Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1172
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ULTANE (Liquid)
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The concentration of sevoflurane
being delivered from a vaporizer during anesthesia should be known.
This may be accomplished by using a vaporizer calibrated specifically
for sevoflurane. The administration of general anesthesia must be
individualized based on the patient's response.<br/>Replacement of Desiccated COAbsorbents: When a clinician
suspects that the COabsorbent may be desiccated, it should
be replaced. The exothermic reaction that occurs with sevoflurane
and COabsorbents is increased when the COabsorbent becomes desiccated, such as after an extended period of
dry gas flow through the COabsorbent canisters (see PRECAUTIONS).<br/>Pre-anesthetic Medication: No specific premedication
is either indicated or contraindicated with sevoflurane. The decision
as to whether or not to premedicate and the choice of premedication
is left to the discretion of the anesthesiologist.<br/>Induction: Sevoflurane has
a nonpungent odor and does not cause respiratory irritability; it
is suitable for mask induction in pediatrics and adults.<br/>Maintenance: Surgical levels
of anesthesia can usually be achieved with concentrations of 0.5 - 3% sevoflurane
with or without the concomitant use of nitrous oxide. Sevoflurane
can be administered with any type of anesthesia circuit.
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ULTANE (sevoflurane), volatile
liquid for inhalation, a nonflammable and nonexplosive liquid administered
by vaporization, is a halogenated general inhalation anesthetic drug.
Sevoflurane is fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl)
ethyl ether and its structural formula is:<br/>Sevoflurane, Physical Constants are::<br/>Distribution Partition Coefficients at 37��C::<br/>Mean Component/Gas Partition Coefficients at 25��C for
Polymers Used Commonly in Medical Applications:: Sevoflurane is
nonflammable and nonexplosive as defined by the requirements of International
Electrotechnical Commission 601-2-13. Sevoflurane
is a clear, colorless, liquid containing no additives. Sevoflurane
is not corrosive to stainless steel, brass, aluminum, nickel-plated
brass, chrome-plated brass or copper beryllium. Sevoflurane is nonpungent.
It is miscible with ethanol, ether, chloroform, and benzene, and it
is slightly soluble in water. Sevoflurane is stable when stored under
normal room lighting conditions according to instructions. No discernible
degradation of sevoflurane occurs in the presence of strong acids
or heat. When in contact with alkaline COabsorbents
(e.g Baralyme and to a lesser extent soda lime) within
the anesthesia machine, sevoflurane can undergo degradation under
certain conditions. Degradation of sevoflurane is minimal, and degradants
are either undetectable or present in non-toxic amounts when used
as directed with fresh absorbents. Sevoflurane degradation and subsequent
degradant formation are enhanced by increasing absorbent temperature
increased sevoflurane concentration, decreased fresh gas flow and
desiccated COabsorbents (especially with potassium hydroxide
containing absorbents e.g. Baralyme). Sevoflurane
alkaline degradation occurs by two pathways. The first results from
the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl
fluoromethyl ether, (PIFE, CHFO), also known as Compound A, and trace amounts of pentafluoromethoxy
isopropyl fluoromethyl ether, (PMFE, CHFO), also known as Compound B. The second pathway for degradation
of sevoflurane, which occurs primarily in the presence of desiccated
COabsorbents, is discussed later. In the first pathway, the defluorination pathway, the production
of degradants in the anesthesia circuit results from the extraction
of the acidic proton in the presence of a strong base (KOH and/or
NaOH) forming an alkene (Compound A) from sevoflurane similar to formation
of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane.
Laboratory simulations have shown that the concentration of these
degradants is inversely correlated with the fresh gas flow rate (See
Figure 1). Since the reaction of
carbon dioxide with absorbents is exothermic, the temperature increase
will be determined by quantities of COabsorbed, which
in turn will depend on fresh gas flow in the anesthesia circle system,
metabolic status of the patient, and ventilation. The relationship
of temperature produced by varying levels of COand Compound
A production is illustrated in the following in vitro simulation where COwas added to a
circle absorber system. Compound A concentration in a circle absorber system increases
as a function of increasing COabsorbent temperature and
composition (Baralyme producing higher levels than soda lime), increased
body temperature, and increased minute ventilation, and decreasing
fresh gas flow rates. It has been reported that the concentration
of Compound A increases significantly with prolonged dehydration of
Baralyme. Compound A exposure in patients also has been shown to
rise with increased sevoflurane concentrations and duration of anesthesia.
