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18
Anaesthesia
and
neuromuscular
block
SYNOPSIS
The
administration
of
general anaesthetics
and
neuromuscular
blocking
drugs
is
generally
confined
to
trained
specialists.
Nevertheless,
nonspecialists
are
involved
in
perioperative
care
and
will
benefit
from
an
understanding
of
how
these drugs act.
Doctors
from
a
variety
of
specialties
use
local anaesthetics
and the
pharmacology
of
these drugs
is
discussed
in
detail.
General anaesthesia
Pharmacology
of
anaesthetics
Inhalation
anaesthetics
Intravenous anaesthetics
Muscle
relaxants: neuromuscular
blocking
drugs
Local anaesthetics
Obstetric
analgesia
and
anaesthesia
Anaesthesia
in
patients
already
taking
drugs
Anaesthesia
in the
diseased,
the
elderly
and
children;
sedation
in
intensive
therapy
units
General
anaesthesia
Until
the
mid-19th century such surgery
as was
possible
had to be
undertaken
at
tremendous speed.
Surgeons
did
their best
for
terrified
patients
by
using alcohol, opium, hyoscine,
1
or
cannabis. With
the
introduction
of
general anaesthesia, surgeons
could
operate
for the
first
time
with
careful
delib-
eration.
The
problem
of
inducing quick,
safe
and
easily
reversible unconsciousness
for any
desired
length
of
time
in man
only began
to be
solved
in
the
1840s when
the
long-known substances nitrous
oxide, ether,
and
chloroform
were introduced
in
rapid
succession.
The
details surrounding
the
first
use of
surgical
anaesthesia were submerged
in
bitter disputes
on
priority
following
an
attempt
to
take
out a
patent
for
ether.
The key
events around this time were:
•
1842
— W. E.
Clarke
of
Rochester,
New
York,
administered
for a
dental extraction. However,
this event
was not
made widely known
at the
time.
•
1844
—
Horace Wells,
a
dentist
in
Hartford,
Connecticut, introduced nitrous oxide
to
produce
anaesthesia during dental extraction.
•
1846
— On
October
16
William Morton,
a
Boston
dentist,
successfully
demonstrated
the
anaesthetic properties
of
ether.
•
1846
—
On
December
21
Robert
Liston
performed
the
first
surgical operation
in
England
under ether anaesthesia.
2
1
A
Japanese pioneer
of
about 1800 wished
to
test
the
anaesthetic
efficacy
of a
herbal mixture including
solanaceous
plants
(hyoscine-type alkaloids).
His
elderly
mother volunteered
as
subject since
she was
anyway
expected
to die
soon.
But the
pioneer administered
it to his
wife
for,
'as all
three
agreed,
he
could
find
another
wife,
but
could never
get
another
mother'
(Journal
of the
American
Medical Association 1966 197:10).
345
18
ANAESTHESIA
AND N E U R O M U S C U L A R
BLOCK
•
1847
—
James
Y.
Simpson, professor
of
midwifery
at the
University
of
Edinburgh,
introduced
chloroform
for the
relief
of
labour
pain.
The
next important developments
in
anaesthesia
were
in the
20th century when
the
appearance
of
new
drugs both
as
primary general anaesthetics
and as
adjuvants (muscle relaxants),
new
apparatus,
and
clinical expertise
in
rendering prolonged anaes-
thesia
safe,
enabled surgeons
to
increase their range.
No
longer
was the
duration
and
type
of
surgery
determined
by
patients' capacity
to
endure pain.
STAGES
OF
GENERAL
ANAESTHESIA
Surgical
anaesthesia
is
classically divided into
four
stages:
analgesia, delirium, surgical anaesthesia
(subdivided into
four
planes),
and
medullary
paralysis (overdose). This gradual procession
of
stages
was
described when ether
was
given
to un-
premedicated
patients,
a
slow unpleasant process.
Ether
is
obsolete
and the
speed
of
induction with
modern inhalational agents
or
intravenous anaes-
thesia drugs makes
a
detailed description
of
these
separate stages superfluous.
Balanced
surgical anaesthesia (hypnosis with
analgesia
and
muscular relaxation) with
a
single
drug requires high doses that will cause adverse
effects
such
as
slow
and
unpleasant recovery,
and
depression
of
cardiovascular
and
respiratory
func-
tion.
In
modern practice,
different
drugs
are
used
to
attain
each objective
so
that adverse
effects
are
minimised.
DRUGS
USED
The
perioperative period
may be
divided into three
phases
and in
each
of
these
a
variety
of
factors
will
determine
the
choice
of
drugs given:
2
Frederick
Churchill,
a
butler
from
Harley Street,
had his leg
amputated
at
University
College
Hospital,
London.
After
removing
the leg in 28
seconds,
a
skill
necessary
to
compensate
for the
previous
lack
of
anaesthetics,
Robert
Listen
turned
to the
watching
students,
and
said
"this
Yankee
dodge,
gentlemen,
beats
mesmerism
hollow".
That
night
he
anaesthetised
his
house
surgeon
in the
presence
of
two
ladies.
Merrington
W
R1976
University
College
Hospital
and its
Medical School:
A
History.
Heinemann,
London.
Before
surgery,
an
assessment
is
made
of:
• the
patient's physical
and
psychological
condition
•
any
intercurrent illness
• the
relevance
of
any
existing drug therapy.
All
of
these
may
influence
the
choice
of
anaesthetic
drugs.
During surgery, drugs will
be
required
to
provide:
•
unconsciousness
•
analgesia
•
muscular relaxation when necessary
•
control
of
blood pressure, heart rate,
and
respiration.
After
surgery, drugs will play
a
part
in:
•
reversal
of
neuromuscular block
•
relief
of
pain,
and
nausea
and
vomiting
•
other aspects
of
postoperative care, including
intensive
care.
