstituting a vial labeled as containing 2.5 g of methohexital sodium with 15 mL of an appropriate diluent, respectively, and then further diluting to a total volume of 250 mL with about 235 mL of the diluent, respectively.100

For continuous IV infusion, a 0.2% solution of methohexital sodium should be used.100 The manufacturer suggests that a 0.2% (2 mg/mL) solution of the drug be prepared by reconstituting a vial labeled as containing 500 mg of methohexital sodium with 250 mL of 5% dextrose injection or 0.9% sodium chloride injection.100 Sterile water for injection should not be used for preparing 0.2% methohexital sodium solutions in order to avoid extreme hypotonicity.100

Care should be taken to avoid extravasation or intra-arterial administration.100 Methohexital sodium injection should be stopped immediately and the situation assessed whenever extravasation or inadvertent intra-arterial injection is suspected. Extravasation can result in local irritation that can progress to ulceration and necrosis. Inadvertent intra-arterial injection of the drug can stimulate platelet aggregation and thrombosis, starting in arterioles distal to the site of injection; the resulting necrosis can progress to gangrene, which may require amputation. In a conscious patient, the first manifestation may be complaint of fiery burning that roughly follows the distribution path of the injected artery, in which case the injection should be stopped immediately and the situation assessed. Transient blanching may or may not be noticeable early; blotchy cyanosis and dark discoloration may be the first manifestation in an unconscious patient. The most appropriate therapy for such inadvertent injection has not been fully established, and efforts aimed at prevention are important; the manufacturer's labeling should be consulted for suggested therapies that may be beneficial. Because the extent of injury is dose-related, concentrations of the drug exceeding 1% should be avoided. Prior to IV infusion, placement of the IV catheter should be checked to ensure that it is in a vein. Injection through a running IV infusion may enhance the possibility of detecting inadvertent intra-arterial placement, but the characteristic bright-red color of arterial blood can be altered by contact with drugs. In addition, the possibility of aberrant arteries should be considered.

IM Administration

Methohexital sodium may be administered IM as a 5% solution in pediatric patients older than 1 month of age.100 The manufacturer suggests that a 5% (50 mg/mL) solution of the drug be prepared by reconstituting a vial labeled as containing 0.5 or 2.5 g of methohexital sodium preferably with 10 or 50 mL of sterile water for injection, respectively; 0.9% sodium chloride or 5% dextrose injection also may be used.100

Rectal Administration

Methohexital sodium may be administered rectally as a 1% solution in pediatric patients older than 1 month of age.100 The manufacturer suggests that a 1% (10 mg/mL) solution of the drug may be prepared by reconstituting a vial labeled as containing 0.5 or 2.5 g of methohexital sodium preferably with 50 or 250 mL sterile water for injection, respectively; 0.9% sodium chloride or 5% dextrose injection also may be used.100

Dosage

Dosage of methohexital sodium is highly individualized, and the drug should be administered only by those completely familiar with its quantitative differences from other barbiturate anesthetics. Dosage of the drug is expressed in terms of the sodium salt.

In addition, dosage of induction anesthetics should be adjusted according to response, age, weight, gender, physical and clinical status, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s).102 Dosages of the drug also should be titrated to clinical effect.102

Induction and Maintenance of Anesthesia

IV Administration

For induction of anesthesia in adults, a 1% (10 mg/mL) solution is administered IV at a rate of about 1 mL/5 seconds. Inhalation anesthetic agents and/or skeletal muscle relaxants may be administered concomitantly. The adult dose required for induction may vary from 50-120 mg or more, but averages about 70 mg. The usual adult induction dose of methohexital sodium ranges from 1-1.5 mg/kg.100 The induction dose usually provides anesthesia for 5-7 minutes.

Maintenance of anesthesia may be accomplished by intermittent injections of a 1% solution or, more easily, by continuous IV infusion of a 0.2% solution. Intermittent injections of about 20-40 mg (2-4 mL of a 1% solution) may be administered as required, usually every 4-7 minutes. For continuous IV infusion, the average rate of administration is about 3 mL of a 0.2% solution per minute (1 drop/second). For longer surgical procedures, gradual reduction in the rate of administration is recommended.100 Other parenteral drugs (e.g., opiate analgesics) usually are administered with methohexital sodium during prolonged anesthesia.100 It should be considered that prolonged administration of methohexital may produce cumulative effects.100 (See Cautions: Precautions and Contraindications.)