In a clinical study in which sevoflurane was administered to patients
under low flow conditions for���2 hours at flow rates of 1 Liter/minute,
Compound A levels were measured in an effort to determine the relationship
between MAC hours and Compound A levels produced. The relationship
between Compound A levels and sevoflurane exposure are shown in Figure
2a. Compound A has been shown to be nephrotoxic
in rats after exposures that have varied in duration from one to three
hours. No histopathologic change was seen at a concentration of up
to 270 ppm for one hour. Sporadic single cell necrosis of proximal
tubule cells has been reported at a concentration of 114 ppm after
a 3-hour exposure to Compound A in rats. The LCreported
at 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490
ppm (male-female). An experiment was performed
comparing sevoflurane plus 75 or 100 ppm Compound A with an active
control to evaluate the potential nephrotoxicity of Compound A in
non-human primates. A single 8-hour exposure of Sevoflurane in the
presence of Compound A produced single-cell renal tubular degeneration
and single-cell necrosis in cynomolgus monkeys. These changes are
consistent with the increased urinary protein, glucose level and enzymic
activity noted on days one and three on the clinical pathology evaluation.
This nephrotoxicity produced by Compound A is dose and duration of
exposure dependent. At a fresh gas flow rate
of 1 L/min, mean maximum concentrations of Compound A in the anesthesia
circuit in clinical settings are approximately 20 ppm (0.002%) with
soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean
maximum concentrations in pediatric patients with soda lime are about
half those found in adults. The highest concentration observed in
a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%)
with soda lime. The levels of Compound A at which toxicity occurs
in humans is not known. The second pathway for
degradation of sevoflurane occurs primarily in the presence of desiccated
COabsorbents and leads to the dissociation of sevoflurane
into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive,
non-genotoxic, rapidly glucuronidated and cleared by the liver. Formaldehyde
is present during normal metabolic processes. Upon exposure to a
highly desiccated absorbent, formaldehyde can further degrade into
methanol and formate. Formate can contribute to the formation of carbon
monoxide in the presence of high temperature that can be associated
with desiccated Baralyme. Methanol can react with
Compound A to form the methoxy addition product Compound B. Compound
B can undergo further HF elimination to form Compounds C, D, and E. Sevoflurane degradants were observed in the
respiratory circuit of an experimental anesthesia machine using desiccated
COabsorbents and maximum sevoflurane concentrations (8%)
for extended periods of time (>2 hours). Concentrations of formaldehyde
observed with desiccated soda lime in this experimental anesthesia
respiratory circuit were consistent with levels that could potentially
result in respiratory irritation. Although KOH containing COabsorbents are no longer commercially available, in the laboratory
experiments, exposure of sevoflurane to the desiccated KOH containing
COabsorbent, Baralyme, resulted in the detection of substantially
greater degradant levels.
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Sevoflurane is an inhalational anesthetic agent for
use in induction and maintenance of general anesthesia. Minimum alveolar
concentration (MAC) of sevoflurane in oxygen for a 40-year-old adult
is 2.1%. The MAC of sevoflurane decreases with age (see DOSAGE AND
ADMINISTRATION for details).<br/>Pharmacokinetics:<br/>Uptake and Distribution:<br/>Metabolism: Sevoflurane
is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP)
with release of inorganic fluoride and CO. Once formed
HFIP is rapidly conjugated with glucuronic acid and eliminated as
a urinary metabolite. No other metabolic pathways for sevoflurane
have been identified. In vivo metabolism studies suggest that approximately 5% of the sevoflurane
dose may be metabolized. Cytochrome P450 2E1 is the principal isoform identified for sevoflurane
metabolism and this may be induced by chronic exposure to isoniazid
and ethanol. This is similar to the metabolism of isoflurane and
enflurane and is distinct from that of methoxyflurane which is metabolized
via a variety of cytochrome P450 isoforms. The metabolism of sevoflurane
is not inducible by barbiturates. As shown in Figure 5, inorganic
fluoride concentrations peak within 2 hours of the end of sevoflurane
anesthesia and return to baseline concentrations within 48 hours post-anesthesia
in the majority of cases (67%). The rapid and extensive pulmonary
elimination of sevoflurane minimizes the amount of anesthetic available
for metabolism. Cousins M.J.,
Greenstein L.R., Hitt B.A., et al: Metabolism and renal effects of
enflurane in man. Anesthesiology 44:44; 1976* and Sevo-93-044. Legend:Pre-Anesth. = Pre-anesthesia<br/>Elimination: Up to 3.5%
of the sevoflurane dose appears in the urine as inorganic fluoride.