Patients
are
often
already taking drugs
affecting
the
central nervous
and
cardiovascular systems
and
there
is
considerable potential
for
interaction with
anaesthetic drugs.
The
techniques
for
giving anaesthetic drugs
and
the
control
of
ventilation
and
oxygenation
are of
great
importance,
but are
outside
the
scope
of
this
book.
Before surgery
(premedication)
The
principal aims
are to
provide:
Anxiolysis
and
amnesia.
A
patient
who is
going
to
have
a
surgical operation
is
naturally apprehensive
and
this anxiety
is
reduced
by
reassurance
and a
clear
explanation
of
what
to
expect.
Very
anxious
patients will secrete
a lot of
adrenaline (epineph-
rine)
from
the
suprarenal medulla
and
this
may
make
them more liable
to
cardiac arrhythmias
with some anaesthetics.
In the
past, sedative
pre-
medication
was
given
to
virtually
all
patients under-
going
surgery. This practice
has
changed dramatically
because
of the
increasing proportion
of
operations
undertaken
as
'day
cases'
and the
recognition
that
sedative premedication prolongs recovery. Sedative
premedication
is now
reserved
for
those
who are
346
18
particularly
anxious
or
those undergoing
major
surgery.
Benzodiazepines,
such
as
temazepam
(10-30mg
for
an
adult), provide anxiolysis
and
amnesia
for
the
immediate presurgical
period.
Analgesia
is
indicated
if the
patient
is in
pain
preoperatively
or it can be
given pre-emptively
to
prevent postoperative pain. Severe preoperative
pain
is
treated with
a
parenteral opioid such
as
morphine.
Nonsteroidal
anti-inflammatory
drugs
and
paracetamol
are
commonly given orally pre-
operatively
to
prevent postoperative
pain
after
minor
surgery.
For
moderate
or
major
surgery,
these
drugs
are
supplemented with
an
opioid towards
the end
of
the
procedure.
Drying
of
bronchial
and
salivary
secretions using
antimuscarinic
drugs
to
inhibit
the
parasympathetic
autonomic system
is
rarely undertaken these days.
The
exceptions include those patients
who are
expected
to
require
an
awake
fibreoptic
intubation
or
those undergoing bronchoscopy. Glycopyrronium
is the
antimuscarinic
of
choice
for
this purpose
and
atropine
and
hyoscine
are
alternatives.
Timing. Premedication
is
given about
an
hour
before
surgery.
Gastric
contents. Pulmonary aspiration
of
gastric
contents
can
cause severe pneumonitis. Patients
at
risk
of
aspiration
are
those with
full
stomachs, e.g.,
bowel obstruction, recently consumed
food
and
drink, third trimester
of
pregnancy,
and
those with
incompetent gastro-oesophageal sphincters, e.g.
hiatus hernia.
A
single dose
of an
antacid, e.g. sodium
citrate,
may be
given
before
a
general anaesthetic
to
neutralise gastric
acid
in
high-risk patients. Alter-
natively
or
additionally,
a
histamine H
2
-receptor
blocker,
e.g. ranitidine,
or
proton-pump inhibitor,
e.g.
omeprazole,
will
reduce gastric
secretion
volume
as
well
as
acidity. Metoclopramide
usefully
hastens
gastric
emptying, increases
the
tone
of the
lower
oesophageal sphincter
and is an
antiemetic.
During
surgery
The
aim is to
induce unconsciousness, analgesia
and
muscular relaxation.
Total
muscular relaxation
GENERAL
ANAESTHESIA
(paralysis)
is
required
for
some surgical procedures,
e.g., intra-abdominal surgery,
but
most surgery
can
be
undertaken without neuromuscular blockade.
A
typical general anaesthetic consists
of:
•
Induction:
1.
Usually intravenous: pre-oxygenation
followed
by a
small dose
of an
opioid, e.g.,
fentanyl
or
alfentanil
to
provide analgesia
and
sedation,
followed
by
propofol
or,
less commonly,
thiopental
or
etomidate
to
induce anaesthesia.
Airway
patency
is
maintained with
an
oral
airway
and
face-mask,
a
laryngeal mask air-
way
(LMA),
or a
tracheal tube. Insertion
of a
tracheal
tube usually requires paralysis with
a
neuromuscular blocker
and is
undertaken
if
there
is a
risk
of
pulmonary aspiration
from
regurgitated gastric contents
or
from
blood.
2.
Inhalational induction, usually with sevo-
flurane,
is
undertaken taken less commonly.
It
is
used
in
children, particularly
if
intravenous
access
is
difficult,
and in
patients
at
risk
from
upper airway obstruction.
•
Maintenance:
1.
Most commonly
with
nitrous oxide
and
oxy-
gen,
or
oxygen
and
air, plus
a
volatile agent,
e.g., isoflurane
or
sevoflurane. Additional doses
of
a
neuromuscular blocker
or
opioid
are
given
as
required.
2.
A
continuous intravenous
infusion
of
propofol
can
be
used
to
maintain anaesthesia. This
technique
of
total
intravenous
anaesthesia
is
becoming more popular because
the
quality
of
recovery
may be
better than
after
inhalational
anaesthesia.
When
appropriate, peripheral nerve block with
a
local
anaesthetic,
or
neural axis block, e.g., spinal
or
epidural, provides intraoperative analgesia
and
muscle
relaxation. These local anaesthetic techniques
provide excellent postoperative analgesia.
After
surgery
The
anaesthetist ensures that
the
effects
of
neuro-
muscular
blocking agents
and
opioid-induced res-
piratory
depression have either worn
off or
have
been adequately reversed
by an
antagonist;
the
patient
is not
left
alone until conscious, with
protective
reflexes
restored,
and a
stable circulation.
