Anesthetics, Inhalation (Systemic)

This monograph includes information on the following:

1) Enflurane
2) Halothane
3) Isoflurane
4) Methoxyflurane
5) Nitrous Oxide

Note: See also the individual Desflurane (Inhalation-Systemic), and Sevoflurane (Inhalation-Systemic) monographs.


VA CLASSIFICATION
Primary: CN201

Commonly used brand name(s): Ethrane1; Fluothane2; Forane3; Penthrane4.

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—Enflurane, halothane, isoflurane, methoxyflurane, and nitrous oxide are indicated for the induction and maintenance of general anesthesia {01} {02} {03} {04} {10}. However, inhalation anesthetic agents are rarely used alone; other medications are frequently administered to induce or supplement anesthesia.
—Because of its weak anesthetic potency and muscle relaxant properties, nitrous oxide must be supplemented with another anesthetic or anesthesia adjunct (such as a barbiturate, benzodiazepine, opioid analgesic, or another inhalation anesthetic) and/or a neuromuscular blocking agent. Also, nitrous oxide is often administered concurrently with one of the other inhalation anesthetics to decrease the requirement for the more potent anesthetic.
—[Enflurane]1,[isoflurane]1 , methoxyflurane, and nitrous oxide are indicated in low doses to provide analgesia for procedures not requiring loss of consciousness.
—Enflurane,[isoflurane]1 , methoxyflurane, and nitrous oxide are indicated in low doses to provide analgesia for vaginal delivery {02} {12}.
—For cesarean section: Enflurane,[halothane]1 , [isoflurane]1 , and [methoxyflurane]1 are indicated in low concentrations {02} to supplement other general anesthetics during delivery by cesarean section {02}.

Unaccepted
Because of potential nephrotoxicity, administration of methoxyflurane in concentrations sufficient to produce muscle relaxation is not recommended {05}; a neuromuscular blocking agent should be used concurrently if necessary. Also, it is recommended that methoxyflurane not be used during vascular surgery at or near renal blood vessels.

Halothane is not recommended for vaginal delivery unless uterine relaxation is required {01} {03}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics



  Enflurane
Halothane
Isoflurane
Methoxyflurane
Nitrous Oxide
Minimum alveolar concentration (MAC) *
         
In oxygen (%)
1.68
{02}
0.75
{03}
1.15
0.16
>100
In 70% Nitrous Oxide (%)
0.57
{02}
0.29
0.5
{04}
0.07

Blood-to-Gas partition coefficient (37 °C)
1.91
{02}
2.5 {03}
{04}
1.43
{04}
10–14
{05}
0.47
Oil-to-Gas partition coefficient (37 °C)
98.5
220 {03}
97.8
825–970
1.4
Biotransformation §
Hepatic
Hepatic
Hepatic
Hepatic

% of dose metabolized #
2.4
Up to 20
0.17
{04}
50
0
Quantity of inorganic fluoride formed **
Small
Almost none
Very small
Substantial

Time to onset of anesthesia ††
Rapid
{02}
Rapid
{03}
Rapid
{04}
Slow

Time to change in depth of anesthesia when administered concentration changed
Rapid
Rapid
Rapid
Slow

Time to recovery from anesthesia ‡‡
Rapid
{02}
Rapid
{03}
Rapid
{04}
May be prolonged
Rapid
Elimination
         
Primary—% excreted unchanged by exhalation
80
60–80
95
{04}
35
100
Secondary §§
Renal
Renal
  Renal
 
* MAC—The minimum alveolar concentration that prevents movement in 50% of patients subjected to a painful stimulus. Slightly higher concentrations may be required to ensure immobility in all patients. MAC decreases with increasing age (being highest in very young children) {04}, pregnancy {04} {24}, hypothermia {04}, hypotension, and concurrent use of other central nervous system (CNS) depressants {04}. The MACs of individual inhaled anesthetics are additive.
 Indicator of solubility in blood, which affects the rate at which the partial pressure of the anesthetic in the blood (and therefore in the brain) equilibrates with that in the alveoli. Low solubility results in rapid rates of induction, changes in depth of anesthesia, and recovery.
 Indicator of solubility in fatty tissues. High solubility increases both anesthetic potency and the rate of elimination of the agent from the body.
§ Via hepatic microsomal enzymes.
# For enflurane, halothane, and methoxyflurane, the percentage metabolized may be increased by induction of hepatic enzymes.
** Indicator of nephrotoxic potential of agent. For enflurane, the quantity of inorganic fluoride produced is not increased by hepatic enzyme induction, but it may be increased by chronic isoniazid administration. Peak concentrations occur 4 to 12 hours postoperatively with enflurane and 2 to 4 days postoperatively with methoxyflurane. Methoxyflurane is also metabolized to other potentially nephrotoxic substances.
†† Rapid=7 to 10 minutes; slow=20 to 30 minutes. The pungent odor of enflurane or isoflurane {04} may cause breath-holding, coughing, or laryngospasm. This may limit the rate at which the administered concentration can be increased, resulting in a slightly longer induction time.
‡‡  Dependent on duration of anesthesia, administered concentration of anesthetic, and whether or not other CNS depressants are used. With isoflurane, administration for longer than 3 hours does not further prolong recovery time {04}.
§§  Primarily as metabolites. Small quantities of nitrous oxide may also be eliminated through the skin.


Table 2. Pharmacology/Pharmacokinetics



Other actions/effects:
 
         
Action or Body System/Function Affected
Enflurane
Halothane
Isoflurane
Methoxyflurane
Nitrous Oxide
Analgesia (low concentrations)
Moderate
Relatively poor
  Good
{05}
Excellent
Brain
         
Convulsive activity in electroencephalogram (EEG)
Yes *
No
No
{04}
No
No
Intracranial pressure
Increase
Increase
{03}
Increase
{04}
Increase
May increase
Cardiovascular System
         
Blood pressure
Decrease
{02}
Decrease
{03}
Decrease
{04}
Decrease
Generally unchanged
{04}
Cardiac function
Decrease
Decrease
No decrease §
{04}
Decrease
{05}
Slight decrease #
Circulation (high concentrations)
Depression
Depression
Depression
{04}
Depression
 
Heart/pulse rate
May
increase **
Decrease
{03}
Increase
{04}
May decrease
Increase
{04}
Peripheral vasculature
Dilation
Dilation
{03}
Dilation
{04}
  Constriction
Intraocular pressure ††
Significant
decrease
{30} {31}
Slight decrease
{32}
     
Muscle relaxation (dose-dependent) ‡‡
Excellent
{02}
Moderate
{03}
Excellent
{04}
  None
Pharyngeal and laryngeal reflexes
Decrease
{02}
Decrease
{03}
Decrease
{04}
   