Studies on fluoride indicate that up to 50% of fluoride clearance
is nonrenal (via fluoride being taken up into bone).<br/>Pharmacokinetics of Fluoride Ion: Fluoride ion concentrations
are influenced by the duration of anesthesia, the concentration of
sevoflurane administered, and the composition of the anesthetic gas
mixture. In studies where anesthesia was maintained purely with sevoflurane
for periods ranging from 1 to 6 hours, peak fluoride concentrations
ranged between 12��M and 90��M. As shown in Figure
6, peak concentrations occur within 2 hours of the end of anesthesia
and are less than 25��M (475 ng/mL) for the majority of the population
after 10 hours. The half-life is in the range of 15-23 hours. It has been reported that
following administration of methoxyflurane, serum inorganic fluoride
concentrations>50��M were correlated with the development of
vasopressin-resistant, polyuric, renal failure. In clinical trials
with sevoflurane, there were no reports of toxicity associated with
elevated fluoride ion levels.<br/>Fluoride Concentrations After Repeat Exposure and in Special
Populations: Fluoride
concentrations have been measured after single, extended, and repeat
exposure to sevoflurane in normal surgical and special patient populations,
and pharmacokinetic parameters were determined. Compared with healthy individuals, the fluoride ion half-life was
prolonged in patients with renal impairment, but not in the elderly.
A study in 8 patients with hepatic impairment suggests a slight prolongation
of the half-life. The mean half-life in patients with renal impairment
averaged approximately 33 hours (range 21-61 hours) as compared to
a mean of approximately 21 hours (range 10-48 hours) in normal healthy
individuals. The mean half-life in the elderly (greater than 65 years)
approximated 24 hours (range 18-72 hours). The mean half-life in
individuals with hepatic impairment was 23 hours (range 16-47 hours).
Mean maximal fluoride values (C) determined in individual
studies of special populations are displayed below.<br/>Pharmacodynamics: Changes in the depth
of sevoflurane anesthesia rapidly follow changes in the inspired concentration. In the sevoflurane clinical
program, the following recovery variables were evaluated: 1. Time to events measured from the end
of study drug: 2. Recovery of cognitive function
and motor coordination was evaluated based on: 3. Other recovery times were: Some of these variables are summarized as follows:<br/>Cardiovascular Effects: Sevoflurane was
studied in 14 healthy volunteers (18-35 years old) comparing sevoflurane-O(Sevo/O) to sevoflurane-NO/O(Sevo/NO/O) during 7 hours of anesthesia.
During controlled ventilation, hemodynamic parameters measured are
shown in Figures 7-10: Sevoflurane is a dose-related
cardiac depressant. Sevoflurane does not produce increases in heart
rate at doses less than 2 MAC. A study investigating the epinephrine induced arrhythmogenic effect
of sevoflurane versus isoflurane in adult patients undergoing transsphenoidal
hypophysectomy demonstrated that the threshold dose of epinephrine
(i.e., the dose at which the first sign of arrhythmia was observed)
producing multiple ventricular arrhythmias was 5 mcg/kg with both
sevoflurane and isoflurane. Consequently, the interaction of sevoflurane
with epinephrine appears to be equal to that seen with isoflurane.<br/>Clinical Trials: Sevoflurane was
administered to a total of 3185 patients prior to sevoflurane NDA
submission. The types of patients are summarized as follows: Clinical experience
with these patients is described below.<br/>Adult Anesthesia: The efficacy
of sevoflurane in comparison to isoflurane, enflurane, and propofol
was investigated in 3 outpatient and 25 inpatient studies involving
3591 adult patients. Sevoflurane was found to be comparable to isoflurane,
enflurane, and propofol for the maintenance of anesthesia in adult
patients. Patients administered sevoflurane showed shorter times
(statistically significant) to some recovery events (extubation, response
to command, and orientation) than patients who received isoflurane
or propofol.<br/>Pediatric Anesthesia: The concentration
of sevoflurane required for maintenance of general anesthesia is age-dependent
(see DOSAGE AND ADMINISTRATION). Sevoflurane or halothane was used to anesthetize 1620 pediatric
patients aged 1 day to 18 years, and ASA physical status I or II (948
sevoflurane, 672 halothane). In one study involving 90 infants and
children, there were no clinically significant decreases in heart
rate compared to awake values at 1 MAC. Systolic blood pressure decreased
15-20% in comparison to awake values following administration of 1
MAC sevoflurane; however, clinically significant hypotension requiring
immediate intervention did not occur. Overall incidences of bradycardia
[more than 20 beats/min lower than normal (80 beats/min)] in comparative
studies was 3% for sevoflurane and 7% for halothane. Patients who
received sevoflurane had slightly faster emergence times (12 vs. 19
minutes), and a higher incidence of post-anesthesia agitation (14%
vs. 10%). Sevoflurane (n = 91) was compared to halothane (n = 89) in a single-center
study for elective repair or palliation of congenital heart disease.