347
18
AN
AESTHESIA
AND
NEUROMUSCULAR
BLOCK
Relief
of
pain
after
surgery
can be
achieved with
a
variety
of
techniques.
An
epidural infusion
of a
mixture
of
local anaesthetic
and
opioid provides
excellent
pain
relief
after
major
surgery such
as
laparotomy. Parenteral
morphine,
given
intermit-
tently
by a
nurse
or by a
patient-controlled system,
will also relieve moderate
or
severe pain
but has the
attendant risk
of
nausea, vomiting, sedation
and
respiratory
depression.
The
addition
of
regular
paracetamol
and a
NSAID, given orally
or
rectally,
will
provide
additional
pain
relief
and
reduce
the
requirement
for
morphine. NSAIDs
are
contra-
indicated
if
there
is a
history
of
gastrointestinal
ulceration
of if
renal blood
flow
is
compromised.
Postoperative
nausea
and
vomiting
(PONV)
is
common
after
laparotomy
and
major
gynaecological
surgery, e.g., abdominal hysterectomy.
The use
of
propofol, particularly
when
given
to
maintain
anaesthesia,
has
dramatically reduced
the
incidence
of
PONV.
Antiemetics, such
as
cyclizine, metoclo-
pramide,
and
ondansetron,
may be
helpful.
SOME
SPECIALTECHNIQUES
Dissociative
anaesthesia
is a
state
of
profound
analgesia
and
anterograde amnesia with minimal
hypnosis
during
which
the
eyes
may
remain
open
(see
ketamine,
p.
353).
It is
particularly
useful
where
modern equipment
is
lacking
or
where access
to the
patient
is
limited, e.g.
at
major
accidents
or on
battlefields.
Sedation
and
amnesia
without
analgesia
are
provided
by
midazolam i.v.
or,
less commonly
nowadays, diazepam. These drugs
can be
used
alone
for
procedures causing mild discomfort, e.g.
endoscopy,
and
with
a
local anaesthetic where more
pain
is
expected, e.g., removal
of
impacted wisdom
teeth.
Benzodiazepines produce
anterograde,
but
not
retrograde, amnesia.
By
definition,
the
sedated
patient remains responsive
and
cooperative. (For
a
general account
of
benzodiazepines
and the
com-
petitive antagonist flumazenil,
see Ch.
19.)
Benzodiazepines
can
cause respiratory depres-
sion
and
apnoea
especially
in the
elderly
and in
patients with respiratory
insufficiency.
The
com-
bination
of an
opioid
and a
benzodiazepine
is
particularly
dangerous. Benzodiazepines depress
laryngeal
reflexes
and
place
the
patient
at
risk
of
inhalation
of
oral secretions
or
dental debris.
Entonox,
a
50:50 mixture
of
nitrous oxide
and
oxygen,
is
breathed
by the
patient using
a
demand
valve.
It is
particularly
useful
in the
prehospital
environment
and for
brief
procedures, such
as
splinting limbs.
Pharmacology
of
anaesthetics
All
successful
general anaesthetics
are
given intra-
venously
or by
inhalation because these routes
allow
closest control over blood concentrations
and
so of
effect
on the
brain.
MODE
OF
ACTION
General
anaesthetics
act on the
brain, primarily
on the
midbrain reticular activating system. Many
anaesthetics
are
lipid soluble
and
there
is
good
correlation
between this
and
anaesthetic
effective-
ness (the
Overton-Meyer
hypothesis);
the
more
lipid soluble tend
to be the
more potent anaes-
thetics,
but
such
a
correlation
is not
invariable.
Some
anaesthetic agents
are not
lipid soluble
and
many lipid soluble substances
are not
anaesthetics.
Until
recently
it was
thought that
the
principal site
of
action
of
general
anaesthetics
was the
neuronal
lipid bilayer membrane.
The
current view
is
that
their anaesthetic activity
is
caused
by
interaction
with protein receptors.
It is
likely that there
are
several
modes
of
action,
but the
central mechanism
of
action
of
volatile anaesthetics
is
thought
to be
facilitation
at the
inhibitory
y-aminobutyric acid
(GABA
A
)
and
glycine receptors. Agonists
at
these
receptors
open chloride
ion
channels
and the
influx
of
chloride ions into
the
neuron results
in
hyper-
polarisation. This prevents propagation
of
nerve
impulses
and
renders
the
patient unconscious. Some
general anaesthetics increase
the
time that
the
chloride channels
are
open while others increase
the
frequency
of
chloride channel opening.
348
18
ASSESSMENT
OF
ANAESTHETIC
AGENTS
Comparison
of the
efficacy
of
inhalational agents
is
made
by
measuring
the
minimum alveolar concen-
tration (MAC)
in
oxygen required
to
prevent move-
ment
in
response
to a
standard surgical skin incision
in 50% of
subjects.
The MAC of the
volatile agent
is
reduced
by the
co-administration
of
nitrous oxide.
Inhalation
anaesthetics
PREFERRED
ANAESTHETICS
The
preferred
inhalation agents
are
those that
are
minimally irritant
and
nonflammable,
and
comprise
nitrous oxide
and the
fluorinated
hydrocarbons,
e.g.,
isoflurane.
PHARMACOKINETICS
(VOLATILE
LIQUIDS,
GASES)
The
level
of
anaesthesia
is
correlated
with
the
tension (partial pressure)
of
anaesthetic drug
in the
brain tissue
and
this
is
dependent
on the
develop-
ment
of a
series
of
tension gradients
from
the
high
partial
pressure delivered
to the
alveoli
and
decreasing through
the
blood
to the
brain
and
other
tissues. These gradients
are
dependent
on the
blood/gas
and
tissue/gas
solubility
coefficients,
as
well
as on
alveolar ventilation
and
organ blood
flow.