Renal function §§
Decrease
{15}
Decrease
Decrease
{04}
Decrease
 
Respiratory System
         
Bronchi
Dilation
Dilation
{03}
     
Respiration (dose-dependent) ##
Depression
{02}
Depression
{03}
Depression
{04}
Depression
Depression
Secretions
May increase
{02} slightly
Decrease
{03}
May increase
slightly
{04}
No increase
 
Salivation
May increase
slightly
{02}
Decrease
{03}
May increase
slightly
{04}
   
* EEG changes characterized by high voltage and fast frequency progressing through spike-dome complexes alternating with periods of electrical silence to frank seizure activity may occur during deeper levels of enflurane anesthesia, especially in the presence of hyperventilation.
 With enflurane, halothane, isoflurane (concentration >1.25 MAC), and methoxyflurane, may be caused by increased cerebral blood flow secondary to cerebral vasodilation. This effect may be eliminated by hyperventilation-induced hypocapnea {04} or reduced by barbiturate administration {04}.
 Effect on blood pressure is dose-dependent and is a useful indication of depth of anesthesia {04}. With enflurane or isoflurane, blood pressure may return to near preanesthetic values with surgical stimulation or stress {02} {04}.
§ With isoflurane only, the reduction in blood pressure is caused primarily by peripheral vasodilation rather than depression of cardiac function. However, recent evidence indicates that isoflurane decreases cardiac function and heart/pulse rate in infants.
# Nitrous oxide may attenuate the cardiovascular effects of other inhaled anesthetics by reducing the requirement for the other anesthetic.
** With enflurane, the heart rate may be decreased if the preanesthetic heart rate is rapid; however, bradycardia usually does not occur.
†† With 1% of enflurane or 0.5% of halothane, given with nitrous oxide and oxygen.
‡‡ Enflurane or isoflurane may produce muscle relaxation sufficient for many types of surgery when used without a neuromuscular blocking agent {02} {04}.
§§ Effect is dose-dependent; reduction in glomerular filtration rate, renal blood flow, and urine volume may reflect decreased mean arterial pressure.
## Respiratory depression may be partially reversed with surgical stimulation or stress.


Physicochemical characteristics:
Molecular weight—
    Enflurane: 184.49 {17}
    Halothane: 197.38 {18}
    Isoflurane: 184.49 {19}
    Methoxyflurane: 164.97 {20}
    Nitrous oxide: 44.01 {21}


Other Characteristics
    Blood-to-gas partition coefficient:
    See Table 1
    Oil-to-gas partition coefficient:
    See Table 1

Mechanism of action/Effect:

The precise mechanism by which inhalation anesthetics produce loss of perception of sensations and unconsciousness is not known. Inhaled anesthetics act at many areas in the CNS. The Meyer-Overton theory suggests that the site of action of inhalation anesthetics may be the lipid matrix of neuronal membranes or other lipophilic sites. Anesthetics may cause changes in membrane thickness, which in turn affect the gating properties of ion channels in neurons. Interference with the hydrophobic portion of neuronal ion channel membrane proteins may be an important mechanism {22} {23}.

Absorption:

Inhalation anesthetics are rapidly absorbed into the circulation via the lungs.


Precautions to Consider

Carcinogenicity

Isoflurane: Although one study indicated that isoflurane may be carcinogenic, it is thought that exposure of the test animals to polybrominated biphenyls may have been responsible. Subsequent studies in which such exposure was avoided have not shown evidence of isoflurane-induced carcinogenicity {04}.

Enflurane, halothane, methoxyflurane, and nitrous oxide: These anesthetics have not been shown to be carcinogenic {04}.

Tumorigenicity

Enflurane: Studies in mice have not shown evidence of tumorigenicity with enflurane {02}.

Mutagenicity

Halothane: In vitro testing (Ames test) has indicated that potential halothane metabolites (but not halothane itself) may be mutagenic.

Enflurane, isoflurane, methoxyflurane, and nitrous oxide: Mutagenic effects have not been observed with these inhalation anesthetics in the Ames test or the sister chromatid exchange test {04}. However, statistically significant increases in sperm abnormalities have been observed in mice following 20 hours of exposure to 1.2% of enflurane {02}.

Pregnancy/Reproduction

Pregnancy—
Inhalation anesthetics cross the placenta. Risk-benefit must be considered because studies (by retrospective survey) of operating room personnel chronically exposed to low concentrations of inhalation anesthetics indicate that pregnancies in female personnel and wives of male personnel may be subject to an increased incidence of spontaneous abortions, stillbirths, and possibly birth defects {13} {14}. However, the methods used in obtaining and interpreting the data in these studies have been questioned. Also, several animal studies (in which operating room conditions were simulated) have failed to show fetotoxic or teratogenic effects following chronic exposure of male and/or female animals to low concentrations of inhalation anesthetics prior to and/or during gestation. {13} {14}

First trimester: Administration of enflurane, halothane, or isoflurane {04} early in pregnancy (for therapeutic abortion) has been reported to increase uterine bleeding. However, blood loss following enflurane administration was considered to be within acceptable limits.

Enflurane—Although studies in patients have not been done, some studies in rats and rabbits have not shown that enflurane causes adverse effects on the fetus {02}. However, other studies in animals have shown that enflurane may be teratogenic.

FDA Pregnancy Category B {02}.

Halothane—Although studies in patients have not been done, some animal studies have shown that halothane may be teratogenic {01} {03}.

FDA Pregnancy Category C {03}.

Isoflurane—Although isoflurane has not been shown to cause fetal malformations in mice or rats, studies in mice receiving 7 MAC hours (the equivalent of 1 MAC [minimum alveolar concentration that prevents movement in 50% of subjects following a painful stimulus] administered for 7 hours) over a period of 10 days during gestation have indicated possible fetotoxicity as manifested by higher implantation losses and a significantly lower live birth index {04}. Studies have not been done in patients.

FDA Pregnancy Category C {04}.

Methoxyflurane—Although adequate and well-controlled studies in patients have not been done, some studies in animals have shown that methoxyflurane may be teratogenic {12}. Also, studies in rats have indicated that exposure to doses equivalent to 67 hours of 0.2% methoxyflurane caused fetal growth retardation.

FDA Pregnancy Category C.

Nitrous oxide—Although problems in patients have not been documented, studies in rats have shown that nitrous oxide causes fetal death, growth retardation, and skeletal anomalies.


Labor and delivery—

Minimum alveolar concentration (MAC) is decreased in pregnancy. MAC continues to be decreased during the early postpartum period. By 72 hours postpartum, MAC returns to normal {25} {26}.