The patients ranged in age from 9 days to 11.8 years with an
ASA physical status of II, III, and IV (18%, 68%, and 13% respectively).
No significant differences were demonstrated between treatment groups
with respect to the primary outcome measures: cardiovascular decompensation
and severe arterial desaturation. Adverse event data was limited
to the study outcome variables collected during surgery and before
institution of cardiopulmonary bypass.<br/>Cardiovascular Surgery:<br/>Cesarean Section: Sevoflurane
(n = 29) was compared to isoflurane (n = 27) in ASA Class I or II
patients for the maintenance of anesthesia during cesarean section.
Newborn evaluations and recovery events were recorded. With both
anesthetics, Apgar scores averaged 8 and 9 at 1 and 5 minutes,
respectively. Use of sevoflurane as part of general anesthesia for elective cesareansection produced no untoward effects in mother or neonate. Sevoflurane
and isoflurane demonstrated equivalent recovery characteristics.
There was no difference between sevoflurane and isoflurane with regard
to the effect on the newborn, as assessed by Apgar Score and Neurological
and Adaptive Capacity Score (average = 29.5). The safety of sevoflurane
in labor and vaginal delivery has not been evaluated.<br/>Neurosurgery: Three studies
compared sevoflurane to isoflurane for maintenance of anesthesia during
neurosurgical procedures. In a study of 20 patients, there was no
difference between sevoflurane and isoflurane with regard to recovery
from anesthesia. In 2 studies, a total of 22 patients with intracranial
pressure (ICP) monitors received either sevoflurane or isoflurane.
There was no difference between sevoflurane and isoflurane with regard
to ICP response to inhalation of 0.5, 1.0, and 1.5 MAC inspired concentrations
of volatile agent during NO-O-fentanyl anesthesia.
During progressive hyperventilation from PaCO= 40 to
PaCO= 30, ICP response to hypocarbia was preserved with
sevoflurane at both 0.5 and 1.0 MAC concentrations. In patients at
risk for elevations of ICP, sevoflurane should be administered cautiously
in conjunction with ICP-reducing maneuvers such as hyperventilation.<br/>Hepatic Impairment: A multicenter
study (2 sites) compared the safety of sevoflurane and isoflurane
in 16 patients with mild-to-moderate hepatic impairment utilizing
the lidocaine MEGX assay for assessment of hepatocellular function.
All patients received intravenous propofol (1-3 mg/kg) or thiopental
(2-7 mg/kg) for induction and succinylcholine, vecuronium, or atracurium
for intubation. Sevoflurane or isoflurane was administered in either
100% Oor up to 70% NO/O. Neither
drug adversely affected hepatic function. No serum inorganic fluoride
level exceeded 45��M/L, but sevoflurane patients had prolonged
terminal disposition of fluoride, as evidenced by longer inorganic
fluoride half-life than patients with normal hepatic function (23
hours vs. 10-48 hours).<br/>Renal Impairment: Sevoflurane
was evaluated in renally impaired patients with baseline serum creatinine>1.5 mg/dL. Fourteen patients who received sevoflurane were
compared with 12 patients who received isoflurane. In another
study, 21 patients who received sevoflurane were compared with 20
patients who received enflurane. Creatinine levels increased in 7%
of patients who received sevoflurane, 8% of patients who received
isoflurane, and 10% of patients who received enflurane. Because of
the small number of patients with renal insufficiency (baseline serum
creatinine greater than 1.5 mg/dL) studied, the safety of sevoflurane
administration in this group has not yet been fully established.
Therefore, sevoflurane should be used with caution in patients with
renal insufficiency (see WARNINGS ).