An
anaesthetic that
has
high
solubility
in
blood,
i.e.,
a
high
blood/gas
partition
coefficient,
will
provide
a
slow induction
and
adjustment
of the
depth
of
anaesthesia. This
is
because
the
blood acts
as
a
reservoir (store)
for the
drug
so
that
it
does
not
enter
the
brain easily until
the
blood reservoir
has
been
filled.
A
rapid induction
can be
obtained
by
increasing
the
concentration
of
drug inhaled initially
and by
hyperventilating
the
patient.
Agents
that have
low
solubility
in
blood,
i.e.,
a
low
blood/gas
partition
coefficient
(nitrous oxide,
sevoflurane),
provide
a
rapid induction
of
anaes-
thesia because
the
blood reservoir
is
small
and
agent
is
available
to
pass into
the
brain sooner.
INHALATION
AGENTS
During induction
of
anaesthesia
the
blood
is
taking
up
anaesthetic agent selectively
and
rapidly
and the
resulting
loss
of
volume
in the
alveoli leads
to a
flow
of
agent into
the
lungs that
is
independent
of
respiratory activity. When
the
anaesthetic
is
discontinued
the
reverse occurs
and it
moves
from
the
blood into
the
alveoli.
In the
case
of
nitrous
oxide, this
can
account
for as
much
as 10% of the
expired
volume
and so can
significantly lower
the
alveolar
oxygen concentration. Thus mild hypoxia
occurs
and
lasts
for as
long
as 10
minutes. Though
harmless
to
most,
it may be a
factor
in
cardiac arrest
in
patients with reduced pulmonary
and
cardiac
reserve, especially when administration
of the gas
has
been
at
high concentration
and
prolonged,
when
the
outflow
is
especially copious. Oxygen
should therefore
be
given
to
such patients during
the
last
few
minutes
of
anaesthesia
and the
early
postanaesthetic period. This phenomenon,
diffusion
hypoxia,
occurs with
all
gaseous anaesthetics,
but is
most prominent with gases that
are
relatively
insoluble
in
blood,
for
they will
diffuse
out
most
rapidly when
the
drug
is no
longer inhaled,
i.e.
just
as
induction
is
faster,
so is
elimination. Nitrous
oxide
is
especially
powerful
in
this respect because
it
is
used
at
concentrations
of up to
70%.
Highly
blood-soluble agents will
diffuse
out
more slowly,
so
that recovery will
be
slower just
as
induction
is
slower,
and
with them
diffusion
hypoxia
is
insignificant.
NITROUS OXIDE
Nitrous oxide
(1844)
is a gas
with
a
slightly sweetish
smell.
It is
neither flammable
nor
explosive.
It
produces light anaesthesia without demonstrably
depressing
the
respiratory
or
vasomotor centre
provided that normal oxygen tension
is
maintained.
Advantages.
Nitrous oxide reduces
the
require-
ment
for
other more potent
and
intrinsically more
toxic
anaesthetic agents.
It has a
strong analgesic
action;
inhalation
of 50%
nitrous oxide
in
oxygen
(Entonox)
may
have similar
effects
to
standard doses
of
morphine. Induction
is
rapid
and not
unpleasant
although transient excitement
may
occur,
as
with
all
agents. Recovery time rarely exceeds
4 min
even
after
prolonged administration.
349
18
ANAESTHESIA
AND N E U R O M U S C U L A R
BLOCK
Disadvantages.
Nitrous oxide
is
expensive
to buy
and to
transport.
It
must
be
used
in
conjuction
with
more potent anaesthetics
to
produce
full
surgical
anaesthesia.
Uses.
Nitrous oxide
is
used
to
maintain surgical
anaesthesia
in
combination
with
other
anaesthetic
agents,
e.g.,
isoflurane
or
propofol,
and,
if
required,
muscle relaxants. Entonox provides analgesia
for
obstetric practice,
for
emergency management
of
injuries,
and
during postoperative physiotherapy.
Dosage
and
administration.
For the
maintenance
of
anaesthesia, nitrous oxide must always
be
mixed
with
at
least
30%
oxygen.
For
analgesia,
a
concen-
tration
of 50%
nitrous oxide with
50%
oxygen
usually
suffices.
Contraindications.
Any
closed, distendable
air-
filled
space expands during administration
of
nitrous oxide, which moves into
it
from
the
blood.
It
is
therefore contraindicated
in
patients with: demon-
strable
collections
of air in the
pleural, pericardial
or
peritoneal spaces; intestinal obstruction; arterial
air
embolism; decompression sickness; severe
chronic
obstructive airway disease; emphysema.
Nitrous oxide will cause pressure changes
in
closed,
noncompliant spaces such
as the
middle
ear,
nasal
sinuses,
and the
eye.
Precautions.
Continued administration
of
oxygen
may
be
necessary during recovery, especially
in
elderly patients
(see
diffusion
hypoxia, above).
Adverse
effects.
The
incidence
of
nausea
and
vomiting increases with
the
duration
of
anaes-
thesia. Nitrous oxide interferes with
the
synthesis
of
methionine, deoxythymidine
and
DNA.
Exposure
of
to
nitrous oxide
for
more than
4
hours
can
cause
megaloblastic changes
in the
bone marrow.
Because
prolonged
and
repeated exposure
of
staff
as
well
as
of
patients
may be
associated with bone-marrow
de-
pression
and
teratogenic risk, scavenging systems
are
used
to
minimise ambient concentrations
in
operating theatres.
Drug
interactions. Addition
of 50%
nitrous
oxide/
oxygen
mixture
to
another inhalational anaesthetic
reduces
the
required dosage (minimum alveolar
concentration, MAC)
of the
latter
by
about 50%.
Storage.
Nitrous oxide
is
supplied under pressure
in
cylinders, which must
be
maintained below
25°C.
Cylinders containing premixed oxygen
50%
and
nitrous
oxide
50%
(Entonox)
are
available
for
analgesia.