Enflurane, halothane, isoflurane, and methoxyflurane produce dose-dependent uterine relaxation, which may delay delivery and increase postpartum bleeding {04} {12}. Subanesthetic (analgesic) concentrations of enflurane, isoflurane, or methoxyflurane do not significantly decrease uterine contractions {02} {04} {05} {12}. Halothane is the most potent uterine relaxant {03}; even low concentrations (< 0.5%) may decrease uterine contractions. Also, enflurane and halothane cause a dose-dependent decrease in the uterine response to oxytocics {01} {02}. Use of halothane during vaginal delivery is not recommended unless uterine relaxation is required (as for version or other intrauterine manipulations) {12}.

Although its safety in obstetrics has not been established by formal studies, isoflurane is used to provide obstetrical analgesia {04}.

Postpartum —
High concentrations of inhalation anesthetics administered during prolonged delivery may increase the risk of neonatal depression.

Methoxyflurane: Inorganic fluoride produced by methoxyflurane metabolism has been detected in cord blood in concentrations that are usually lower than, but sometimes equal to, the maternal blood concentration {05}. The effect of inorganic fluoride on the neonate is not known; however, nephrotoxicity in the infant is thought to be unlikely following recommended doses of methoxyflurane {05}.

Breast-feeding

It is not known if enflurane, halothane, isoflurane or methoxyflurane is distributed into breast milk {03}. However, problems in humans have not been documented.

Pediatrics

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of inhalation anesthetics in children. However, the MAC of inhalation anesthetics is higher in children than in adults. The MAC is highest in very young children and decreases as the age of the child increases {04}.


Geriatrics


The MAC an anesthetic is decreased in geriatric patients {04}. Also, geriatric patients may be more susceptible to anesthetic-induced hypotension and circulatory depression and to methoxyflurane-induced nephrotoxicity; especially careful attention to dosage is recommended {04}.

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):

Table 3. Drug Interactions and/or Related Problems



Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Legend:
I=Enflurane
II=Halothane
III=Isoflurane
IV=Methoxyflurane
V=Nitrous Oxide

I
 
II
 
III
 
IV
 
V
 
Alcohol, chronic ingestion
         
(may increase anesthetic requirement) {04}





Alfentanil or
         
Fentanyl or
         
Sufentanil
         
(in addition to the increased CNS depressant, respiratory depressant, and hypotensive effects that may occur when an anesthetic is used concurrently with any CNS depressant, concurrent use of high doses of fentanyl or its derivatives with nitrous oxide may decrease heart rate and cardiac output; these effects may be more pronounced in patients with poor left ventricular function)
       
» Aminoglycosides, systemic, or
         
» Capreomycin or
         
» Citrate-anticoagulated blood (massive transfusions) or
         
» Lincomycins, systemic, or
         
» Neuromuscular blocking agents, nondepolarizing, or
         
» Polymyxins, systemic
(caution should be used in concurrent administration with halogenated anesthetics, especially enflurane or isoflurane, because of the possibility of additive neuromuscular blockade {02} {03} {04} {05} {08}; although increased or prolonged skeletal muscle weakness and respiratory depression or paralysis [apnea] may occur, clinical significance is minimal if the patient is being mechanically ventilated; however, dosage of nondepolarizing neuromuscular blocking agents should be decreased to 1/2 to 1/3 of the usual dose or as determined using a peripheral nerve stimulator {05}; treatment with anticholinesterase agents or calcium salts may help reverse the blockade, but calcium salts are not recommended if tubocurarine has been given because they may potentiate, rather than reverse, its effects)




 
Amiodarone
         
(concurrent use with inhalation anesthetics may potentiate hypotension and increase the risk of atropine-resistant bradycardia)





Anticoagulants, coumarin- or indandione-derivative
         
(inhalation anesthetics have been reported to increase the effects of these anticoagulants; although clinical significance has not been determined, the possibility of increased anticoagulation during or shortly following concurrent use should be considered)





Antidepressants, tricyclic
         
(administration of anesthesia with halothane and neuromuscular block with pancuronium in patients receiving tricyclic antidepressants has resulted in severe ventricular arrhythmias {03} {29})
 
     
Antihypertensive agents, especially diazoxide or ganglionic blockers such as guanadrel, guanethidine, mecamylamine, or trimethaphan, or
         
Chlorpromazine or
         
Diuretics or
         
Hypotension-producing medications, other (See Appendix II )
         
(hypotensive effects may be potentiated when these medications are used concurrently with inhalation anesthetics; patients should be monitored for excessive fall in blood pressure during and following concurrent use)





(halothane may prevent or reduce trimethaphan-induced tachycardia)
 
     
Antimyasthenics
         
(antimyasthenics, especially neostigmine and pyridostigmine, may decrease neuromuscular blocking activity of halogenated hydrocarbon anesthetics; also, the neuromuscular blocking activity of these anesthetics, especially enflurane or isoflurane, may interfere with the efficacy of antimyasthenics so that temporary dosage adjustment may be required to control symptoms of myasthenia gravis postoperatively)




 
Beta-adrenergic blocking agents, including ophthalmic betaxolol, levobunolol, or timolol
         
(concurrent use with hydrocarbon inhalation anesthetics may result in prolonged severe hypotension because the beta-blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli; if necessary to reverse the effects of beta-adrenergic blocking agents during surgery, agonists such as dobutamine, dopamine, isoproterenol, or norepinephrine may be used but should be administered with caution, especially in patients receiving halothane. Some clinicians recommend gradual withdrawal of beta-adrenergic blocking agents 48 hours prior to elective surgery; however, this recommendation is controversial)




 
(it is recommended that high concentrations of halothane [3% or above] or other halogenated hydrocarbon anesthetics not be used when labetalol is used to produce controlled hypotension during surgery; possible additive effects may lead to excessive hypotension, large reduction in cardiac output, and increased central venous pressure)




 
» Catecholamines {03} such as dopamine, epinephrine, or norepinephrine, or
         
» Cocaine or
         
» Ephedrine or
         
» Levodopa or
         
» Metaraminol or
         
» Methoxamine or
         
Other sympathomimetic agents
         
(halothane greatly sensitizes the myocardium to the effects of sympathomimetics, especially catecholamines, so that the risk of severe ventricular arrhythmias is increased; sympathomimetics should be used with caution and in substantially reduced dosage in patients receiving halothane) {03}
 
     
(enflurane, isoflurane, or methoxyflurane may also cause some sensitization of the myocardium to the effects of sympathomimetics; caution is recommended during concurrent use) {02} {04}

 

 
(levodopa increases endogenous dopamine concentration and should be discontinued 6 to 8 hours prior to anesthesia with these agents, especially halothane)




