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Ultane Drug Description
ULTANE®
(sevoflurane) Volatile Liquid for Inhalation
NOVAPLUS™
DRUG DESCRIPTION
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:








Sevoflurane, Physical Constants are:



Molecular weight
200.05


Boiling point at 760 mm Hg
58.6°C


Specific gravity at 20°C
1.520 - 1.525


Vapor pressure in mm Hg
157 mm Hg at 20°C


197 mm Hg at 25°C


317 mm Hg at 36°C


Distribution Partition Coefficients at 37°C:



Blood/Gas
0.63 - 0.69


Water/Gas
0.36


Olive Oil/Gas
47 聳 54


Brain/Gas
1.15


Mean Component/Gas Partition Coefficients at 25°C for Polymers Used
Commonly in Medical Applications:



Conductive rubber
14.0


Butyl rubber
7.7


Polyvinylchloride
17.4


Polyethylene
1.3


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 CO2 absorbents (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 CO2
absorbents (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, C4H2F6O), also known
as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl
ether, (PMFE, C5H6F6O), also known as Compound
B. The second pathway for degradation of sevoflurane, which occurs primarily
in the presence of desiccated CO2 absorbents, 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).
Figure 1. Fresh Gas Flow Rate versus Compound A Levels in
a Circle Absorber System







Since the reaction of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed, 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 CO2 and Compound A production is illustrated
in the following in vitro simulation where CO2 was added to
a circle absorber system.
Figure 2. Carbon Dioxide Flow versus Compound A and Maximum
Temperature







Compound A concentration in a circle absorber system increases as a function
of increasing CO2 absorbent 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.
Figure 2a. ppm路hr versus MAC·hr at Flow Rate of 1 L/min







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 LC50 reported 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 CO2 absorbents 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 CO2 absorbents 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 CO2 absorbents
are no longer commercially available, in the laboratory experiments, exposure
of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme,
resulted in the detection of substantially greater degradant levels.Last reviewed on RxList: 2/10/2010




Ultane Drug Description
ULTANE®
(sevoflurane) Volatile Liquid for Inhalation
NOVAPLUS™
DRUG DESCRIPTION
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:








Sevoflurane, Physical Constants are:



Molecular weight
200.05


Boiling point at 760 mm Hg
58.6°C


Specific gravity at 20°C
1.520 - 1.525


Vapor pressure in mm Hg
157 mm Hg at 20°C


197 mm Hg at 25°C


317 mm Hg at 36°C


Distribution Partition Coefficients at 37°C:



Blood/Gas
0.63 - 0.69


Water/Gas
0.36


Olive Oil/Gas
47 聳 54


Brain/Gas
1.15


Mean Component/Gas Partition Coefficients at 25°C for Polymers Used
Commonly in Medical Applications:



Conductive rubber
14.0


Butyl rubber
7.7


Polyvinylchloride
17.4


Polyethylene
1.3


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 CO2 absorbents (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 CO2
absorbents (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, C4H2F6O), also known
as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl
ether, (PMFE, C5H6F6O), also known as Compound
B. The second pathway for degradation of sevoflurane, which occurs primarily
in the presence of desiccated CO2 absorbents, 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).
Figure 1. Fresh Gas Flow Rate versus Compound A Levels in
a Circle Absorber System







Since the reaction of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed, 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 CO2 and Compound A production is illustrated
in the following in vitro simulation where CO2 was added to
a circle absorber system.
Figure 2. Carbon Dioxide Flow versus Compound A and Maximum
Temperature







Compound A concentration in a circle absorber system increases as a function
of increasing CO2 absorbent 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.
Figure 2a. ppm路hr versus MAC·hr at Flow Rate of 1 L/min







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 LC50 reported 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 CO2 absorbents 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 CO2 absorbents 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 CO2 absorbents
are no longer commercially available, in the laboratory experiments, exposure
of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme,
resulted in the detection of substantially greater degradant levels.Last reviewed on RxList: 2/10/2010




Ultane Drug Description
ULTANE®
(sevoflurane) Volatile Liquid for Inhalation
NOVAPLUS™
DRUG DESCRIPTION
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:








Sevoflurane, Physical Constants are:



Molecular weight
200.05


Boiling point at 760 mm Hg
58.6°C


Specific gravity at 20°C
1.520 - 1.525


Vapor pressure in mm Hg
157 mm Hg at 20°C


197 mm Hg at 25°C


317 mm Hg at 36°C


Distribution Partition Coefficients at 37°C:



Blood/Gas
0.63 - 0.69


Water/Gas
0.36


Olive Oil/Gas
47 聳 54


Brain/Gas
1.15


Mean Component/Gas Partition Coefficients at 25°C for Polymers Used
Commonly in Medical Applications:



Conductive rubber
14.0


Butyl rubber
7.7


Polyvinylchloride
17.4


Polyethylene
1.3


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 CO2 absorbents (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 CO2
absorbents (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, C4H2F6O), also known
as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl
ether, (PMFE, C5H6F6O), also known as Compound
B. The second pathway for degradation of sevoflurane, which occurs primarily
in the presence of desiccated CO2 absorbents, 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).
Figure 1. Fresh Gas Flow Rate versus Compound A Levels in
a Circle Absorber System