The
constituents separate
out at
-7°C,
in
which case adequate mixing must
be
assured
before
use.
HALOGENATED ANAESTHETICS
Halothane
was the
first
halogenated
agent
to be
used widely,
but in the
developed world
it has
been
largely
superseded
by
isoflurane
and
sevoflurane.
We
provide
a
detailed description
of
isoflurane,
and
of
the
others
in so far as
they
differ.
The MAC of
some volatile agents
is:
•
Isoflurane
1.2%
•
Enflurane
1.7%
•
Sevoflurane
2.0%
•
Halothane
0.74%.
Isoflurane
Isoflurane
is a
volatile colourless liquid, which
is
not flammable at
normal anaesthetic concentrations.
It
is
relatively insoluble,
and has a
lower
blood/gas
coefficient
than halothane
or
enflurane, which allows
rapid
adjustment
of the
depth
of
anaesthesia.
It has
a
pungent odour
and can
cause bronchial irritation,
which makes inhalational induction unpleasant.
Isoflurane
is
minimally metabolised
(0.2%),
and
none
of the
breakdown products
has
been related
to
anaesthetic
toxicity.
Respiratory
effects.
Isoflurane
causes respiratory
depression:
the
respiratory rate increases, tidal
vol-
ume
decreases,
and the
minute volume
is
reduced.
The
ventilatory response
to
carbon dioxide
is
diminished. Although
it
irritates
the
upper airway
it is a
bronchodilator.
Cardiovascular
effects.
Anaesthetic concentrations
of
isoflurane,
i.e. 1-1.5 MAC,
cause only
a
slight
impairment
of
myocardial contractility
and
stroke
volume
and
cardiac output
is
usually maintained
350
18
by a
reflex
increase
in
heart rate.
Isoflurane
causes
peripheral vasodilatation
and
reduces blood press-
ure.
It
does
not
affect
atrioventricular conduction
and
does
not
sensitise
the
heart
to
catecholamines.
Low
concentrations
of
isoflurane
(< 1
MAC)
do not
increase cerebral blood
flow
or
intracranial
press-
ure,
and
cerebral autoregulation
is
maintained.
Isoflurane
is a
potent
coronary vasodilator
and in
the
presence
of a
coronary artery stenosis
it may
cause
redistribution
of
blood away
from
an
area
of
inadequate perfusion
to one of
normal perfusion.
This phenomenon
of
'coronary
steal'
may
cause
regional
myocardial ischaemia.
Other
effects.
Isoflurane relaxes voluntary muscles
and
potentiates
the
effects
of
nondepolarising
muscle relaxants. Isoflurane
depresses
cortical
EEG
activity
and
does
not
induce abnormal electrical
activity
or
convulsions.
Sevoflurane
is a
chemical analogue
of
isoflurane.
It
is
less
chemically stable than
the
other volatile
anaesthetics
in
current
use.
About
3% is
metabolised
in the
body
and it is
degraded
by
contact with
carbon
dioxide absorbents, such
as
soda lime.
The
reaction
with
soda lime causes
the
formation
of a
vinyl ether (Compound
A),
which
may be
nephro-
toxic.
Sevoflurane
is
less soluble
than
isoflurane
and is
very pleasant
to
breathe, which makes
it an
excellent
choice
for
inhalational induction
of
anaes-
thesia, particularly
in
children.
The
respiratory
and
cardiovascular
effects
of
Sevoflurane
are
very similar
to
isoflurane.
Enflurane
is a
structural isomer
of
isoflurane.
It is
more soluble than isoflurane.
It
causes more
respiratory depression than
the
other volatile
anaesthetics
and
hypercapnia
is
almost inevitable
in
patients breathing spontaneously.
It
causes more
cardiovascular
depression than
isoflurane
and is
occasionally associated with cardiac arrythmias.
Two
percent
of
enflurane
is
metabolised
and
prolonged administration
or use in
enzyme-induced
patients generates
sufficient
free
inorganic
fluoride
from
the
drug molecule
to
cause polyuric renal
failure.
There have been
a few
cases
of
jaundice
and
heptatoxicity
associated with enflurane
but the
incidence
of
about
one in 1-2
million anaesthetics
is
lower than with halothane.
INHALATION
AGENTS
Desflurane
has the
lowest
blood/gas
partition
co-
efficient
of any
inhaled anaesthetic agent
and
thus
gives particularly rapid onset
and
offset
of
effect.
As
it
undergoes negligible metabolism
(0.03%),
any
release
of
free
inorganic
fluoride
is
minimised; this
characteristic
favours
its use for
prolonged anaes-
thesia. Desflurane
is
extremely volatile
and
cannot
be
administered with conventional vaporisers.
It
has a
very pungent odour
and
causes airway
irritation
to an
extent that limits
its
rate
of
induction
of
anaesthesia.
Halothane
has the
highest
blood/gas
partition
coefficient
of the
volatile anaesthetic agents
and
recovery
from
halothane anaesthesia
is
compara-
tively slow.
It is
pleasant
to
breathe
and is
second
choice
to
Sevoflurane
for
inhalational induction
of
anaesthesia. Halothane reduces cardiac output
more
than
any of the
other volatile anaesthetics.
It
sensitises
the
heart
to the
arrhythmic
effects
of
catecholamines
and
hypercapnia; arrhythmias
are
common,
in
particular atrioventricular dissociation,
nodal rhythm
and
ventricular extrasystoles. Halo-
thane
can
trigger malignant hyperthermia
in
those
who are
genetically predisposed
(see
p.
363).
About
20% of
halothane
is
metabolised
and it
induces hepatic enzymes, including those
of
anaes-
thetists
and
operating theatre
staff.
Hepatic damage
occurs
in a
small proportion
of
exposed patients.