 
CNS depression–producing medications, other, including those commonly used for preanesthetic medication or induction or supplementation of anesthesia (see Appendix II )
         
(concurrent administration may increase the CNS depressant, respiratory depressant, and hypotensive effects of inhalation anesthetics; decrease anesthetic requirement; and prolong recovery from anesthesia; careful attention to the dosage of each agent is required) {04}





Doxapram
         
(doxapram may cause catecholamine release; it is recommended that initiation of doxapram therapy be delayed for at least 10 minutes following discontinuation of anesthetics known to sensitize the myocardium to catecholamines)




 
Hepatic enzyme–inducing agents (see Appendix II )
         
(chronic use of these medications prior to anesthesia may increase anesthetic metabolism leading to increased risk of hepatotoxicity) {05} {15}


 
 
(chronic use of these medications prior to anesthesia may increase formation of nephrotoxic metabolites leading to increased risk of nephrotoxicity) {05}
     
 
Isoniazid and possibly other hydrazine-containing compounds
         
(may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane or isoflurane) {02} {09} {11}

       
Ketamine
         
(volatile anesthetics may prolong elimination half-life of ketamine; recovery from anesthesia may be prolonged; increased hypotensive and cardiac depressant effects ) {04} {07}




 
Methyldopa
         
(concurrent use with general anesthetics may decrease the anesthetic requirement)





» Nephrotoxic agents, other (see Appendix II )
         
(may increase the risk of severe nephrotoxicity if administered prior to, during, or following administration of methoxyflurane; concurrent or sequential use is generally not recommended) {05}
     
 
Nitrous oxide
         
(concurrent administration with another inhalation anesthetic reduces the requirement for the other anesthetic and may therefore attenuate some of its cardiovascular effects)




 
Oxytocics
         
(enflurane [concentrations >1.5%] {02}, halothane [concentrations >1%] {03}, or possibly isoflurane produces a dose-dependent decrease in the uterine response to oxytocics and may abolish the response if sufficient concentrations [>3% of enflurane are administered; uterine hemorrhage may result) {03}



   
Phenytoin
         
(concurrent use may increase the risk of halothane hepatotoxicity; also, halothane-induced hepatic function impairment may increase the risk of phenytoin toxicity)
 
     
Ritodrine, intravenous
         
(concurrent use of halogenated hydrocarbon anesthetics may lead to potentiation of ritodrine's cardiovascular effects, especially cardiac arrhythmias or hypotension)




 
Succinylcholine
         
(concurrent use with halogenated hydrocarbon anesthetics may increase the risk of malignant hyperthermia; also, repeated concurrent use may increase the risk of bradycardia)




 
(halogenated hydrocarbon anesthetics may potentiate succinylcholine-induced neuromuscular blockade but to a lesser extent than they potentiate the effects of nondepolarizing neuromuscular blocking agents)




 
Xanthines
         
(concurrent use with anesthetics, especially halothane, may increase the risk of cardiac arrhythmias {06})








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 physiology/laboratory test values
Cerebrospinal fluid (CSF) pressure {04}    (anesthetics may increase CSF pressure)


Liver function {04}    (abnormalities in liver function as shown by transient, mild increases in serum transaminase and/or lactate dehydrogenase activity may occur in the absence of hepatotoxicity; with enflurane, halothane, or methoxyflurane, significant abnormalities indicating hepatotoxicity may occur rarely)


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).

Table 4. Medical considerations/Contraindications



  Legend:
I=Enflurane
II=Halothane
III=Isoflurane
IV=Methoxyflurane
V=Nitrous Oxide

I
 
II
 
III
 
IV
 
V
 
Except under special circumstances, these medications should not be used when the following medical problem exists:
 
         
» Malignant hyperthermia, history of or suspected genetic predisposition to
(risk of malignant hyperthermic crisis during or following anesthesia) {02}




 
Risk-benefit should be considered when the following medical problems exist:
 
         
Air-enclosing cavities, such as pulmonary, renal, or occluded middle ear air cysts or air embolism, or
         
Intestinal obstruction, acute, or
         
Pneumoencephalography, during or recently following the procedure (pneumoencephalography), or
         
Pneumothorax
         
(may increase pressure within rigid-walled cavities or volume within nonrigid-walled cavities)
       
Biliary tract disease or
         
» Hepatic function impairment or disease or
         
» Jaundice or acute hepatic damage, not attributable to other causes, following previous exposure to enflurane, halothane, or methoxyflurane
         
(increased risk of hepatotoxicity) {03} {05}


 
 
Cardiac arrhythmias
         
(may be induced or exacerbated) {03}
 
     
Diabetes, uncontrolled or with polyuria or obesity {02} {05}, or
         
» Renal function impairment or disease {05} or
         
» Toxemia of pregnancy {05}
         
(increased risk of nephrotoxicity)
     
 
Head injury or
         
Increased intracranial pressure, pre-existing, or
         
Intracranial lesions, space-occupying, or tumors
         
(may increase intracranial pressure) {03} {04}





Myasthenia gravis
         
(muscle weakness may be increased because of neuromuscular blocking effects of anesthetics, especially enflurane and isoflurane)




 
Pheochromocytoma
         
(increased risk of cardiac arrhythmias because patient has high endogenous catecholamine concentrations)
 
     
Sensitivity to the anesthetic being considered for use, history of







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):


For all inhalation anesthetics
Blood pressure {03} and
Cardiac/pulse rate {03} and
Cardiac rhythm {03} and
» Respiratory and ventilatory status {03} {05}    (monitoring recommended during anesthetic administration)


Body temperature {03}    (continuous monitoring advisable)


For methoxyflurane
» Renal function determinations {05}    (may be needed to detect possible nephrotoxicity if the patient's postoperative urine output is excessive)




