TERRELL™ (Isoflurane, USP) Liquid
for Inhalation
DESCRIPTION
Isoflurane, USP, a nonflammable liquid administered by vaporizing, is
a general inhalation anesthetic drug. It is l-chloro-2,2,2-trifluoroethyl
difluoromethyl ether.
Some physical constants are:
Molecular weight 184.5
Boiling point at 760 mm Hg 48.5°C (uncorr.)
Refractive index n 20 D 1.2990-1.3005
Specific gravity 25°/25°C 1.496
Vapor pressure in mm Hg :
20°C 238
25°C 295
30°C 367
35°C 450
Partition coefficients at 37°C:
Water/gas 0.61
Blood/gas 1.43
Oil/gas 90.8
Partition coefficients at 25°C - rubber and plastic
Conductive rubber/gas 62.0
Butyl rubber/gas 75.0
Polyvinyl chloride/gas 110.0
Polyethylene/gas ~2.0
Polyurethane/gas ~1.4
Polyolefin/gas ~1.1
Butyl acetate/gas ~2.5
Purity by gas chromatography >99.9%
Lower limit of flammability in oxygen or nitrous oxide at 9 joules/sec.
and 23°C: None
Lower limit of flammability in oxygen or nitrous oxide at 900 joules/sec.
and 23°C : Greater than useful concentration in anesthesia.
Isoflurane is a clear, colorless, stable liquid containing no additives
or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal
odor. Isoflurane in one normal sodium methoxide-methanol solution, a
strong base, for over six months consumed essentially no alkali, indicative
of strong base stability. Isoflurane does not decompose in the presence
of soda lime, (at normal operating temperatures) and does not attack
aluminum, tin, brass, iron or copper.
CLINICAL PHARMACOLOGY
Isoflurane is an inhalation anesthetic. The MAC (Minimum Alveolar Concentration)
in man is as follows:
| Age |
100% Oxygen
|
70% N 2 O
|
| 26 ± 4 |
1.28
|
0.56
|
| 44 ± 7 |
1.15
|
0.50
|
| 64 ± 5 |
1.05
|
0.37
|
Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane
has a mild pungency which limits the rate of induction, although excessive
salivation or tracheobronchial secretions do not appear to be stimulated.
Pharyngeal and laryngeal reflexes are readily obtunded. The level of
anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound
respiratory depressant.
RESPIRATION MUST BE MONITORED CLOSELY AND SUPPORTED WHEN NECESSARY.
As anesthetic dose is increased, tidal volume decreases and respiratory
rate is unchanged. This depression is partially reversed by surgical
stimulation, even at deeper levels of anesthesia. Isoflurane evokes
a sigh response reminiscent of that seen with diethyl ether and enflurane,
although the frequency is less than with enflurane.
Blood pressure decreases with induction of
anesthesia but returns toward nor-mal with surgical stimulation. Progressive
increases in depth of anesthesia pro-duce corresponding decreases in
blood pressure. Nitrous oxide diminishes the inspiratory concentration
of isoflurane required to reach a desired level of anes-thesia and may
reduce the arterial hypotension seen with isoflurane alone. Heart rhythm
is remarkably stable. With controlled ventilation and normal PaCO2,
car-diac output is maintained despite increasing depth of anesthesia
primarily through an increase in heart rate which compensates for a
reduction in stroke volume. The hypercapnia which attends spontaneous
ventilation during isoflu-rane anesthesia further increases heart rate
and raises cardiac output above awake levels. Isoflurane does not sensitize
the myocardium to exogenously administered epinephrine in the dog. Limited
data indicate that subcutaneous injec-tion of 0.25 mg of epinephrine
(50 mL of 1:200,000 solution) does not produce an increase in ventricular
arrhythmias in patients anesthetized with isoflurane.
Muscle relaxation is often adequate for intra-abdominal
operations at normal levels of anesthesia. Complete muscle paralysis
can be attained with small doses of muscle relaxants. ALL COMMONLY USED
MUSCLE RELAXANTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT
BEING MOST PRO-FOUND WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses
the effect of nondepolarizing muscle relaxants in the presence of isoflurane.
All commonly used muscle relaxants are compatible with isoflurane.