IM Administration

For induction of anesthesia in pediatric patients older than 1 month of age, IM injections of about 6.6-10 mg/kg are administered as a 5% (50 mg/mL) solution.100

Rectal Administration

For induction of anesthesia in pediatric patients older than 1 month of age, the usual rectal dose of methohexital sodium is 25 mg/kg administered as a 1% (10 mg/mL) solution.100

Adverse Effects

Adverse effects of methohexital sodium are extensions of the drug's pharmacologic effects.100

Cardiopulmonary Effects

Similar to other barbiturates, administration of methohexital sodium may produce hiccups, coughing, and laryngospasm, which may impair pulmonary ventilation. Laryngospasm may be caused by secretions and accentuated reflexes following induction of anesthesia or may result from painful stimuli during light anesthesia.100 Respiratory depression, apnea, dyspnea, cardiorespiratory arrest (sometimes in association with seizures), or hypotension may occur. Apnea and/or hypoventilation also may occur during induction of anesthesia and may result in impaired pulmonary ventilation.100 Duration of apnea may be longer than that associated with other barbiturate anesthetics.100 In addition, circulatory depression, tachycardia, peripheral vasculatory collapse, and bronchospasm may occur.

Local, Sensitivity, and Dermatologic Reactions

Extravascular injection of the drug may cause local irritation manifested as pain, swelling, ulceration, and necrosis. Intra-arterial administration of methohexital sodium is dangerous and may produce gangrene of an extremity. (See Dosage and Administration: Reconstitution and Administration.) Thrombophlebitis, pain at the injection site, and injury to nerves adjacent to the injection site have occurred in patients receiving methohexital sodium.

Acute allergic reactions including erythema, pruritus, urticaria, rhinitis, hypotension, dyspnea, anxiety, restlessness, abdominal pain, and peripheral vascular collapse also have been reported in patients receiving methohexital sodium.

Nervous System Effects

Skeletal muscle hyperactivity (twitching), postanesthetic shivering, seizures (particularly in those with a seizure history; especially those with partial seizure disorders), restlessness, anxiety (especially in the presence of postoperative pain), emergence delirium, and headache have been reported in patients receiving methohexital sodium.

GI Effects

Salivation, nausea, vomiting, and abdominal pain have been reported with administration of methohexital sodium. Incidence of postoperative nausea or vomiting appears to be low in fasting patients.100

Hepatic Effects

Abnormalities in liver function test results have been reported with administration of methohexital sodium.100

Precautions and Contraindications

The usual precautions associated with barbiturate anesthetics should be observed with methohexital sodium. Methohexital should be administered only in a hospital or an ambulatory-care setting, in which continuous monitoring of respiratory (i.e., pulse oximetry) and cardiac function is possible during and after administration of the drug, since cardiorespiratory arrest may occur.100 In deeply sedated patients, the drug should be administered by individuals qualified in the use of IV anesthetics who otherwise are not involved in the conduct of the procedures; appropriate resuscitative drugs and equipment for prevention and treatment of anesthetic emergencies must be readily available.100 Facilities for intubation, assisted respiration, and administration of oxygen must be available whenever methohexital is used. Repeated or continuous infusion of methohexital sodium may produce cumulative effects resulting in prolonged somnolence and respiratory and circulatory depression.

Patients should be warned that methohexital sodium may cause drowsiness and may impair their ability to perform activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle) for about 8-12 hours after undergoing anesthesia.100 In addition, the manufacturer states that outpatients who have received methohexital sodium should be discharged in the company of another individual.100

Methohexital sodium should be used with caution in debilitated patients or in those with respiratory, circulatory, renal, hepatic, or endocrine dysfunction and in patients with asthma, obstructive pulmonary disease, severe hypertension or hypotension, myocardial disease, congestive heart failure, severe anemia, or extreme obesity. Because demethylation and oxidation of methohexital involve the liver and because barbiturates may enhance preexisting circulatory depression, selection of another induction agent should be considered in patients with severe hepatic dysfunction, severe cardiovascular instability, or a shock-like condition. The drug should be used with extreme caution during status asthmaticus. Methohexital sodium is contraindicated when general anesthesia is contraindicated and in patients with latent or manifest porphyria or with known hypersensitivity to barbiturates.