Typically
fever
develops
2 or 3
days
after
anaes-
thesia accompanied
by
anorexia, nausea
and
vomit-
ing.
In
more severe cases this
is
followed
by
transient
jaundice
or,
very
rarely,
fatal
hepatic necrosis. Severe
hepatitis
is a
complication
of
repeatedly administered
halothane anaesthesia
and has an
incidence
of
1:50000.
It
follows
immune sensitisation
to an
oxidative metabolite
of
halothane
in
susceptible
individuals. This serious complication, along with
the
other
disadvantages
of
halothane
and the
popularity
of
sevoflurane
for
inhalational induction,
has
almost
eliminated
its use in the
developed
world.
It
remains
in
common
use
other parts
of the
world
because
it is
comparatively inexpensive.
OXYGEN
IN
ANAESTHESIA
Supplemental oxygen
is
always used with inhala-
tional
agents
to
prevent hypoxia, even
when
air is
used
as the
carrier
gas.
The
concentration
of
oxygen
351
18
AN
AESTHESIA
AND N E U R O M U S C U L A R
BLOCK
in
inspired anaesthetic gases
is
usually
at
least 30%,
but
oxygen should
not be
used
for
prolonged
periods
at a
greater concentration than
is
necessary
to
prevent hypoxaemia.
After
prolonged adminis-
tration, concentrations greater than
80%
have
a
toxic
effect
on the
lungs, which presents initially
as
a
mild substernal irritation progressing
to
pul-
monary congestion, exudation
and
atelectasis.
Use
of
unnecessarily high concentrations
of
oxygen
in
incubators causes retrolental
fibroplasia
and
per-
manent blindness
in
premature
infants.
Oxygen
is
supplied under pressure
in
cylinders,
when
it
remains
in the
gaseous
state.
In
most
hospitals
a
vacuum insulated evaporator
is
used
to
store oxygen
in
liquid
form.
This provides
for
huge
volumes
of
gaseous oxygen
and
will supply
all the
piped oxygen outlets
in the
hospital.
ATMOSPHERIC
POLLUTION
OF
OPERATING
THEATRES
Pollution
by
inhalation anaesthetics
has
been
suspected
of
being harmful
to
theatre
personnel.
Epidemiological studies have raised questions
relating
to
excess
of
fetal
malformations
and
mis-
carriages, hepatitis
and
cancer
in
operating theatre
personnel. Sensible
use of
preventive measures
renders
the
risks
negligible,
e.g.
use of
circle systems
that allow
low
fresh
gas
flows,
scavenging systems,
and
improved ventilation
of
theatres.
The
increasing
use of
total intravenous anaesthesia
(TIVA)
and
regional anaesthesia will also reduce pollution.
Intravenous
anaesthetics
Intravenous anaesthetics should
be
given only
by
those
fully
trained
in
their
use and who are
experi-
enced with
a
full
range
of
techniques
of
managing
the
airway, including tracheal intubation.
PHARMACOKINETICS
Intravenous anaesthetics allow
an
extremely rapid
induction because
the
blood concentration
can be
raised rapidly, establishing
a
steep concentration
gradient
and
expediting
diffusion
into
the
brain.
The
rate
of
transfer
depends
on the
lipid solubility
and
arterial concentration
of the
unbound,
non-
ionised
fraction
of the
drug.
After
a
single,
induction
dose
of an
intravenous anaesthetic recovery occurs
quite
rapidly
as the
drug
is
redistributed around
the
body
and the
plasma concentration reduces.
Recovery
from
a
single dose
of
intravenous anaes-
thetic
is not
related
to its
rate
of
metabolic break-
down. With
the
exception
of
propofol, repeated
doses
or
infusions
of
intravenous anaesthetics will
result
in
considerable accumulation
and
prolonged
recovery.
Attempts
to use
thiopental
as the
sole
anaesthetic
in war
casualties
led to its
being described
as an
ideal
form
of
euthanasia.
3
It is
common practice
to
induce anaesthesia intravenously
and
then
to use
a
volatile anaesthetic
for
maintenance. When
administration
of a
volatile anaesthetic
is
stopped,
it
is
eliminated quickly through
the
lungs
and the
patient regains consciousness.
The
recovery
from
propofol
is
rapid, even
after
repeat doses
or an
infusion.
This advantage,
and
others,
has
resulted
in
propofol
displacing thiopental
as the
most popular
intravenous
anaesthetic.
Propofol
Propofol
(2,6-diisopropylphenol)
is
available
as a
1%
or 2%
emulsion,
which contains soya bean
oil
and
purified
egg
phosphatide. Induction
of
anaes-
thesia with
1.5-2.5
mg/kg
occurs within
30
seconds
and is
smooth
and
pleasant with
a low
incidence
of
excitatory movements.
It
causes pain
on
injection
but
adding
lidocaine
20 mg to an
ampoule
of
propofol
eliminates this.
The
recovery
from
propofol
is
rapid
and the
incidence
of
nausea
and
vomiting
is
extremely
low,
particularly when
propofol
is
used
as the
sole anaesthetic.
Recovery
from
a
continuous
infusion
of
propofol
is
relatively rapid.
On
stopping
the
infusion
the
plasma concentration decreases
rapidly
as a
result
of
both redistribution
and
clear-
ance
of the
drug. Special syringe pumps incor-
porating pharmacokinetic algorithms allow
the
anaesthetist
to
select
a
target plasma propofol
con-
centration
(e.g.
6
micrograms/ml
for
induction
of
anaesthesia) once details
of the
patient's
age and
weight have been entered. This technique
of
target-
3
Halford
J J
1943
A
critique
of
intravenous anaesthesia
in
war
surgery.
Anesthesiology
4: 67.
352
18
controlled
infusion
(TCI) provides
a
convenient
method
for
giving
a
continuous
infusion
of
propofol.
Central nervous system.