Isoflurane can produce coronary vasodilation
at the arteriolar level in selected animal models 1,2 ; the drug is
probably also a coronary dilator in humans. Isoflurane, like some other
coronary arteriolar dilators, has been shown to divert blood from collateral
dependent myocardium to normally perfused areas in an animal model ("coronary
steal")3 . Clinical studies to date evaluating myocardial ischemia,
infarction and death as outcome parameters have not established that
the coronary arteriolar dilation property of isoflurane is associated
with coronary steal or myocardial ischemia in patients with coronary
artery disease 4,5,6,7.
Pharmacokinetics
Isoflurane undergoes minimal biotransformation in man. In the postanesthesia
period, only 0.17% of the isoflurane taken up can be recovered as urinary
metabolites.
INDICATIONS AND USAGE
Isoflurane may be used for induction and maintenance of general anesthesia.
Adequate data have not been developed to establish its application in
obstetrical anesthesia.
CONTRAINDICATIONS
Known sensitivity to isoflurane or to other halogenated agents.
Known or suspected genetic susceptibility
to malignant hyperthermia.
WARNINGS
Since levels of anesthesia may be altered easily and rapidly, only vaporizers
pro-ducing predictable concentrations should be used. Hypotension and
respiratory depression increase as anesthesia is deepened.
Increased blood loss comparable to that seen
with halothane has been observed in patients undergoing abortions.
Isoflurane markedly increases cerebral blood
flow at deeper levels of anesthe-sia. There may be a transient rise
in cerebral spinal fluid pressure which is fully reversible with hyperventilation.
PRECAUTIONS
General
As with any potent general anesthetic, isoflurane should only be administered
in an adequately equipped anesthetizing environment by those who are
familiar with the pharmacology of the drug and qualified by training
and experience to manage the anesthetized patient.
Regardless of the anesthetics employed, maintenance
of normal hemodynamics is important to the avoidance of myocardial ischemia
in patients with coronary artery disease 4,5,6,7.
Isoflurane, like some other inhalational anesthetics,
can react with desiccated carbon dioxide (CO2) absorbents to produce
carbon monoxide which may result in elevated levels of carboxyhemoglobin
in some patients. Case reports suggest that barium hydroxide lime and
soda lime become desiccated when fresh gases are passed through the
CO2 absorber canister at high flow rates over many hours or days. When
a clinician suspects that CO2 absorbent may be desiccated, it should
be replaced before the administration of isoflurane.
Information for Patients
Isoflurane, as well as other general anesthetics, may cause a slight
decrease in intellectual function for 2 or 3 days following anesthesia.
As with other anesthetics, small changes in moods and symptoms may persist
for up to 6 days after administration.
Laboratory Tests
Transient increases in BSP retention, blood glucose and serum creatinine
with decrease in BUN, serum cholesterol and alkaline phosphatase have
been observed.
Drug Interactions
Isoflurane potentiates the muscle relaxant effect of all muscle relaxants,
most notably nondepolarizing muscle relaxants, and MAC (minimum alveolar
concentration) is reduced by concomitant administration of N2O. (See
CLINICAL PHARMACOLOGY).
Carcinogenesis
Swiss ICR mice were given isoflurane to determine whether such exposure
might induce neoplasia. Isoflurane was given at 1/2 , 1/8 and 1/32 MAC
for four in-utero exposures and for 24 exposures to the pups during
the first nine weeks of life. The mice were killed at 15 months of age.
The incidence of tumors in these mice was the same as in untreated control
mice which were given the same background gases, but not the anesthetic.
Pregnancy, Teratogenic
Effects, Pregnancy Category C
Isoflurane has been shown to have a possible anesthetic-related fetotoxic
effect in mice when given in doses 6 times the human dose. There are
no adequate and well-controlled studies in pregnant women. Isoflurane
should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nursing
Mothers
It is not known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when
isoflurane is administered to a nursing woman.
Malignant Hyperthermia
In susceptible individuals, isoflurane anesthesia may trigger a skeletal
muscle hypermetabolic state leading to high oxygen demand and the clinical
syndrome known as malignant hyperthermia. The syndrome includes nonspecific
features such as muscle rigidity, tachycardia, tachypnea, cyanosis,
arrhythmias, and unstable blood pressure. (It should also be noted that
many of these nonspecific signs may appear with light anesthesia, acute
hypoxia, etc.) An increase in overall metabolism may be reflected in
an elevated temperature (which may rise rapidly early or late in the
case, but usually is not the first sign of augmented metabolism) and
an increased usage of the CO2 absorption system (hot canister).