Side/Adverse Effects

Note: Hepatotoxicity ranging in severity from mild jaundice to hepatic necrosis has been reported following administration of enflurane {03} {05}, halothane, or methoxyflurane {03} {05}. Although a definite causal relationship has not been established, it has been proposed that a hypersensitivity reaction to the anesthetic may be involved. Hepatic damage has been reported much less frequently with enflurane {15} or methoxyflurane than with halothane; however, the biochemical, clinical, and histologic features of the hepatotoxicity reported with each of these agents are similar {15}. The risk of hepatotoxicity may be increased by intra- or postoperative hypoxia {16}, repeated or sequential use of these agents {05}, patient predisposition to hepatotoxicity, and patient history of hepatotoxicity not attributable to other causes following previous exposure to one of these anesthetics.
The risk of methoxyflurane-induced nephrotoxicity is related to the total dose (concentration and time) administered, degree of metabolism (which may be increased by hepatic enzyme induction), and patient predisposition to nephrotoxicity. Although polyuric renal failure has been most often reported, some patients have developed oliguric renal failure {05}. Renal tubular necrosis may occur {05}. Laboratory findings indicative of methoxyflurane-induced nephrotoxicity include elevations of blood sodium, blood urea nitrogen, blood creatinine, serum and urine fluoride, serum chloride, urine oxalic acid, and blood uric acid concentrations, and reductions of urine specific gravity and osmolality. Isolated cases of nephrotoxicity have also been reported with enflurane (following prolonged administration to patients with impaired renal function) {15} and halothane; however, a definite causal relationship has not been established.
Impairment of psychomotor skills may occur following anesthesia and may persist for varying lengths of time, depending upon the anesthetic and/or combination of medications used and the total dosages administered. With halothane, it is thought that the impairment may be at least partially caused by bromide metabolites. Possible adverse effects on the patient's ability to drive or perform other tasks requiring alertness and coordination should be kept in mind when anesthesia is administered for outpatient surgery.



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses)—not necessarily inclusive: *
Legend:
I=Enflurane
II=Halothane
III=Isoflurane
IV=Methoxyflurane
V =Nitrous Oxide

I
 
II
 
III
 
IV
 
V
 
Medical attention needed
 
         
Bronchospasm {05}
 
R
X
U
R
U
Cardiac arrhythmias—Supraventricular arrhythmias and bradycardia are relatively common during induction of anesthesia and are not considered dangerous in patients with adequate cardiovascular function. Ventricular arrhythmias are rare in the absence of hypercapnea or hypoxia but may be more likely to occur with halothane. Other arrhythmias reported with halothane include nodal rhythm and atrioventricular dissociation {02} {03} {04}.
R
R
R
R
R
Circulatory depression
 
R
R
R
R
R
CNS excitation—may lead to convulsions
R
X
X
X
X
Emergence delirium, postanesthesia {04} {05}
 
L
M
L
L
L
Hepatotoxicity (black or bloody vomit, severe or continuing headache, loss of appetite, severe or continuing nausea, pain in abdomen, yellow eyes or skin) {03} {05} {15} {16}
R
R
U
R
X
Hypoxia—with nitrous oxide, diffusion hypoxia may occur after discontinuation unless oxygen is administered {03}
R
R
R
R
R
Leukopenia —with prolonged use; may be first sign of reversible bone marrow depression
X
X
X
X
R
Malignant hyperthermic crisis {02} {03} {04}
 
R
R
U
R
R
Nephrotoxicity (increased urination and rapid weight loss or decreased urination and rapid weight gain) {05} {15}
R
R
U
L
U
Neurologic injury —with prolonged or repeated exposure
X
X
X
X
R
Respiratory depression {02} {03} {04} {05}
 
R
R
R
R
R
Medical attention needed only if continuing or bothersome
 
         
Drowsiness, prolonged {05}
 
U
U
U
L
U
Headache, mild {05}
 
U
R
L
R
U
Nausea or vomiting, mild {02} {03} {04} {05} {28}
 
L
L
L
L
M
Shivering or trembling {03} {04}
 
M
M
M
L
L
* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents. M=more frequent; L=less frequent; R=rare; U=unknown; X=does not occur.
 Operating room or dental office personnel may be at risk for this effect if they are chronically exposed to nitrous oxide because precautions to prevent contamination of the atmosphere in the room in which it is being used are not utilized or are inadequate.



Overdose
For specific information on the agents used in the management of an inhalation anesthetic overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.


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

Clinical effects of overdose
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
    
Bradycardia
    
circulatory depression or hypotension, severe
    
respiratory depression


Specific treatment
For bradycardia—Administering atropine {03}.

For circulatory depression or severe hypotension—Discontinuing or lightening anesthesia (if still being administered) and administering plasma and/or intravenous fluids. If surgical or postsurgical conditions permit, positioning the patient to improve venous return to the heart (i.e., in the Trendelenburg position) is recommended. If necessary, a vasopressor may be administered.

For respiratory depression {02} {04}—Decreasing anesthetic dosage (if still being administered), establishing a clear airway, and instituting assisted or controlled respiration with pure oxygen {02} {04}.


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 the anesthetic considered for use

Pregnancy—Inhalation anesthetics cross the placenta; enflurane, halothane, and isoflurane may increase the risk of bleeding when used for first trimester abortion; hydrocarbon anesthetics used during labor and delivery may slow delivery, increase bleeding, and cause neonatal depression, depending on dosage





Use in the elderly—Increased risk of adverse effects
Any other medication, including use of “street” drugs
Other medical problems

Proper use of this medication

Proper dosing

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

» Avoiding use of alcohol or CNS depressants within 24 hours following anesthesia unless specifically prescribed or otherwise authorized by physician or dentist


Side/adverse effects
Signs and symptoms of potential delayed side effects, especially hepatotoxicity and nephrotoxicity.


General Dosing Information
Inhalation anesthetics are to be administered only by those individuals experienced in airway management and respiratory support. Equipment and personnel for support of ventilation must be immediately available.

The stated dosages are given as a guideline for use in the average adult. The dosage of inhaled anesthetics must be individualized according to surgical requirements; concurrent use of adjuvant medications and/or nitrous oxide; and patient variables, especially age, body temperature, and physical condition.

Anesthetic requirements are increased in very young children and decreased in geriatric patients.

Preanesthetic medications should be selected according to the needs of the individual patient and surgical requirements.

For patients who may be adversely affected by increases in intracranial pressure, measures (such as barbiturate administration or institution of hyperventilation) to reduce or abolish the increase produced by enflurane, halothane, isoflurane, or methoxyflurane should be carried out prior to or concurrently with administration of these agents. However, the fact that hyperventilation may increase the risk of enflurane-induced convulsive activity should be kept in mind.

Administration of inhalation anesthetics other than nitrous oxide to patients with known or suspected susceptibility to malignant hyperthermia should be avoided. Although prophylactic administration of dantrolene prior to anesthesia may prevent the occurrence of a malignant hyperthermic crisis during or shortly following surgery, this use of dantrolene is controversial and should be undertaken with caution. See Dantrolene (Systemic) .

An intravenous induction agent is often administered prior to an inhalation anesthetic to facilitate induction of anesthesia and prevent the transient initial CNS excitation that may occur with some of the inhaled anesthetics.

Enflurane, halothane, isoflurane, or methoxyflurane may be vaporized in a flow of oxygen or a nitrous oxide–oxygen mixture.