Pediatric Precautions

Safety and efficacy of IM or rectal methohexital sodium in pediatric patients 1 month of age or younger have not been established.100 Studies to determine safety and efficacy of IV methohexital sodium in pediatric patients have been inadequate because of limitations (e.g., study design, biopharmaceutical issues, wide range of effects associated with similar IV doses of the drug).100 Therefore, further studies and experience are needed to elucidate fully the efficacy and safety of IV methohexital sodium in pediatric patients.100

FDA warns that repeated or prolonged use of general anesthetics and sedation drugs, including methohexital sodium, in children younger than 3 years of age or during the third trimester of pregnancy may affect brain development.750,753 Animal studies in multiple species, including nonhuman primates, have demonstrated that use for longer than 3 hours of anesthetic and sedation drugs that block N -methyl-d-aspartic acid (NMDA) receptors and/or potentiate γ-aminobutyric acid (GABA) activity leads to widespread neuronal and oligodendrocyte cell loss and alterations in synaptic morphology and neurogenesis in the brain, resulting in long-term deficits in cognition and behavior.750,751,752,753 Across animal species, vulnerability to these neurodevelopmental changes occurs during the period of rapid brain growth or synaptogenesis; this period is thought to correlate with the third trimester of pregnancy through the first year of life in humans, but may extend to approximately 3 years of age.750 The clinical relevance of these animal findings to humans is not known.750

While some published evidence suggests that similar deficits in cognition and behavior may occur in children following repeated or prolonged exposure to anesthesia early in life, other studies have found no association between pediatric anesthesia exposure and long-term adverse neurodevelopmental outcomes.750,752 Most studies to date have had substantial limitations, and it is not clear whether the adverse neurodevelopmental outcomes observed in children were related to the drug or to other factors (e.g., surgery, underlying illness).750 There is some clinical evidence that a single, relatively brief exposure to general anesthesia in generally healthy children is unlikely to cause clinically detectable deficits in global cognitive function or serious behavioral disorders;750,751,752 however, further research is needed to fully characterize the effects of exposure to general anesthetics in early life, particularly for prolonged or repeated exposures and in more vulnerable populations (e.g., less healthy children).750 For further information, see Cautions: Pediatric Precautions, in the Barbiturates General Statement 28:24.04.

Anesthetic and sedation drugs are an essential component of care for children and pregnant women who require surgery or other procedures that cannot be delayed;750,753 no specific general anesthetic or sedation drug has been shown to be less likely to cause neurocognitive deficits than any other such drug.750 Pending further accumulation of data in humans from well-designed studies, decisions regarding the timing of elective procedures requiring anesthesia should take into consideration both the benefits of the procedure and the potential risks.750 When procedures requiring the use of general anesthetics or sedation drugs are considered for young children or pregnant women, clinicians should discuss with the patient, parent, or caregiver the benefits, risks (including potential risk of adverse neurodevelopmental effects), and appropriate timing and duration of the procedure.750,753 FDA states that procedures that are considered medically necessary should not be delayed or avoided.750,753

Geriatric Precautions

While reported clinical experience to date has not revealed age-related differences in response to methohexital sodium, clinical studies evaluating methohexital sodium have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults.

Geriatric adults commonly have conditions in which methohexital sodium should be used cautiously such as obstructive pulmonary disease, severe hypertension or hypotension, preexisting circulatory depression, myocardial disease, congestive heart failure, or severe anemia. Caution should be exercised in debilitated patients and in those with impaired respiratory, circulatory, renal hepatic, or endocrine function. The possibility that methohexital sodium may influence the metabolism of other drugs commonly used in the elderly (e.g., anticoagulants, corticosteroids) should be considered.

Dosage of methohexital sodium for geriatric patients should be selected carefully, usually starting at the low end of the dosing range, because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits and rats using methohexital sodium doses 4 and 7 times the usual human dose, respectively, have not revealed evidence of harm to the fetus. The manufacturer states that although the drug has been used in women undergoing delivery by cesarean section, it should be considered that methohexital readily and rapidly crosses the placenta.100 There are no adequate and controlled studies to date using methohexital sodium in pregnant women, and the drug should be used during pregnancy only when clearly needed.100

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including methohexital sodium, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus.750,753 The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.750 (See Cautions: Pediatric Precautions.)

Fertility

Reproduction studies in animals using methohexital sodium have not revealed evidence of impaired fertility.100

Lactation

Because barbiturates are distributed into milk, the drug should be used with caution in nursing women.100

The CNS depressant effect of methohexital sodium may be additive with that of other CNS depressants, including alcohol and propylene glycol. Prior chronic administration (e.g., for seizure disorder) of barbiturates or phenytoin appears to reduce efficacy of methohexital sodium.100

Concomitant use of barbiturates may affect absorption and elimination of several drugs (e.g., phenytoin, halothane, anticoagulants, corticosteroids, alcohol, solutions containing propylene glycol).100

Pharmacology

Pharmacologic effects of methohexital sodium are similar to those of thiopental sodium.104 Compared with thiamylal and thiopental, methohexital is at least twice as potent on a weight basis and its duration of action is only about one-half as long.

