A SHORT PRIMER ON

SEVOFLURANE ANAESTHESIA

HISTORY OF SEVOFLURANE
First synthesized in 1968 by Regan at Travenol Labs, Illinois, while
investigating a series of halomethyl polyfluoroisopropyl ethers. The
compound was initially reported by his co-workers in 1971.
Holaday and Smith in 1981 reported first volunteer trials.
Further work was slowed because of problems of biotransformation
and stability with soda lime.

Baxter Travenol sold the rights to sevoflurane to Anaquest

(Ohmeda/BOC), who in turn sold these to Maruishi Company.

Sevoflurane released for clinical use in Japan in May 1990.

Properties of Sevoflurane

Chemical structure : fluorinated methyl isopropyl

ether

Molecular weight : 200.1

Boiling Point : 58.6 C

Vapour Pressure : 157 mmHg

Oil/Gas partition coefficient at 37 C : 47 54

Blood/Gas partition coefficient at 37 C : 0.65

Odour : Non Pungent

No preservative required

Minimum Alveolar Concentration

Infants 16 months
old
3.2%
Neonates
3.3%

MAC
(at 37 C
at 760
mmHg)

Children
>6
months
2.5%
Adults
2.05%

During
During
storage
storage
Dry
where
where
formulation
concentration
concentration
containing <
of added
of
added
is <100
<100
130 ppm
Hence,
Hydrofuoric water is
water
Stored in
ppm it is
water
formulated acid corrodes
ppm
it
is
polyethylene
susceptible to
to
available in
with 300
glass,
susceptible
naphthalate
attack by
attack
by
an
ppm of water
exposing
bottles
Lewis acids at
at
acids
aluminium
(acts as a
sevofurane Lewis
rather than
its ether
ether and
and
its
bottle lined
Lewis acid
to further
glass.
halogen
halogen
).
with an
inhibitor).
Lewis acids..
bonds,
bonds,
epoxyphenoli
releasing the
the
releasing
c resin
highly toxic
toxic
highly
lacquer..
hydrofuoric
hydrofuoric
acid (HF).
(HF).
acid

Respiratory effects
SEVOFLURANE
RESPIRATORY RATE

TIDAL VOLUME

PaCO2

VENTILATORY RESPONSE TO
CO2

AIRWAY IRRITATION

minimal;
causes moderate
bronchodilatation

Produces profound decreases in ventilation leading to

apnoea
between 1.5 and 2.0 MAC.
Potent bronchodilator and effects on hypoxic pulmonary
vasoconstriction small.

Anesthetic-induced tachypnea
compensates in part for the
ventilatory depression caused by
all volatile anesthetics (decrease
in minute ventilation and tidal
volume, and concomitant
increase in PaCO2). Desfurane
results in the greatest increase in
PaCO2 with corresponding
reductions in tidal volume and
minute ventilation. Isofurane,
like all other inhaled agents,
increases respiratory rate, but
does not result in dosedependent tachypnea.
(Adapted from: Lockhart SH, Rampil IJ, Yasuda N, et al.
Depression of ventilation by desfurane in humans.
Anesthesiology. 1991;74:484; Doi M, Ikeda K. Respiratory
effects of sevofurane. Anesth Analg. 1987;66:241; Fourcade
HE, Stevens WC, Larson CP Jr, et al. The ventilatory effects
of Forane, a new inhaled anesthetic. Anesthesiology.
1971;35:26)

Respiratory system resistance (Rrs) during the 10 min

after thiopental (baseline), separated by current smoking
status. Administration of desflurane to patients who are
smokers caused significant bronchoconstriction compared
with nonsmokers receiving desflurane (*P< 0.05).
From: Absence of Bronchodilation during Desflurane Anesthesia:A Comparison to Sevoflurane and Thiopental
Anesthesiology. 2000;93(2):404-408.

Cardiovascular effects
SEVOFLURANE

CONTRACTILITY
HEART RATE

(only at conc > 1.5

MAC)

SYSTEMIC VASCULAR RESISTANCE

BLOOD PRESSURE

CORONARY STEAL SYNDROME

SPLANCHNIC BLOOD FLOW
SENSITISATION TO
CATECHOLAMINES

no
unchanged
nil

Central Nervous System effects

SEVOFLURANE COMMENTS
CBF
ICP
CO2 RESPONSIVENESS
PRESERVING
AUTOREGULATION
CMO2
SEIZURES

+ upto 1.0
MAC
preserves upto
1.5
MAC

proconvulsant in
animal models

Minimal at
1 1.5 MAC
Mild at > 1
MAC

Metabolism and Toxicity

An estimated 5% of absorbed
sevoflurane undergoes
oxidative metabolism by
CYP2E1 enzymes at the
fluoromethoxy C-H bond to
form organic
(hexafluoroisopropanol) and
inorganic fluoride metabolites.

Hexafluoroisopropanol
undergoes conjugation with
glucoronic acid and this
conjugate is excreted in urine.
No evidence of toxicity .

The chemical structure of sevoflurane dictates

that it cannot undergo metabolism to acetyl
halide.

Metabolism does not produce trifluoroacetylated

liver proteins and does not stimulate formation of
antitrifluoroacetylated protein antibodies.

Therefore, sevoflurane is not expected to produce

immune mediated hepatitis or cause cross
sensitivity in patients previously exposed to
halothane.

Much ado over Compound A?

Halogenated anesthetics can undergo chemical breakdown

while interacting with CO2 absorbents that contain strong
bases such as NaOH and KOH, present in soda lime and
Baralyme.

Strong bases extract a proton from the isopropyl group of

sevoflurane, primarily forming a haloalkene (fluoromethyl-2,2difluoro-1-[trifluoromethyl] vinyl ether), known as compound
A.