During maintenance of anesthesia, the concentration of inhaled anesthetic may be progressively decreased as necessary to prevent further increases in depth of anesthesia and/or hypotension {04}.

Assisted or controlled respiration may be necessary, especially during deep levels of anesthesia, to control respiratory depression and/or respiratory acidosis.

Desiccation of carbon dioxide (CO 2) absorbents may occur, especially with the use of high flow-rates of gases. Some inhalation anesthetics (e.g., desflurane, enflurane and isoflurane) can react with desiccated CO 2 absorbents to produce carbon monoxide {02} {04} {27}. This reaction may result in elevated levels of carboxyhemoglobin in some patients {02} {04} {27}.

For treatment of adverse effects
Recommended treatment includes:

   • For cardiac arrhythmias—Determining whether the level of anesthesia is adequate for the given surgical stimulus and adjusting (deepening or lightening) the level of anesthesia accordingly or discontinuing anesthesia. Also, determining whether the arrhythmia is caused by hypercarbia, hypocarbia, or hypoxia and correcting as required.
   • For malignant hyperthermic crisis—Discontinuing administration of possible triggering agents (such as potent inhalation anesthetics, succinylcholine, or stress), managing increased oxygen requirement, cooling the patient, and correcting fluid and electrolyte imbalances and metabolic acidosis. If necessary, administering dantrolene {02} {03} by continuous rapid intravenous push (at least 1 mg per kg of body weight [mg/kg] initially, continued until the symptoms subside or the maximum total dose of 10 mg/kg has been administered). Intravenous dantrolene administration may be repeated if symptoms recur. Dantrolene (4 to 8 mg/kg per day in four divided doses) may be administered orally or intravenously, with caution, for 1 to 3 days postoperatively to prevent recurrence of symptoms.
   • For inadequate postoperative ventilation—Decreasing anesthetic dosage (if still being administered), establishing a clear airway, and instituting assisted or controlled respiration with oxygen {02} {04}.
   • For emergence delirium—Administering small doses of an opioid (narcotic) analgesic.

ENFLURANE

Summary of Differences


Indications:
Indicated in low concentrations to supplement other anesthetics for cesarean section.

Also used in low doses to provide analgesia in obstetrics and for procedures not requiring loss of consciousness.



Pharmacology/pharmacokinetics:


Minimum alveolar concentration (MAC)—
In oxygen: 1.68%.

In 70% nitrous oxide: 0.57%.



Blood-to-gas partition coefficient (37 °C)—
1.91



Oil-to-gas partition coefficient (37 °C)—
98.5



Biotransformation—
2.4% of dose metabolized.



Elimination—
Primary: 80% excreted unchanged by exhalation.



Other actions/effects—
Deeper levels of enflurane anesthesia, especially in the presence of hyperventilation, may produce convulsive activity in electroencephalogram (EEG).




Precautions:


Mutagenicity—
Studies in mice have shown that enflurane may cause sperm abnormalities.



Pregnancy—
May cause dose-dependent uterine relaxation (anesthetic doses).

May cause dose-dependent decrease in uterine response to oxytocics.



Drug interactions and/or related problems—
Isoniazid and possibly other hydrazine-containing compounds may increase the formation of potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane.




Additional Dosing Information
See also General Dosing Information.

When enflurane is used for induction of anesthesia, it is recommended that the concentration be increased slowly, i.e., by 0.5% every few breaths.

When assisted or controlled respiration is required, extreme hyperventilation should be avoided in order to minimize the risk of CNS excitation and convulsions.

Following enflurane administration, little or no postoperative analgesia is produced because of its short duration of action. Therefore, earlier administration of analgesics for pain relief may be necessary after enflurane than after other inhalation anesthetics.


Inhalation Dosage Forms

ENFLURANE USP

Usual adult dose
Anesthetic (general)


Surgical anesthesia:
Induction—Dosage must be individualized.

Maintenance—Inhalation, 0.5 to 3% {02}.



Supplemental obstetrical anesthesia (for cesarean section):
Inhalation, 0.5 to 1% {02}.



For vaginal delivery in obstetrics:
Inhalation, 0.25 to 1% {02}.



Usual adult prescribing limits
For surgical anesthesia
Induction: The final concentration for induction should not exceed 4.5%.

Maintenance: Maintenance concentration should not exceed 3% {02}.


Usual pediatric dose
Dosage must be individualized.

Product(s) usually available:
U.S.—


[Ethrane][Generic]

Canada—


[Ethrane]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


HALOTHANE

Summary of Differences


Indications:
Also used in low concentrations to supplement other anesthetics for cesarean section.

Not recommended for vaginal delivery unless uterine relaxation is required.



Pharmacology/pharmacokinetics:


Minimum alveolar concentration (MAC)—
In oxygen: 0.75%.

In 70% nitrous oxide: 0.29%.



Blood-to-gas partition coefficient (37 °C)—
2.3



Oil-to-gas partition coefficient (37 °C)—
224



Biotransformation—
Up to 20% of dose metabolized.



Elimination—
Primary: 60 to 80% excreted unchanged by exhalation.



Other actions/effects—
Cardiovascular system: Heart/pulse rate decrease.

Respiratory system secretions and salivation decrease.




Precautions:


Mutagenicity—
Potential halothane metabolites have been shown to be mutagenic in the Ames test.



Pregnancy—
May cause uterine relaxation even in low concentrations.

May cause dose-dependent decrease in uterine response to oxytocics.



Breast-feeding—
It is not known if halothane is distributed into breast milk {03}.



Drug interactions and/or related problems—
Halothane may prevent or reduce trimethaphan-induced tachycardia.

Halothane greatly sensitizes the myocardium to the effects of sympathomimetics, especially catecholamines, so that the risk of severe ventricular arrhythmias is increased; sympathomimetics should be used with caution and in substantially reduced dosage in patients receiving halothane.

Concurrent use of phenytoin may increase the risk of halothane hepatotoxicity; also, halothane-induced hepatic function impairment may increase the risk of phenytoin toxicity.



Medical considerations/contraindications—
Caution needed in cardiac arrhythmias since halothane may induce or exacerbate arrhythmias.

In pheochromocytoma, there may be an increased risk of cardiac arrhythmias because the patient has high endogenous catecholamine concentrations.




Inhalation Dosage Forms

HALOTHANE USP

Usual adult dose
Anesthetic (general)


Induction:
Dosage must be individualized.



Maintenance:
Inhalation, 0.5 to 1.5% {03}.



Usual pediatric dose
Dosage must be individualized.