Propofol
causes dose-
dependent
cortical
depression
and is an
anticon-
vulsant.
It
depresses laryngeal
reflexes
more than
barbiturates, which
is an
advantage
when
inserting
a
laryngeal mask airway.
Cardiovascular system.
Propofol
reduces vascular
tone, which lowers systemic vascular resistance
and
central venous pressure.
The
heart rate remains
unchanged
and the
result
is a
fall
in
blood pressure
to
about 70-80%
of the
preinduction level
and a
small reduction
in
cardiac output.
Respiratory system. Unless
it is
undertaken very
slowly,
induction with
propofol
causes transient
apnoea.
On
resumption
of
respiration there
is a
reduction
in
tidal volume
and
increase
in
rate.
Metabolism.
Propofol
is
conjugated
in the
liver
by
glucuronidation making
it
more water soluble;
88%
then
appears
in the
urine
and 2% in the
faeces.
Thiopental
(thiopentone)
Thiopental
is a
very short-acting barbiturate, which
induces anaesthesia smoothly, within
one
arm-to-
brain circulation time.
The
typical induction dose
is
3-5mg/kg.
Rapid distribution (initial t
1
/
2
4min)
allows
swift
recovery
after
a
single dose.
The
terminal
t
l
/
2
of
thiopental
is 11 h and
repeated doses
or
continuous
infusion
lead
to
significant accumu-
lation
in fat and
very
prolonged
recovery.
Thiopental
is
metabolised
in the
liver.
The
incidence
of
nausea
and
vomiting
after
thiopental
is
slightly higher than
after
propofol.
The pH of
thiopental
is 11 and
considerable local damage results
if it
extravasates.
Accidental
intra-arterial
injection
will also cause
serious
injury
distal
to the
injection
site.
Central nervous system. Thiopental
has no
anal-
gesic
activity
and may be
antanalgesic.
It is a
potent
anticonvulsant. Cerebral metabolic rate
of
oxygen
consumption
(CMRO
2
)
is
reduced,
which
leads
to
cerebral vasoconstriction with
a
concomitant
reduction
in
cerebral blood
flow
and
intracranial
pressure.
INTRAVENOUS
AGENTS
Cardiovascular system. Thiopental reduces
vas-
cular
tone, causing hypotension
and a
slight com-
pensatory increase
in
heart rate. Antihypertensives
or
diuretics
may
augment
the
hypotensive
effect.
Respiratory system. Thiopental reduces respiratory
rate
and
tidal volume.
Methohexitone
is a
barbiturate similar
to
thiopental
but its
terminal
t
l
/
2
is
considerably shorter. Since
the
introduction
of
propofol,
its use is
almost entirely
confined
to
inducing anaesthesia
for
electrocontro-
vulsive therapy
(ECT).
Propofol shortens seizure
duration
and may
reduce
the
efficacy
of
ECT.
Etomidate
is a
carboxylated imidazole,
which
is
formulated
in a
mixture
of
water
and
propylene
glycol.
It
causes pain
on
injection
and
excitatory
muscle
movements
are
common
on
induction
of
anaesthesia.
It is
associated with
a 20%
incidence
of
nausea
and
vomiting. Etomidate causes adreno-
cortical
suppression
by
inhibiting
11 (3- and 17 [3-
hydroxylase
and for
this reason
is not
used
for
prolonged
infusion;
single
bolus doses cause short-
lived, clinically insignificant adrenocortical
sup-
pression. Despite
all
these disadvantages
it
remains
in
common
use,
particularly
for
emergency anaes-
thesia, because
it
causes less cardiovascular depres-
sion
and
hypotension than thiopental
or
propofol.
Ketamine
Ketamine
is a
phencyclidine (hallucinogen) deriva-
tive
and an
antagonist
of the
NMDA-receptor.
4
In
anaesthetic
doses
it
produces
a
trance-like state
known
as
dissociative
anaesthesia
(sedation, amnesia,
dissociation, analgesia).
Advantages. Anaesthesia persists
for up to 15 min
after
a
single intravenous injection
and is
charac-
terised
by
profound analgesia. Ketamine
may be
used
as the
sole analgesic agent
for
diagnostic
and
minor surgical interventions.
In
contrast
to
most
other anaesthetic drugs, ketamine usually produces
a
tachycardia
and
increases blood pressure
and
cardiac
output.
This
effect
makes
it a
popular
choice
for
inducing anaesthesia
in
shocked patients.
The
4
N-methyl-D-aspartate.
353
18
AN
AESTH
ESI A AN D N E U R O M U S C U L A R
BLOCK
cardiovascular
effects
of
ketamine
are
accompanied
by an
increase
in
plasma noradrenaline (norepi-
nephrine) concentration.
Because
pharyngeal
and
laryngeal
reflexes
are
only slightly impaired,
the
airway
may be
less
at
risk than with other general
anaesthetic techniques.
It is a
potent bronchodilator
and is
sometimes used
to
treat severe bronchospasm
in
those asthmatics requiring mechanical ventilation.
(See
also Dissociative anaesthesia,
p.
348.)
Disadvantages. Ketamine produces
no
muscular
relaxation.
It
increases intracranial
and
intraocular
pressure. Hallucinations
can
occur
during recovery
(the
emergence reaction),
but
they
are
minimised
if
ketamine
is
used solely
as an
induction agent
and
followed
by a
conventional inhalational anaesthetic.
Their incidence
is
reduced
by
administration
of a
benzodiazepine both
as a
premedication
and
after
the
procedure.
Uses. Subanaesthetic doses
of
ketamine
can be
used
to
provide analgesia
for
painful
procedures
of
short
duration such
as the
dressing
of
burns, radio-
therapeutic procedures, marrow sampling
and
minor
orthopaedic
procedures. Ketamine
can be
used
for
induction
of
anaesthesia prior
to
administration
of
inhalational anaesthetics,
or for
both induction
and
maintenance
of
anaesthesia
for
short-lasting diag-
nostic
and
surgical interventions, including dental
procedures that
do not
require skeletal muscle
relaxation.