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Sevoflurane can cause malignant
hyperthermia. It should not be used in patients with known sensitivity
to sevoflurane or to other halogenated agents nor in patients with
known or suspected susceptibility to malignant hyperthermia.
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ULTANE (sevoflurane), Volatile
Liquid for Inhalation, is packaged in amber colored bottles containing
250 mL sevoflurane, List 4456, NDC # 0074-4456-04 (plastic).
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In the event of overdosage,
or what may appear to be overdosage, the following action should be
taken: discontinue administration of sevoflurane, maintain a patent
airway, initiate assisted or controlled ventilation with oxygen, and
maintain adequate cardiovascular function.
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sevoflurane
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ULTANE (Liquid)
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Adverse events are derived
from controlled clinical trials conducted in the United States,
Canada, and Europe. The reference drugs were isoflurane, enflurane,
and propofol in adults and halothane in pediatric patients. The studies
were conducted using a variety of premedications, other anesthetics,
and surgical procedures of varying length. Most adverse events reported
were mild and transient, and may reflect the surgical procedures,
patient characteristics (including disease) and/or medications administered. Of the 5182 patients enrolled in
the clinical trials, 2906 were exposed to sevoflurane, including 118
adults and 507 pediatric patients who underwent mask induction. Each
patient was counted once for each type of adverse event. Adverse
events reported in patients in clinical trials and considered to be
possibly or probably related to sevoflurane are presented within each
body system in order of decreasing frequency in the following listings.
One case of malignant hyperthermia was reported in pre-registration
clinical trials.<br/>Adverse Events During the Induction Period (from Onset of Anesthesia
by Mask Induction to Surgical Incision) Incidence>1%:<br/>Adult Patients (N = 118):<br/>Pediatric Patients (N = 507):<br/>Adverse Events During Maintenance and Emergence Periods, Incidence>1% (N = 2906):<br/>Body as a whole: Fever 1%,
Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1%<br/>Cardiovascular: Hypotension
11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2%<br/>Nervous System: Somnolence
9%, Agitation 9%, Dizziness 4%, Increased salivation 4%<br/>Digestive System: Nausea 25%,
Vomiting 18%<br/>Respiratory System: Cough increased
11%, Breathholding 2%, Laryngospasm 2%<br/>Adverse Events, All Patients in Clinical Trials (N = 2906),
All Anesthetic Periods, Incidence<1% (Reported in 3 or More
Patients):<br/>Body as a whole: Asthenia,
Pain<br/>Cardiovascular: Arrhythmia,
Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete
AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation,
Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed<br/>Nervous System: Crying,
Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia<br/>Respiratory System: Sputum Increased,
Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis,
Hiccup, Hypoventilation, Dyspnea, Stridor<br/>Metabolism and Nutrition: Increases
in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia,
Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia<br/>Hemic and Lymphatic System: Leucocytosis,
Thrombocytopenia<br/>Skin and Special Senses: Amblyopia,
Pruritus, Taste Perversion, Rash, Conjunctivitis<br/>Urogenital: Urination
Impaired, Urine Abnormality, Urinary Retention, Oliguria See WARNINGS for information regarding malignant
hyperthermia.<br/>Adverse Events During Post-Marketing Experience: Post-marketing reports
indicate that sevoflurane use has been associated with seizures.
The majority of cases were in children and young adults, most of whom
had no medical history of seizures. Several cases reported no concomitant
medications, and at least one case was confirmed by EEG. Although
many cases were single seizures that resolved spontaneously or aftertreatment, cases of multiple seizures have also been reported. Seizures
have occurred during, or soon after sevoflurane induction, during
emergence, and during post-operative recovery up to a day following
anesthesia. Rare
cases of malignant hyperthermia (see CONTRAINDICATIONS
and WARNINGS) and
allergic reactions, such as rash, urticaria, pruritis, bronchospasm,
anaphylactic or anaphylactoid reactions (see CONTRAINDICATIONS) have been reported. Very rare cases of mild, moderate and severe post-operative hepatic
dysfunction or hepatitis with or without jaundice have been reported.
Histological evidence was not provided for any of the reported hepatitis
cases. In most of these cases, patients had underlying hepatic conditions
or were under treatment with drugs known to cause hepatic dysfunction.