Product(s) usually available:
U.S.—


[Fluothane][Generic]

Canada—


[Fluothane]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Stability:
Stability of halothane is maintained by the addition of thymol and ammonia. Because the thymol does not vaporize along with the halothane, it accumulates in the vaporizer and may lead to a yellow discoloration of the remaining liquid or wick. Discolored solutions should be discarded and the vaporizer and wick cleaned by washing with diethyl ether. Complete removal of the diethyl ether is required to make certain that ether is not introduced into the system.

Incompatibilities:
Halothane vapor, in the presence of moisture, reacts with aluminum, brass, and lead, but not copper.

Some plastics and rubber are soluble in halothane and will deteriorate rapidly in contact with halothane vapor or liquid.


ISOFLURANE

Summary of Differences


Indications:
Also used in low doses to provide analgesia in obstetrics and for procedures not requiring loss of consciousness, and to supplement other anesthetics for cesarean section.



Pharmacology/pharmacokinetics:


Minimum alveolar concentration (MAC)—
In oxygen: 1.15%.

In 70% nitrous oxide: 0.5%.



Blood-to-gas partition coefficient (37 °C)—
1.43



Oil-to-gas partition coefficient (37 °C)—
97.8



Biotransformation—
0.17% of dose metabolized.



Elimination—
Primary: 95% excreted unchanged by exhalation.



Other actions/effects—
Cardiac function: No decrease. Reduction in blood pressure is caused primarily by peripheral vasodilation rather than depression of cardiac function; however, recent evidence indicates that isoflurane decreases cardiac function and heart/pulse rate in infants.

Heart/pulse rate: Increase.




Precautions:


Pregnancy—
Animal studies have indicated possible fetotoxicity.

May cause uterine relaxation (anesthetic concentrations).

Safety in obstetrics has not been established.




Additional Dosing Information
See also General Dosing Information.

When isoflurane is used for induction of anesthesia, it is recommended that the concentration be increased slowly, i.e., by 0.1 to 0.25% every few breaths {04}.


Inhalation Dosage Forms

ISOFLURANE USP

Usual adult dose
Anesthetic (general)


Induction:
Inhalation, 1.5 to 3% {04}.



Maintenance:
Inhalation, 1 to 3.5% {04}.



Usual pediatric dose
Dosage must be individualized.

Product(s) usually available:
U.S.—


[Forane]

Canada—


[Forane]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


METHOXYFLURANE

Summary of Differences


Indications:
Administration of concentrations sufficient to provide muscle relaxation is not recommended.

Not recommended for vascular surgery at or near the renal blood vessels.

Also indicated in low doses to provide analgesia in obstetrics and for procedures not requiring loss of consciousness.

Also used in low concentrations to supplement other anesthetics for cesarean section.



Pharmacology/pharmacokinetics:


Minimum alveolar concentration (MAC)—
In oxygen: 0.16%.

In 70% nitrous oxide: 0.07%.



Blood-to-gas partition coefficient (37 °C)—
10 to 14



Oil-to-gas partition coefficient (37 °C)—
825 to 970



Biotransformation—
50% of dose metabolized.

A substantial quantity of inorganic fluoride is formed; also metabolized to other potentially nephrotoxic substances.



Time to onset of anesthesia—
Slow.



Time to change in depth of anesthesia when administered concentration is changed—
Slow.



Time to recovery from anesthesia—
May be prolonged.



Elimination—
Primary: 35% excreted unchanged by exhalation.



Other actions/effects—
Respiratory system secretions do not increase.




Precautions:


Pregnancy—
May cause dose-dependent uterine relaxation.



Drug interactions and/or related problems—
Chronic use of hepatic enzyme–inducing agents may increase the formation of nephrotoxic metabolites, leading to increased risk of nephrotoxicity.

Concurrent use of other nephrotoxic agents may increase the risk of severe nephrotoxicity.



Medical considerations/contraindications—
Caution needed in diabetes, uncontrolled or with polyuria or obesity; in renal function impairment or disease; or in toxemia of pregnancy, as methoxyflurane may increase the risk of nephrotoxicity.



Patient monitoring—
Monitoring of renal function may be needed to detect possible nephrotoxicity if patient's postoperative urine output is excessive.




Additional Dosing Information
See also General Dosing Information .

A parenteral induction agent is recommended prior to administration of methoxyflurane {05}.

Concurrent administration of at least 50% nitrous oxide is recommended, unless specifically contraindicated, to reduce the methoxyflurane requirement {05}.

During long procedures, it is recommended that methoxyflurane be administered in decreasing concentrations because of the risk of nephrotoxicity {05}. See manufacturer's prescribing information for an example of recommended concentrations at various times following initiation of methoxyflurane administration. Also, it is recommended that administration be limited to 4 hours or less {05}.

Low doses of methoxyflurane may be self-administered using a hand-held inhaler {05}. It is recommended that such use be limited to the briefest practical time and that the patient be under observation by trained personnel. The patient may be transferred to a conventional anesthesia machine if necessary. In obstetrics, methoxyflurane should not be self-administered until relief is necessary.


Inhalation Dosage Forms

METHOXYFLURANE USP

Usual adult dose
Anesthetic (general)
Inhalation, up to 2% {05} administered with at least 50% nitrous oxide and oxygen initially, then decreased to the lowest effective concentration {05}.

For obstetrics or procedures not requiring loss of consciousness
Inhalation, 0.3 to 0.8%, intermittently {05} {12}.

Note: For patient self-administration, no more than a single 15-mL charge of liquid should be available to the patient {05}.



Usual adult prescribing limits
For surgical anesthesia, administration should not exceed four hours of 0.25% methoxyflurane or two hours of 0.5% methoxyflurane or the equivalent total dosage {05}.

Usual pediatric dose
Dosage must be individualized.

Product(s) usually available:
U.S.—


[Penthrane]

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

Stability:
Solutions of methoxyflurane contain an antioxidant, butylated hydroxytoluene, which may oxidize to a yellow pigment that progressively turns to brown. This substance may accumulate on the vaporizer wick. Diethyl ether may be used to clean the wick; complete removal of the diethyl ether is required to make certain that ether is not introduced into the system.

Incompatibilities:
Methoxyflurane is very soluble in rubber and in soda lime.

Polyvinyl chloride plastics are extracted by methoxyflurane; contact with such plastics should be avoided.


NITROUS OXIDE

Summary of Differences


Indications:
Anesthetic potency relatively weak; usually must be supplemented with other agents.

Often given concurrently with one of the more potent inhalation anesthetics to reduce the requirement for the other anesthetic.

Also indicated in low doses to provide analgesia in obstetrics and for procedures not requiring loss of consciousness.



Pharmacology/pharmacokinetics:


Minimum alveolar concentration (MAC) in oxygen—
> 100%.