CNS Effects

Following IV injection, methohexital sodium has a rapid onset of action and will produce a loss of consciousness within 1 arm-brain circulation time (within 30 seconds).100,102 Induction with methohexital results in dose-related hypnotic effects (progressing from light sleep to unconsciousness) and anterograde amnesia, but not analgesia.100,102 The exact mechanism(s) by which barbiturates (e.g., methohexital sodium, thiopental sodium) exert their effect on the CNS, has not been fully elucidated.103,104,105,106 However, it is believed that such effects are related, at least partially, to the drugs' ability to enhance the activity of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS,104,105,106,107,108 by altering inhibitory synaptic transmissions that are mediated by GABA_A receptors.105,106,108

Other Effects

Methohexital does not produce skeletal muscle relaxation and must be supplemented by inhalation anesthetic agents or skeletal muscle relaxants when muscle relaxation is required. Barbiturates are associated with little, if any, analgesic effects and their use in the presence of pain may result in excitation.100

For further information on the CNS and other pharmacologic effects of barbiturates, see Pharmacology in the Barbiturates General Statement 28:24.04.

Pharmacokinetics

The pharmacokinetics of methohexital after IV administration are best described by a 2-compartment model.109 Pharmacokinetics of methohexital are similar to those of thiopental110 and are characterized by an initial rapid distribution of the drug from blood into tissues (similar to thiopental), but with an elimination phase that is more rapid than that of thiopental.109

Absorption

Following IV administration of usual induction doses of methohexital sodium in adults, the onset of action of methohexital is about 30 seconds.100 Following IM or rectal administration of methohexital sodium in pediatric patients, onset of action (sleep) occurs in about 2-10 or 5-15 minutes, respectively.100 The duration of action of single doses of methohexital sodium is determined by the redistribution of the drug from CNS.100 Duration of action of methohexital is about one-half of that of thiopental.100 The absolute bioavailability of rectally administered methohexital is about 17%.100

Methohexital does not appear to concentrate in fat depots to as great an extent as do other barbiturate anesthetics (e.g., thiopental). Thus, cumulative effects are less and recovery is more rapid than those following use of thiobarbiturates. In animals, methohexital cannot be detected in the blood 24 hours after administration.

Limited data indicate that plasma methohexital concentrations necessary to provide hypnosis in 50% of patients (EC₅₀) are estimated to be 3-5 mcg/mL.110 Some clinicians suggest that target plasma methohexital concentrations to achieve anesthesia reportedly range from 5-15 mcg/mL.102,110 Following IM administration of a 10-mg/kg dose (as a 5% solution) in pediatric patients, plasma concentrations of 3 mcg/mL were achieved in 15 minutes.100 The manufacturer states that following rectal administration of the drug, plasma methohexital concentrations appear to be dose-dependent and tend to increase when using a more diluted solution of a certain dose.100 Following rectal administration, of a 25-mg/kg dose of methohexital sodium (as a 1% solution), plasma concentrations of 6.9-7.9 mcg/mL were achieved in 15 minutes.100

Distribution

Following absorption or IV injection, barbiturates (e.g., methohexital) are rapidly distributed to all tissues and fluids with high concentrations in brain and liver. Plasma concentrations fall rapidly as methohexital (a highly lipid-soluble drug) is distributed into total body water and tissue binding sites including fat and the high concentrations of the drugs in the brain decline. Termination of the anesthetic effects of highly lipid soluble barbiturates apparently depends more upon redistribution than metabolism.

Methohexital is less ionized and less lipid soluble than thiopental; however, plasma protein binding is similar for both drugs.109 Following IV administration, volume of distribution of methohexital is about 1.13 L/kg109 while steady-state volume of distribution reportedly is 1.7 L/kg.110

Methohexital readily and rapidly crosses the placenta.100 Barbiturates are distributed into milk in concentrations much lower than those in plasma.

Elimination

The elimination half-life of methohexital is about 97 minutes109

Methohexital is metabolized in the liver;100 the drug undergoes demethylation and oxidation.100 The manufacturer states that the most important route of biotransformation involves side-chain oxidation which is associated with termination of biologic activity.100 Methohexital sodium is excreted mainly by the kidneys via glomerular filtration.100

Chemistry and Stability

Chemistry

Methohexital sodium is a barbiturate anesthetic. The drug differs from other barbiturate anesthetics (e.g., thiobarbiturates) in that it contains no sulfur atom at the 2-position of barbituric acid.100 Methohexital sodium occurs as a white, crystalline powder freely soluble in water. Methohexital sodium for injection is a freeze-dried, sterile, nonpyrogenic mixture of the drug with anhydrous sodium carbonate added as a buffer.100

Stability

Methohexital sodium powder for injection should be stored at room temperatures less than 25°C.