Compound A is volatile and can be absorbed via alveolar gas

exchange.

Nephrotoxic in lab animals, causing PTN and, with sufficient

exposure, death.

Pts given sevoflurane anesthesia are routinely exposed to

compound A in rebreathing circuits, and inhaled conc is
dependent on the fresh gas flow rate and the type of CO2
absorbent present.

Fresh gas flows of 1 L/min result in maximal compound A

conc of approx 20 ppm & 30 ppm with soda lime and
Baralyme respectively.

Numerous studies in which human subjects or patients were

exposed to > 200 ppm-hours of compound A, reported that
clinical measures of renal function (BUN, creatinine, urinary
protein/ glucose, & urine concentrating ability) and lab tests
for subtle renal damage (N-acetyl--glucoaminidase, alanine
aminopeptidase, -GTP, and 2-microglobulin) remained
unchanged.

No threshold exposure level known to cause more than

subclinical renal damage.

Compound A exposure can be limited by careful selection

of fresh gas flows, vaporizer output, and CO2 absorbent
materials.

Use of 2 L/min fresh gas flows ensures exposure to

compound A below the most conservative threshold for
nephrotoxicity.

Use of higher flow rates increases washout of breakdown

products, while reducing rebreathing and producing lower
absorbent temperatures.

Carbon monoxide and Heat

Production of CO with sevoflurane requires nearly complete

desiccation of CO2 absorbent and produces the most heat.
Absorbent canister and anesthetic circuit can reach
extremely
high temperatures, leading to explosion or fire, or both.
CO produced when water content of soda lime or Baralyme
falls
below 1.4% and 5%, respectively.
CO accumulation in breathing circuit is inversely related to
FGF.
Associated with MONDAY MORNING PHENOMENON
Current recommendations machine maintenance and use
of absorbents that contain less KOH and NaOH.

Composition of base chemicals and water

content of carbon dioxide absorbents

Role in pediatric anaesthesia

Rate of induction more rapid with sevoflurane.

Less pungent than isoflurane and desflurane; may be

superior or equivalent to halothane for inhaled induction of
anesthesia.

MAC - 3.3% for neonates, 3.2% for infants 1 to 6 months

old, and 2.5% for children older than 6 months.

Sevoflurane and halothane equivalent in terms of airway

complications during induction of anesthesia .

Halothane produces a in tidal volume , in respiratory

rate, whereas sevoflurane decreases both the respiratory
rate and the tidal volume. Respirations may need to be
assisted during the early induction stage in sevofluraneanesthetized children.

SUMMARY STATISTICS FOR 17 STUDIES COMPARING THE CHARACTERISTICS OF SEVOFLURANE AND HALOTHANE

Major concern - EMERGENCE AGITATION .

Unrelated to pain and especially frequent in
children 5 years of age.
Incidence can be reduced with midazolam
and/or administration of clonidine (orally or
epidurally), ketorolac, fentanyl, or
dexmedetomidine.

Sevoflurane causes less myocardial depression as compared to

halothane.

When inducing anesthesia with sevoflurane with resultant apnea,

inspired conc of sevoflurane should be reduced while gently
assisting respirations. After intravenous access is established, a
decision must be made regarding continued management with just
a face mask, with a supraglottic airway , or with a tracheal tube.

If a supraglottic device is to be inserted, then propofol (1 mg/kg)

can be administered and device inserted 30 to 45 secs later.

Most children maintain spontaneous respiration from this dose of

propofol, whereas others become apneic and require assisted
ventilation for several minutes.

Techniques for endotracheal intubation

For a brief procedure, the
inspired conc of sevoflurane
is increased to 8% and
controlled ventilation is
instituted for a brief period
(1 to 2 mins) to rapidly
deepen the plane of
anesthesia.

When spontaneous
respirations cease,
propofol (1-2 mg/kg)
administered, the
vaporizer is shut off
and ET tube inserted.

If muscle relaxation
required, sevoflurane
administered with an
inspired concentration of
3.5% - 4% (lower for a
neonate). An appropriate
muscle relaxant is
administered and ET tube
inserted.
At this point, inspired
conc of sevoflurane
can be reduced or
changed to an
appropriate
concentration of
halothane or
isoflurane for
maintenance.

Why suitable for mask induction

Smooth, rapid induction, and

predictable recovery
Rapid adjustment of
anaesthetic depth
Stable haemodynamic profile
Patient acceptance due to
pleasant smell and minimal
respiratory irritation

Low risk of airway complications

Spontaneous ventilation
maintained
Neuromuscular blockade can be
avoided
Avoids problems of iv
access/needle phobia

Techniques of Mask Induction

1.
2.

Vital capacity induction

Tidal breathing

FGF rate 46 Lmin initially and to 3 L/min after 3 min.

FGF further reduced depending on clinical circumstances.

Rapid induction without excitation can be achieved using

vital capacity rapid inhalation ; an extended excitatory
phase avoided.

Using rapid induction, a patient exhales to residual volume

and inhales high concentrations of anesthetic up to vital
capacity .

Anesthetics currently used for vital capacity rapid inhalation

induction include sevoflurane and halothane

Conclusion

Sevoflurane possesses a number of characteristics that

approach those of the ideal anesthetic.
Versatile mask as well as iv induction
Suitable for all ages.
Low blood:gas solubility allows precise control over the
depth of anesthesia and a rapid, smooth induction and
recovery period.
Compatible with epinephrine
Can be used solely with Oxygen
Pleasant odour
Minimal airway irritation.
Can be used when intravenous access cannot be secured
or refused.
Can be used with standard vaporiser.