Blood-to-gas partition coefficient (37 °C)—
0.47



Oil-to-gas partition coefficient (37 °C)—
1.4



Biotransformation—
None of dose metabolized.



Elimination—
Primary: 100% excreted unchanged by exhalation.



Other actions/effects—
Blood pressure generally unchanged.

Heart/pulse rate increases.

Constriction of peripheral vasculature.

No dose-related muscle relaxation.




Precautions:


Pregnancy—
Studies in animals have shown that nitrous oxide causes fetal death, growth retardation, and skeletal anomalies.



Drug interactions and/or related problems—
In addition to the increased CNS depressant, respiratory depressant, and hypotensive effects that may occur when an anesthetic is used concurrently with any CNS depressant, concurrent use of high doses of fentanyl or its derivatives with nitrous oxide may decrease the heart rate and cardiac output. These effects may be more pronounced in patients with poor left ventricular function.



Medical considerations/contraindications—
Caution needed in the presence of air-enclosing cavities (such as pulmonary, renal, or occluded middle ear air cysts or air embolism), acute intestinal obstruction, or pneumothorax, or during or recently following the procedure of pneumoencephalography, as nitrous oxide may increase pressure within rigid-walled cavities or volume within nonrigid-walled cavities.




Additional Dosing Information
See also General Dosing Information.

Nitrous oxide must be administered with at least 30% of oxygen to reduce the risk of hypoxia.

For anesthesia
Premedication of the patient with an opioid analgesic or a barbiturate may be necessary in order to achieve induction of anesthesia.

Nitrous oxide may diffuse into the cuff of an endotracheal tube; periodic deflation of the endotracheal tube is recommended during administration.

The concentration administered during maintenance of anesthesia must be individualized, depending upon the condition of the patient and the type and quantity of supplemental medications administered.

When prolonged administration of nitrous oxide is discontinued, 100% oxygen should be administered briefly to reduce the risk of diffusion hypoxia {04}.


Inhalation Dosage Forms

NITROUS OXIDE USP

Usual adult dose
Anesthetic (general)


Induction:
Inhalation, 70% with 30% of oxygen.



Maintenance:
Inhalation, 30 to 70% with oxygen.


For obstetrics or procedures not requiring loss of consciousness
Inhalation, 25 to 50% with oxygen.


Usual pediatric dose
Dosage must be individualized.

Product(s) usually available:
U.S.—


[Generic]

Canada—


[Generic]

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



Revised: 06/14/99



References
  1. Halothane package insert (Halocarbon Laboratories), Rev 4/93, Rec 5/99.
  1. Enflurane package insert (Ethrane—Ohmeda), Rev 7/95, Rec 10/95.
  1. Halothane package insert (Fluothane—Wyeth-Ayerst), Rec 5/99.
  1. Isoflurane package insert (Forane—Ohmeda), Rev 7/95, Rec 10/95.
  1. Methoxyflurane package insert (Penthrane—Abbott), Rec 5/90.
  1. Richards W, Thompson J, Lewis G, et al. Cardiac arrest associated with halothane anesthesia in a patient receiving theophylline. Ann Allergy 1988; 61: 83-4.
  1. Stanley TH. Blood-pressure and pulse-rate responses to ketamine during general anesthesia. Anesthesiology 1973; 39: 648-9.
  1. Withington DE, Donati F, Bevan DR, et al. Potentiation of atracurium neuromuscular blockade by enflurane: time-course of effect. Anesth Analg 1991; 72: 469-73.
  1. Gauntlett IS, Koblin DD, Fahey MR, et al. Metabolism of isoflurane in patients receiving isoniazid. Anesth Analg 1989; 69: 245-9.
  1. Forrest JB, Buffington C, Cahalan MK, et al. A multi-centre clinical evaluation of isoflurane. Can Anaesth Soc J 1982; 29 Suppl:S1-69.
  1. Mazze RI, Woodruff RE, Heerdt ME. Isoniazid-induced enflurane defluorination in humans. Anesthesiology 1982; 57: 5-8.
  1. Rayburn, WF and Zuspan FP: Drug Therapy in Obstetrics and Gynecology; l982: 149-51.
  1. Rosenberg P, Kirves A. Miscarriages among operating theatre staff. Acta Anaesthesiol Scand 1973; 53: 37-42.
  1. Holmberg K, Lambert B, Lindstein J, et al. DNA and chromosomal alterations in lymphocytes of operating room personnel and inpatients before and after inhalational anaesthesia. Acta Anaesthesiol Scand 1982; 26: 531-9.
  1. Lewis JH, Zimmerman HJ, Ishak KG, et al. Enflurane hepatotoxicity. A clinicopathologic study of 24 cases. Ann Intern Med 1983; 98: 984-92.
  1. Cousins, M J. Halothane hepatitis: what's new? Drugs 1980; 19: 1-6.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 272.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 352.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 396.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 463.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 515.
  1. Urban BW. Differential effects of gaseous and volatile anaesthetics on sodium and potassium channels. Br J Anaesth 1993; 71: 25-38.
  1. Elliott JR, Elliott AA, Harper AA, et al. Effects of general anaesthetics on neuronal sodium and potassium channels. Gen Pharmacol 1992; 23: 1005-11.
  1. Chan MT, Mainland P, Gin T. Minimum alveolar concentration of halothane and enflurane are decreased in early pregnancy. Anesthesiology 1996; 85: 782-6.
  1. Chan MT, Gin T. Postpartum changes in minimum alveolar concentration of isoflurane. Anesthesiology 1995; 82: 1360-3.
  1. Zhou HH, Norman P, DeLima LG, et al. The minimum alveolar concentration of isoflurane in patients undergoing bilateral tubal ligation in the postpartum period. Anesthesiology 1995; 82: 1364-8.
  1. Baum J, Sachs G, Driesch C, et al. Carbon monoxide generation in carbon dioxide absorbents. Anesth Analg 1995; 81: 144-6.
  1. Tramer M, Moore A, McQuay H. Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 1996; 76: 186-93.
  1. Edwards RP, Miller RD, Roizen MF, et al. Cardiac responses to imipramine and pancuronium during anesthesia with halothane or enflurane. Anesthesiology 1979; 50: 421-5.
  1. Roth S, Pietrzyk Z, Crittenden AP. The effects of enflurane on ocular blood flow. Ocul Pharmacol 1993; 9: 251-6.
  1. Zindel G, Meistelman C, Gaudy JH. Effects of increasing enflurane concentrations on intraocular pressure. Br J Anaesth 1987; 59: 440-3.
  1. Varghese C, Chopra SK, Daniel R, et al. Intraocular pressure profile during general anesthesia. Ophthalmic Surg 1990; 21: 856-9.
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