PaO2 and pH may decrease, and hyperkalemia and a base deficit
may appear. Treatment includes discontinuance of triggering agents (e.g.,
isoflurane), administration of intravenous dantrolene sodium, and application
of supportive therapy. Such therapy includes vigorous efforts to restore
body temperature to normal, respiratory and circulatory support as indicated,
and management of electrolyte-fluid-acid-base derangements. (Consult
prescribing information for dantrolene sodium intravenous for additional
information on patient management.) Renal failure may appear later,
and urine flow should be sustained if possible.
ADVERSE
REACTIONS
Adverse reactions encountered in the administration of isoflurane are
in general dose dependent extensions of pharmacophysiologic effects
and include respiratory depression, hypotension and arrhythmias. Shivering,
nausea, vomiting and ileus have been observed in the postoperative period.
As with all other general anesthetics, transient
elevations in white blood count have been observed even in the absence
of surgical stress. See PRECAUTIONS for information regarding malignant
hyperthermia. During marketing, there have been rare reports of mild,
moderate and severe (some fatal) post-operative hepatic dysfunction.
The causal relationship is unknown.
OVERDOSAGE
In the event of overdosage, or what may appear to be overdosage, the
following action should be taken:
Stop drug administration, establish a clear airway and initiate assisted
or controlled ventilation with pure oxygen.
DOSAGE AND ADMINISTRATION
Premedication
Premedication should be selected according to the need of the individual
patient, taking into account that secretions are weakly stimulated by
isoflurane and the heart rate tends to be increased. The use of anticholinergic
drugs is a matter of choice.
Inspired Concentration
The concentration of isoflurane being delivered from a vaporizer during
anesthesia should be known. This may be accomplished by using:
a) vaporizers calibrated specifically for isoflurane;
b) vaporizers from which delivered flows can be calculated, such as
vaporizers delivering a saturated vapor which is then diluted. The delivered
concentration from such a vaporizer may be calculated using the formula:
% isoflurane = 100 PVFV / FT(PA
- PV)
where:
PA = Pressure of atmosphere
PV = Vapor pressure of isoflurane
FV = Flow of gas through vaporizer (mL/min)
FT = Total gas flow (mL/min)
Isoflurane contains no stabilizer. Nothing
in the agent alters calibration or operation of these vaporizers.
Induction
Induction with isoflurane in oxygen or in combination with oxygen-nitrous
oxide mixtures may produce coughing, breath holding, or laryngospasm.
These difficulties may be avoided by the use of a hypnotic dose of an
ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3.0%
isoflurane usually produce surgical anesthesia in 7 to 10 minutes.
Maintenance
Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration
when nitrous oxide is used concomitantly. An additional 0.5 to 1.0%
may be required when isoflurane is given using oxygen alone. If added
relaxation is required, supplemental doses of muscle relaxants may be
used.
The level of blood pressure during maintenance
is an inverse function of isoflurane concentration in the absence of
other complicating problems. Excessive decreases may be due to depth
of anesthesia and in such instances may be corrected by lightening anesthesia.
HOW SUPPLIED
Isoflurane, USP is packaged in 100 mL AND 250 ML amber-colored bottles.
100 ML - NDC 60307-110-10
250 ML - NDC 60307-110-25
Storage
Store at controlled room temperature 15° to 30°C (59° to
86°F). Isoflurane, USP contains no additives.
References
1. JC Sill, et al, Anesthesiology 66:273-279, 1987
2. RF Hickey, et al, Anesthesiology 68:21-30, 1988
3. CW Buffington, et al, Anesthesiology 66:280-292, 1987
4. S Reiz, et al, Anesthesiology 59:91-97, 1983
5. S Slogoff and AS Keats, Anesthesiology 70:179-188, 1989
6. KJ Tuman, et al, Anesthesiology 70:189-198, 1989
7. DT Mangano, Editorial Views, Anesthesiology 70:175-178, 1989