Following reconstitution, preferably with sterile water for injection (although 5% dextrose injection or 0.9% sodium chloride also may be used), solutions of methohexital sodium are chemically stable at room temperature for 24 hours.100 The reconstituted solutions must be freshly prepared immediately before administration and used promptly.100

Sterile water for injection should not be used for preparing 0.2% methohexital sodium solutions, because administration of the resulting hypotonic solutions will cause hemolysis.100 Solutions containing bacteriostatic agents or lactated Ringer's injection should not be used to reconstitute or dilute methohexital sodium injections.100

When the 2.5-g preparation of methohexital sodium is initially reconstituted, the solution is yellow; however, when it is further diluted to prepare a 1% solution, the final solution must be clear and colorless or it should not be used. The pH of a 1% solution of methohexital sodium in sterile water for injection is approximately 10-11, while the pH of a 0.2% solution of the drug in 5% dextrose injection is approximately 9.5-10.5.

Similar to salts of other barbituric acid derivatives, solutions of methohexital sodium are alkaline and are incompatible with acidic solutions and those that contain phenol as a preservative. The manufacturer states that methohexital sodium should not be mixed with acidic solutions such as atropine sulfate, metocurine iodide (no longer commercially available in the US), or succinylcholine chloride. Any factor or condition that tends to lower the pH of methohexital sodium solution will increase the likelihood of precipitation of free barbituric acid, since the solubility of soluble sodium salts of barbiturates (e.g., methohexital sodium) is only maintained at relatively high (alkaline) pH.100 Methohexital sodium has been reported to be physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature).101 Specialized references and the manufacturer's labeling should be consulted for specific compatibility and stability information.

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of methohexital, see the Barbiturates General Statement 28:24.04.

Only references cited for selected revisions after 1984 are available electronically.

100. Jones-Pharma. Brevital sodium (methohexital sodium) for injection prescribing information (dated 2001 Mar 28). In: Physicians' desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:1815-17.

101. Newton DW. Introduction: physiochemical determinants of incompatibility and instability drugs for injection and infusion. In: Trissel LA. Handbook on injectable drugs. 3rd ed. Bethesda, MD: American Society of Hospital Pharmacists, Inc; 1983:xi-xxi.

102. Fragen RJ. Clinical pharmacology and applications of intravenous anesthetic induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:319-36. Witzum JL.

103. Abbott. Pentothal^® thiopental sodium for injection prescribing information. North Chicago, IL; 1993 Nov.

104. Carmichael FJ, Haas DA. General Anesthetics. In: Kalant H and Roschlau WHE, eds. Principles of Medical Pharmacology. 6th edition. New York: Oxford University Press; 1998:278-92.

105. Evers AS, Crowder CM. General Anesthetics. In: Hardman JG, Gilman AG, Limbird LE, eds Goodman and Gilman's The pharmacological basis of therapeutics. 10th ed. McGraw-Hill; 2001: 337-44.

106. Donnelly AJ, Shafer AL. Perioperative care. In: Young LL, Koda-Kimble MA, eds. Applied Therapeutics: The clinical use of drugs. 6th ed. Vancouver WA: Applied Therapeutics, Inc.; 1995:8-1-8-24.

107. Tanelian DL, Kosek P, Mody I et al. The role of the GABAA receptor/chloride channel complex in anesthesia. Anesthesiology . 1993; 78:757-76. [PubMed 8385426]

108. Hales TG, Olsen RW. Basic pharmacology of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED, eds. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:295-306.

109. Duvaldestin P. Pharmacokinetics in intravenous anesthetic practice. Clin Pharmacokinet . 1981; 6:61-82. [PubMed 6113908]

110. Henthorn TK. Pharmacokinetics of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:307-18

750. US Food and Drug Administration. Drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Silver Spring, MD; 2016 Dec 14. From FDA website. [Web]

751. Davidson AJ, Disma N, de Graaff JC et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet . 2016; 387:239-50. [PubMed 26507180]

752. Sun LS, Li G, Miller TL et al. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA . 2016; 315:2312-20. [PubMedCentral][PubMed 27272582]

753. US Food and Drug Administration. Drug safety communication: FDA approves labeling changes for use of general anesthetic and sedation drugs in young children. Silver Spring, MD; 2017 Apr 27. From FDA website. [Web]