Since the reaction of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed, 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 CO2 and Compound A production is illustrated
in the following in vitro simulation where CO2 was added to
a circle absorber system.
Figure 2. Carbon Dioxide Flow versus Compound A and Maximum
Temperature







Compound A concentration in a circle absorber system increases as a function
of increasing CO2 absorbent 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.
Figure 2a. ppm路hr versus MAC·hr at Flow Rate of 1 L/min







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 LC50 reported 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 CO2 absorbents 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 CO2 absorbents 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 CO2 absorbents
are no longer commercially available, in the laboratory experiments, exposure
of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme,
resulted in the detection of substantially greater degradant levels.Last reviewed on RxList: 2/10/2010




Ultane Drug Description
ULTANE®
(sevoflurane) Volatile Liquid for Inhalation
NOVAPLUS™
DRUG DESCRIPTION
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:








Sevoflurane, Physical Constants are:



Molecular weight
200.05


Boiling point at 760 mm Hg
58.6°C


Specific gravity at 20°C
1.520 - 1.525


Vapor pressure in mm Hg
157 mm Hg at 20°C


197 mm Hg at 25°C


317 mm Hg at 36°C


Distribution Partition Coefficients at 37°C:



Blood/Gas
0.63 - 0.69


Water/Gas
0.36


Olive Oil/Gas
47 聳 54


Brain/Gas
1.15


Mean Component/Gas Partition Coefficients at 25°C for Polymers Used
Commonly in Medical Applications:



Conductive rubber
14.0


Butyl rubber
7.7


Polyvinylchloride
17.4


Polyethylene
1.3


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 CO2 absorbents (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 CO2
absorbents (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, C4H2F6O), also known
as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl
ether, (PMFE, C5H6F6O), also known as Compound
B. The second pathway for degradation of sevoflurane, which occurs primarily
in the presence of desiccated CO2 absorbents, 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).
Figure 1. Fresh Gas Flow Rate versus Compound A Levels in
a Circle Absorber System







Since the reaction of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed, 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 CO2 and Compound A production is illustrated
in the following in vitro simulation where CO2 was added to
a circle absorber system.
Figure 2. Carbon Dioxide Flow versus Compound A and Maximum
Temperature







Compound A concentration in a circle absorber system increases as a function
of increasing CO2 absorbent 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.
Figure 2a. ppm路hr versus MAC·hr at Flow Rate of 1 L/min







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 LC50 reported 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 CO2 absorbents 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 CO2 absorbents 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 CO2 absorbents
are no longer commercially available, in the laboratory experiments, exposure
of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme,
resulted in the detection of substantially greater degradant levels.Last reviewed on RxList: 2/10/2010




Ultane Drug Description
ULTANE®
(sevoflurane) Volatile Liquid for Inhalation
NOVAPLUS™
DRUG DESCRIPTION
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:








Sevoflurane, Physical Constants are:



Molecular weight
200.05


Boiling point at 760 mm Hg
58.6°C


Specific gravity at 20°C
1.520 - 1.525


Vapor pressure in mm Hg
157 mm Hg at 20°C


197 mm Hg at 25°C


317 mm Hg at 36°C


Distribution Partition Coefficients at 37°C:



Blood/Gas
0.63 - 0.69


Water/Gas
0.36


Olive Oil/Gas
47 聳 54


Brain/Gas
1.15


Mean Component/Gas Partition Coefficients at 25°C for Polymers Used
Commonly in Medical Applications:



Conductive rubber
14.0


Butyl rubber
7.7


Polyvinylchloride
17.4


Polyethylene
1.3


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 CO2 absorbents (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 CO2
absorbents (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, C4H2F6O), also known
as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl
ether, (PMFE, C5H6F6O), also known as Compound
B. The second pathway for degradation of sevoflurane, which occurs primarily
in the presence of desiccated CO2 absorbents, 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).
Figure 1. Fresh Gas Flow Rate versus Compound A Levels in
a Circle Absorber System







Since the reaction of carbon dioxide with absorbents is exothermic, the temperature
increase will be determined by quantities of CO2 absorbed, 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 CO2 and Compound A production is illustrated
in the following in vitro simulation where CO2 was added to
a circle absorber system.
Figure 2. Carbon Dioxide Flow versus Compound A and Maximum
Temperature







Compound A concentration in a circle absorber system increases as a function
of increasing CO2 absorbent 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.
Figure 2a. ppm路hr versus MAC·hr at Flow Rate of 1 L/min







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 LC50 reported 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 CO2 absorbents 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 CO2 absorbents 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 CO2 absorbents
are no longer commercially available, in the laboratory experiments, exposure
of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme,
resulted in the detection of substantially greater degradant levels.Last reviewed on RxList: 2/10/2010





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