It is of
particular value
for
children
requiring
frequent
repeated anaesthetics.
Dosage
and
administration. Premedication with
atropine will reduce
the
salivary secretions produced
by
ketamine
and a
benzodiazepine will reduce
the
incidence
of
hallucinations.
Induction.
Intravenous
route:
1-2
mg/kg
by
slow
intravenous
injection
over
a
period
of 60
seconds.
A
dose
of 2
mg/kg
produces surgical anaesthesia
within
1-2
min,
which will last
5-10 min.
Intra-
muscular
route:
5-10
mg/kg
by
deep intramuscular
injection.
This dose produces surgical anaesthesia
within
3-5 min and may be
expected
to
last
up to
25
min.
Maintenance. Following induction, serial doses
of
50%
of the
original intravenous dose
or 25% of the
intramuscular dose
is
given
to
prevent movement
in
response
to
surgical stimuli. Tonic
and
clonic
movements resembling seizures occur
in
some
patients. These
do not
indicate
a
light plane
of
anaesthesia
or a
need
for
additional doses
of the
anaesthetic.
A
dose
of 0.5
mg/kg
i.m.
or
i.v.
provides excellent
analgesia
and may be
supplemented
by
further
doses
of
0.25
mg/kg.
Recovery.
Return
to
consciousness
is
gradual.
Emergence
reactions with delirium
may
occur.
Their
incidence
is
reduced
by
benzodiazepine
pre-
medication
and by
avoiding unnecessary disturb-
ance
of the
patient during
recovery.
Contraindications include: moderate
to
severe
hypertension, congestive cardiac
failure
or a
history
of
stroke; acute
or
chronic alcohol intoxication,
cerebral
trauma, intracerebral mass
or
haemorrhage
or
other causes
of
raised intracranial pressure;
eye
injury
and
increased intraocular pressure; psychi-
atric
disorders such
as a
schizophrenia
and
acute
psychoses.
Precautions. Ketamine should
be
used under
the
supervision
of a
clinician experienced
in
tracheal
intubation, should this become necessary. Pulse
and
blood
pressure must
be
monitored closely. Supple-
mentary opioid analgesia
is
often
required
in
surgical
procedures causing visceral pain.
Use
in
pregnancy. Ketamine
is
contraindicated
in
pregnancy
before
term, since
it has
oxytocic
activity.
It
is
also contraindicated
in
patients
with
eclampsia
or
pre-eclampsia.
It may be
used
for
assisted vaginal
delivery
by an
experienced anaesthetist. Ketamine
is
better suited
for use
during caesarean section;
it
causes
less
fetal
and
neonatal depression than other
anaesthetics.
Muscle
relaxants
NEUROMUSCULAR BLOCKING
DRUGS
A
lot of
surgery, especially
of the
abdomen, requires
354
[...]... AN D N E U R O M U S C U L A R B L O C K Neuromuscular blocking agents used in clinical practice interfere with this process Natural substances that prevent the release of acetylcholine at nerve endings exist, e.g Clostridium botulinum toxin (see p 429) and some venoms There are two principal mechanisms by which drugs used clinically interfere with neuromuscular transmission: 1 By competition with acetylcholine... comparatively short acting (10-15 minutes), depending on the initial dose Mivacurium can cause some hypotension because of histamine release Pancuronium was the first steroid-derived neuromuscular blocker in clinical use It is longer acting than vecuronium and causes a slight tachycardia Tubocurarine is obsolete and is no longer available in the UK It is a potent antagonist at autonomic ganglia and causes... hyperthermia, p 427) ANAPHYLAXIS Anaphylactic reactions result from the interaction of antigens with specific IgE antibodies, which have been formed by previous exposure to the antigen Anaphylactoid reactions are clinically indistinguishable from anaphylaxis but do not result from prior exposure to a triggering agent and do not involve IgE Intravenous anaesthetics and muscle relaxants can cause anaphylactic or... relaxants are responsible for 70% of anaphylactic reactions during anaesthesia and suxamethonium accounts for almost half of these Local anaesthetics Cocaine had been suggested as a local anaesthetic for clinical use when Sigmund Freud investigated the alkaloid in Vienna in 1884 with Carl Koller The latter had long been interested in the problem of local anaesthesia in the eye, for general anaesthesia... in ophthalmology Observing that numbness of the mouth occurred after taking cocaine orally he realised that this was a local anaesthetic effect He tried cocaine on animals' eyes and introduced it into clinical ophthalmological practice, whilst Freud was on holiday Freud had already thought of this use and discussed it but, appreciating that sex was of greater importance than surgery, he had gone to... then began to search for less toxic substitutes, with the result that procaine was introduced in 1905 Desired properties Innumerable compounds have local anaesthetic properties, but few are suitable for clinical use Useful substances must be watersoluble, sterilisable by heat, have a rapid onset of effect, a duration of action appropriate to the operation to be performed, be nontoxic, both locally 358... which, in the concentrations used, does not affect the heart rate or blood pressure and may be preferable in patients with cardiovascular disease OTHER EFFECTS Local anaesthetics also have the following clinically important effects in varying degree: • Excitation of parts of the central nervous system, which may manifest as anxiety, restlessness, tremors, euphoria, agitation and even convulsions, which . of
specialties
use
local anaesthetics
and the
pharmacology
of
these drugs
is
discussed
in
detail.
General anaesthesia
Pharmacology
of
anaesthetics
Inhalation
. general anaesthetics
and as
adjuvants (muscle relaxants),
new
apparatus,
and
clinical expertise
in
rendering prolonged anaes-
thesia
safe,
enabled surgeons