Most of the reported events were transient and resolved spontaneously
(see PRECAUTIONS). In addition,
there have been rare post-marketing reports of hepatic failure and
hepatic necrosis associated with the use of potent volatile anesthetic
agents, including sevoflurane. However, the actual incidence and
relationship of sevoflurane to these events cannot be established
with certainty.<br/>Laboratory Findings: Transient elevations
in glucose, liver function tests, and white blood cell count may occur
as with use of other anesthetic agents.
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Although data from controlled
clinical studies at low flow rates are limited, findings taken from
patient and animal studies suggest that there is a potential for renal
injury which is presumed due to Compound A. Animal and human studies
demonstrate that sevoflurane administered for more than 2 MAC��hours
and at fresh gas flow rates of<2 L/min may be associated
with proteinuria and glycosuria. While a level of Compound A exposure at which clinical nephrotoxicity
might be expected to occur has not been established, it is prudent
to consider all of the factors leading to Compound A exposure in humans,
especially duration of exposure, fresh gas flow rate, and concentration
of sevoflurane. During sevoflurane anesthesia the clinician should
adjust inspired concentration and fresh gas flow rate to minimize
exposure toCompound A. To minimize exposure to Compound A, sevoflurane
exposure should not exceed 2 MAC��hours at flow rates of 1 to<2 L/min. Fresh gas flow rates<1 L/min are not
recommended. Because clinical
experience in administering sevoflurane to patients with renal insufficiency
(creatinine>1.5 mg/dL) is limited, its safety in these patients
has not been established. Sevoflurane may be associated with glycosuria and proteinuria when
used for long procedures at low flow rates. The safety of low flow
sevoflurane on renal function was evaluated in patients with normal
preoperative renal function. One study compared sevoflurane (N =
98) to an active control (N = 90) administered for���2 hours
at a fresh gas flow rate of���1 Liter/minute. Per study defined
criteria (Hou et al.) one patient in the sevoflurane group developed
elevations of creatinine, in addition to glycosuria and proteinuria.
This patient received sevoflurane at fresh gas flow rates of���800 mL/minute.
Using these same criteria, there were no patients in the active control
group who developed treatment emergent elevations in serum creatinine. Sevoflurane may present an increased risk in patients
with known sensitivity to volatile halogenated anesthetic agents.
KOH containing COabsorbents are not recommended for use
with sevoflurane.<br/>Malignant Hyperthermia: In susceptible individuals,
potent inhalation anesthetic agents, including sevoflurane, may trigger
a skeletal muscle hypermetabolic state leading to high oxygen demand
and the clinical syndrome known as malignant hyperthermia. In clinical
trials, one case of malignant hyperthermia was reported. In genetically
susceptible pigs, sevoflurane induced malignant hyperthermia. The
clinical syndrome is signaled by hypercapnia, and may include muscle
rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable
blood pressure. Some of these nonspecific signs may also appear during
light anesthesia, acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia
includes discontinuation of triggering agents, administration of intravenous
dantrolene sodium, and application of supportive therapy. (Consult
prescribing information for dantrolene sodium intravenous for additional
information on patient management.) Renal failure may appear later,
and urine flow should be monitored and sustained if possible.<br/>Perioperative Hyperkalemia: Use of inhaled anesthetic agents has been associated
with rare increases in serum potassium levels that have resulted in
cardiac arrhythmias and death in pediatric patients during the postoperative
period. Patients with latent as well as overt neuromuscular disease,
particularly Duchenne muscular dystrophy, appear to be most vulnerable.
Concomitant use of succinylcholine has been associated with most,but not all, of these cases. These patients also experienced significant
elevations in serum creatine kinase levels and, in some cases, changes
in urine consistent with myoglobinuria. Despite the similarity in
presentation to malignant hyperthermia, none of these patients exhibited
signs or symptoms of muscle rigidity or hypermetabolic state. Early
and aggressive intervention to treat the hyperkalemia and resistant
arrhythmias is recommended; as is subsequent evaluation for latent
neuromuscular disease.
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Sevoflurane is indicated
for induction and maintenance of general anesthesia in adult and pediatric
patients for inpatient and outpatient surgery. Sevoflurane should be administered only by persons trained in the
administration of general anesthesia. Facilities for maintenance
of a patent airway, artificial ventilation, oxygen enrichment, and
circulatory resuscitation must be immediately available. Since level
of anesthesia may be altered rapidly, only vaporizers producing predictable
concentrations of sevoflurane should be used.
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ULTANE
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